program 2020 vision - genomecanada.ca€¦ · laboratory include the search for genes predisposing...

Program2020 Vision:

Variation and Function in the Genome

ProgrammeVision 2020 :

variation et fonction du génome

October 25–27 octobre, 2006 | Château Frontenac, Québec City, Canada

Wednesday, October 25Understanding Human Disease

8:00 – 12:00 Registration (Downstairs Lobby)

12:00 – 13:45 Lunch (Frontenac)Keynote Speaker:Tom Hudson, Bridging Genomes and Medicine

14:00 – 16:30 Session 1: (Jacques Cartier)Human Genome Variation in Health and Disease

14:00 – 16:30 Session 2: (Place D’Armes)Splicing Variations: Finding Hidden Markers and Targets

16:45 – 17:45 Information Session on Genome Canada Position Papers (Jacques Cartier)

18:00 – 20:00 Poster Session and Reception (Verchères)

Thursday, October 26Molecular Evolution and Biosphere Diversity

7:30 – 8:45 Breakfast (Salle de Bal)Keynote Speaker : Joe Ecker, Systems Biology and the Virtual Plant

9:00 – 12:00 Session 3: (Frontenac)Diversity and Evolution in Plant Genome Structure and Function

9:00 – 12:00 Session 4: (Bellevue)Population Genetics

12:00. – 13:45 Lunch (Salle de Bal)Keynote Speaker: Fotis Kafatos, Comparative Genomics and Our Current Understanding of Pathogen Control in Mosquitos

14:00 – 16:30 Session 5: (Frontenac)Models of Biology and Disease Control

14:00 – 16:30 Session 6: (Bellevue)Systems Approaches in Structural & Functional Genomics

18:00 – 21:00 Reception and Banquet (Salle de Bal)Keynote Speaker : Stephen Lewis, Genomics: Another Dimension ofPreventive Technology in the Battle Against AIDS?

Agenda at a Glance Aperçu de l’ordre du jour

Mercredi, 25 octobre La compréhension de la

maladie chez les humains

Jeudi, 26 octobreL’évolution moléculaire et

la diversité de la biosphère

1

Friday, October 27Prospects, Challenges and Issues

7:30 – 8:45 Breakfast (Salle de Bal)Keynote Speaker:Wylie Burke, Moving (Slowly) from Promise to Benefit

9:00 – 12:00 Session 7: (Frontenac)Out of the Genomics Box: Applications for 2020

12:00. – 14:00 Lunch (Salle de Bal)Keynote Speaker: Allen Roses, Drug Development withPharmacogenetics in 2006

Agenda at a Glance Aperçu de l’ordre du jour

Guy Bellemare (Co-Chair)Génome QuébecQuébec, Canada

William Bridger (Co-Chair)R.M. Spencer & AssociatesAlberta, Canada

Sherif Abou ElelaUniversité de SherbrookeQuébec, Canada

Cheryl ArrowsmithStructural Genomics ConsortiumOntario, Canada

Cindy BellGenome CanadaOntario, Canada

Timothy CaulfieldUniversity of AlbertaAlberta, Canada

William L. CrosbyUniversity of WindsorOntario, Canada

Carol Anne Esnard Genome CanadaOntario, Canada

Robert FletterickUniversity of CaliforniaCalifornia, USA

William M. GelbartHarvard UniversityMassachusetts, USA

Martin GodboutGenome CanadaOntario, Canada

Victor LingBC Cancer AgencyBritish Columbia, Canada

John MackayUniversité LavalQuébec, Canada

Michael MorganGenome CanadaOntario, Canada

Stephen W. SchererUniversity of TorontoOntario, Canada

Elizabeth Vavasour Health CanadaOntario, Canada

Program CommitteeVendredi, 27 octobre

Les perspectives, les défis et les enjeux de la génomique

2

Genome Canada is proud to welcome distinguishedspeakers and delegates from Canada, the United Statesand Europe to 2020 Vision:Variation and Function inthe Genome.The program is wide ranging, featuring

exciting and thought-provoking presentations that will carry research intogenomics and proteomics, including the ethical, environmental, economic,legal and social impact of this work, well into the next decade and beyond.

2020 Vision inaugurates the first of what will be an annual forum forresearchers and Genome Canada to share information and challenge ideasin a variety of fields related to the study of genomics, proteomics andrelated societal issues.This year’s speakers are addressing research topicsranging from autism to GM crops, from mosquitoes to metagenomics andtheir implications on both science and society.

I urge you to participate in as many poster viewing, presentations andplenary sessions as you can.With 2020 Vision, Genome Canada invites youto gaze into the future of genomics and proteomics research. I know youwill enjoy what you see.

Génome Canada est fier d’accueillir des conférenciers et des déléguésdistingués du Canada, des États-Unis et de l’Europe à sa conférenceVision 2020 :Variation et fonction du génome. Le programme aborde dessujets diversifiés qui feront l’objet d’exposés passionnants et inspirants quiprojetteront dans la prochaine décennie et au-delà la recherche engénomique et en protéomique, y compris les enjeux de ces domaines derecherche sur l’éthique, l’environnement, l’économie, le droit et la société.

Vision 2020 inaugure la première conférence qui deviendra une rencontreannuelle des chercheurs et de Génome Canada pour partager del’information et sonder des idées dans divers domaines liés à l’étude de lagénomique, de la protéomique et de questions sociétales connexes. Lesconférenciers de cette année abordent des sujets de recherche allant del’autisme aux cultures génétiquement modifiées, en passant par lesmoustiques et la métagénomique, et leurs répercussions sur la science etla société.

Je vous invite à participer au plus grand nombre possible de séancesde présentation d’affiches, d’exposés et de plénières. Génome Canadavous convie, avec Vision 2020, à observer l’avenir de la recherche engénomique et en protéomique. Je sais que vous aimerez ce quevous verrez.

Calvin R. Stiiler, O.C.

Chairman’s Message Message du président du conseil

3

Welcome to Genome Canada’s first internationalconference 2020 Vision: Variation and Function inthe Genome.Thanks to the members of the Conference

Program and Steering Committees, we have prepared an exciting, wide-ranging program featuring distinguished international participants fromCanada and abroad. In a matter of months, the Program Committee notonly designed and developed the format of this conference, they alsoidentified and recruited speakers from around the world to ensure that themany facets of genome research are represented on our program.

2020 Vision builds on the momentum Genome Canada has generated overthe last number of years through its national-level scientific conferences andinternational GE3LS symposia (Genomic and proteomic research involvingEthical, Environmental, Economic, Legal and Social issues).With this inauguralconference, we present seven sessions featuring internationally-respectedspeakers and equally high-profile chairs who have been urged to becreative and provocative in their vision of what the next ten years ofgenome research might bring.

As President of Genome Canada, I am proud to present 2020 Vision, thefirst of what will be an annual conference “must” for researchers, policymakers, biotech executives and venture capitalists from around the world,whose work involves genomics or proteomics and related societal issues.

Bienvenue à la première conférence internationale de Génome CanadaVision 2020 : Variation et fonction du génome. Grâce aux membres duComité du programme et du Comité directeur de la Conférence, nousvous offrons un programme captivant et diversifié dans lequel figurent dedistingués participants du Canada et de l’étranger. En quelques moisseulement, le Comité du programme a non seulement conçu et élaboré laformule de la Conférence, mais ciblé et invité des conférenciers de partoutdans le monde qui aborderont avec vous les nombreuses facettes de larecherche en génomique.

Vision 2020 mise sur l’impulsion donnée par Génome Canada au cours desdernières années par ses conférences scientifiques nationales et sessymposiums internationaux GE3DS (enjeux de la recherche en génomiqueet en protéomique liés à l’éthique, à l’environnement, à l’économie, au droitet à la société). Cette conférence inaugurale comprend sept séances quiprésentent des conférenciers de renommée internationale et desprésidents d’assemblée tout aussi éminents à qui nous avons demandé dese montrer créatifs et provocateurs dans leur vision de ce que pourraientoffrir les dix prochaines années de recherche sur le génome.

En ma qualité de président de Génome Canada, je suis fier d’inaugurerVision 2020, la première de ce qui deviendra une conférence annuelle« incontournable » des chercheurs, des décideurs, des dirigeants desociétés de biotechnologie et de sociétés financières d’innovation dont letravail est lié à la génomique, à la protéomique et aux questionssociétales connexes.

Martin Godbout, O.C.

President’s Message Message du président et chef de la direction

Wednesday, October 25Understanding HumanDisease

Mercredi, 25 octobreLa compréhension de la maladie

chez les humains

Bridging Genomes and MedicineThomas J. Hudson President and Scientific Director, Ontario Institute for Cancer Research,Acting Scientific Director, McGill University andGenome Quebec Innovation Centre Ontario, Canada

Dr.Thomas J. Hudson is founder and Director of the McGill University and Genome QuebecInnovation Centre and past Assistant-Director of the Whitehead Institute/MIT Center forGenome Research. Dr. Hudson is internationally renowned for his work in Genomics. At theWhitehead Institute, Dr. Hudson led the effort to generate dense physical and gene maps ofthe human and mouse genomes. He is a leader in the development and applications ofrobotic systems and DNA-chip based methodologies for genome research. In June 1996, hefounded the Montreal Genome Centre based at the McGill University Health CentreResearch Institute. In 2003, this group expanded to become the McGill University andGenome Quebec Innovation Centre. Dr. Hudson and his team were founding members of theInternational Haplotype Map Consortium. Dr Hudson’s interests in human genetic diseasesfocus on the dissection of complex genetic diseases. Ongoing disease projects in Dr. Hudson’slaboratory include the search for genes predisposing to lupus, inflammatory bowel disease,coronary artery disease, asthma, diabetes and colon cancer.The laboratory is also using DNA-chip technology in order to characterize breast and ovarian cancer.

Dr. Hudson is editor-in-chief of the journal Human Genetics. Dr. Hudson teaches in thedepartments of Human Genetics and Medicine at McGill University and practices medicineat the McGill University Health Centre – Montreal General Hospital (Division of Immunologyand Allergy). He has received numerous awards, including the 2005 Achievement of the Yearin Healthcare from Maclean’s magazine, the 2005 Award for Research in Immunology by theCanadian Society for Allergy and Clinical Immunology, the André-Dupont 2002 YoungInvestigator Award given by Quebec’s Clinical Research Club, an Investigator Award from theCanadian Institutes of Health Research, a Burroughs-Wellcome Clinician-Scientist Award,The2002 Prix de la Santé from the Armand-Frappier Foundation, the 2001 Young Scientist Awardby the Genetics Society of Canada, the 2000 Scientist of the Year by Radio-Canada, the1999 Canada Top 40 Under 40, and more.

Keynote Speaker

Lunch 12:00 – 13:45 Déjeuner

Conférencier d’honneurFrontenac

4

Bridging Genomes and MedicineThomas J. Hudson Directeur scientifique, Institut de recherche sur le cancer de l’OntarioDirecteur scientifique intérimaire de l’Université McGill et du Centre d’innovation Génome QuébecOntario, Canada

Dr Thomas J. Hudson est le fondateur et directeur du Centre d’innovation Génome Québec etde l’Université McGill en plus d’avoir été directeur-adjoint du réputé Center for GenomeResearch du Whitehead Institute/Massachusetts Institute of Technology (MIT)–principallaboratoire des États-Unis impliqué dans le Projet Génome Humain, où il a acquis unerenommée internationale pour avoir dirigé les projets de cartographie des génomes del’homme et de la souris. Dr Hudson demeure un chef de file dans la conception et l’applicationde systèmes robotisés et de puces à ADN dans la recherche en génomique. En 1996, leDr Hudson mettait sur pied un centre de recherche en génomique qui est maintenant devenule Centre d’innovation Génome Québec et de l’Université McGill. Outre sa participation auconsortium international de cartes d’haplotypes du génome humain, les recherches dulaboratoire du Dr Hudson portent sur les maladies génétiques humaines dites « complexes »,se penchant par exemple sur les gènes de prédisposition au lupus, aux maladiesinflammatoires intestinales, à la coronaropathie, à l’asthme, au diabète et au cancer du colon.Ses études se concentrent aussi sur la caractérisation de cancers du sein et de l’ovaire à l’aidede la technologie de puce à ADN.

Dr Hudson est éditeur-en-chef de la revue Human Genetics. Il cumule aussi le titre deprofesseur associé aux départements de génétique humaine et de médecine de l’UniversitéMcGill, tout en pratiquant comme médecin-spécialiste en immunologie clinique et allergologieau Centre universitaire de santé McGill (Hôpital général de Montréal). Il a reçu plusieurs prixet bourses, parmi lesquels : lauréat de la Réalisation de l’année en soins de santé (2005) de larevue Maclean’s, le prix de la recherche en immunologie de 2005 de la Société canadienned'allergie et d'immunologie clinique, le Prix du Jeune Chercheur André-Dupont 2002 du Clubde recherches cliniques du Québec, une bourse de chercheur des Instituts de recherche ensanté du Canada, une bourse de chercheur-clinicien Bourroughs Wellcome, la bourse WilliamDawson, le Prix 2002 de la Santé de la Fondation Armand-Frappier décerné au Centred’innovation, le prix du jeune chercheur 2001 de la Société de génétique du Canada, le prix duScientifique de l’année 2000 de Radio-Canada, et le prix canadien Top 40 Under 40 en 1999.



chez les humains

Chair | PrésidentTimothy CaulfieldCanada Research Chair in Health Law and Policy, Professor, Faculty of Law and Faculty of Medicine and Dentistry,Research Director, Health Law Institute, University of Alberta Canada

Speakers | conférenciers

Human Genome Variation inHealth and Disease

Genome Architecture in Autism Spectrum DisorderStephen Scherer University of Toronto,Canada

Regulatory Barriers to Clinical Introduction of GeneticallyTargeted TherapiesBarbara Evans Indiana University,USA

Pharmacogenomics: Paving the Way toImproved Drug Development and HealthcareMichael Phillips Université de Montréal,Canada

Genetics and Drugs: How Genetic Variations Leads to NewApproaches to TherapyMichael Hayden University of British Columbia,Canada

Session 1 14:00 – 16:30

14:00 – 14:30

14:30 – 15:00

15:30 – 16:00

16:00 – 16:30

Variation du génome humain dans lesétats de santé et de maladie

Jacques Cartier

5



chez les humains

Chair | PrésidentBenoit ChabotProfessor and Director, Department of Microbiology and Infectious Diseases, Faculty of Medicine and CanadaResearch Chair in Functional Genomics, University of Sherbrooke,Canada


Splicing Variants: Finding HiddenMarkers and Targets

Investigation of Splice Variants Provides NewResolution in Gene Expression Profiling: Applicationsto Drug and Biomarker Discovery and DevelopmentLaurent Bracco ExonHit Therapeutics,France

Global Analyses of Alternative Splicing in MammalsBenjamin J. BlencoweUniversity of Toronto,Canada

Applications of Splicing-sensitive MicroarraysManuel Ares, Jr.University of California,USA

Mechanisms of Alternative Pre-mRNA Splicing RegulationJuan Valcárcel Centre de Regulació Genòmica,Spain

Session 2 14:00 – 16:30

14:00 – 14:30

14:30 – 15:00

15:30 – 16:00

16:00 – 16:30

Variantes de l’épissage : à la recherchede marqueurs cachés et de cibles

Place D’Armes

6

18:00 – 20:00 Poster Session and Reception (Verchères)

Thursday, October 26Molecular Evolution andBiosphere Diversity



Systems Biology and the Virtual PlantJoe EckerProfessor of Biology, Salk Institute for Biological Studies California, USA

Joseph Ecker earned his Ph.D. in Microbiology at the Pennsylvania State University Collegeof Medicine. He served on the faculty at the University of Pennsylvania (1987-2000)before joining The Salk Institute for Biological Studies (2000) where he is a Professor in thePlant Biology Laboratory and Director of the Salk Institute Genomic Analysis Laboratory. Hisresearch on the gaseous plant hormone ethylene has yielded basic insights into themechanisms of plant growth control and its application has resulted in technologies thatdelay fruit ripening and disease processes. His laboratory participated in mapping andsequencing of genome of Arabidopsis thaliana and his group continues to explore theencyclopedia of DNA elements in Arabidopsis through the development and applicationof technologies for genome-wide analysis of plant gene function. In 2006, Professor Eckerwas elected to the National Academy of Science and he currently serves as President ofthe International Society for Plant Molecular Biology.

Systems Biology and the Virtual PlantJoe EckerProfesseur,The Salk Institute for Biological StudiesCalifornie, É.-U.

M. Joseph Ecker a obtenu un doctorat en microbiologie au Collège de médecine de l’Universitéd’État de la Pennsylvanie. Il a fait partie du personnel enseignant de l’Université de laPennsylvanie (1987-2000) avant de joindre les rangs du Salk Institute for Biological Studies(2000) où il est professeur au laboratoire de biologie végétale et directeur du Salk InstituteGenomic Analysis Laboratory. Ses recherches sur l’éthylène, l’hormone végétale gazeuse, ontpermis d’acquérir des notions fondamentales sur les mécanismes de la régulation de lacroissance des plantes et leur application a permis d’élaborer des technologies qui retardent lemûrissement des fruits et les processus des maladies. Son laboratoire a participé à lacartographie et au séquençage du génome d’Arabidopsis thaliana et son groupe continued’explorer l’encyclopédie des éléments d’ADN de l’Arabidopsis par l’élaboration etl’application de technologies pour l’analyse pangénomique de la fonction des gènes végétaux.En 2006, le professeur Ecker a été élu à la National Academy of Science et il estactuellement président de l’International Society for Plant Molecular Biology.

Breakfast 7:30 – 8:45 Petit déjeuner

Salle de Bal

7

Keynote Speaker Conférencier d’honneur




Co-Chair | CoprésidentWilliam Crosby Professor and Head, Department of Biological SciencesUniversity of Windsor Canada


Diversity and Evolution in PlantGenome Structure and Function

Molecular Mechanisms Shaping the Rice GenomeTom Bureau McGill University,Canada

Genomic Strategies for Identifying SNPs of Adaptive Significancein Undomesticated Non Model Species Jean Bousquet Université Laval,Canada

Analysis of the Small RNA Component of the Riceand Aradidopsis Transcriptomes Cheng Lu University of Delaware,USA

Towards Organo-transgenic Crops?Klaus Ammann University of Bern,Switzerland

Session 3 9:00 – 12:00

Co-Chair | CoprésidentJohn MacKay Co-director, Arborea II and Associate Professor, Departmentof Wood and Forest Sciences, Laval University Canada

9:00 – 9:30

9:30 – 10:00

The Evolutionary Genomics of DomesticatedAsian RiceMichael D. Purugganan North Carolina State University,USA

10:30 – 11:00

11:00 – 11:30

11:30 – 12:00

Diversité et évolution de la structure etde la fonction du génome des plantes

Frontenac

8




Chair | PrésidenteBartha Maria KnoppersCanada Research Chair in Law and Medicine Université de Montréal Canada

Population Genetics

Session 4 9:00 – 12:00

Génétique des populationsBellevue

9


The NPS-NPSR1 Pathway in Asthma: FromPositional Cloning to MechanismJuha Kere Karolinska Institute,Sweden

Genetic Variation in Caffeine Metabolism and Sensitivity and Riskof Myocardial InfarctionAhmed El-Sohemy University of Toronto,Canada

Genomics of Metabolic Disease in VulnerableFamilies and CommunitiesRobert Hegele University of Western Ontario,Canada

Population Genetics and Ethics of DifferenceDavid CastleUniversity of Ottawa,Canada

9:00 – 9:30

9:30 – 10:00

Networking and Sharing Genomic Resources—A Legal Quagmire?Jane Kaye University of Oxford,UK

10:30 – 11:00

11:00 – 11:30

11:30 – 12:00




10


Salle de BalKeynote Speaker Conférencier d’honneur

Comparative Genomics and our Current Understanding ofPathogen Control in Mosquitoes Fotis Kafatos Chair in Immunogenomics, Division of Cell and Molecular Biology, Imperial College,London, UK

Fotis C. Kafatos was born in Crete, Greece, where he received his primary and secondaryeducation. He graduated from Cornell University with a bachelor’s degree with high honoursand earned his Masters and PhD degrees (1965) in biology from Harvard. He became theyoungest full Professor at Harvard in 1969, serving until 1994. In parallel, he promotedtraining and development of the life sciences in Greece, holding adjunct professorships at theUniversity of Athens (1972-1982) and the University of Crete (1982—now, currently onleave). His institution-building activities included founding and directing the Institute ofMolecular Biology and Biotechnology at the Research Centre of Crete from 1982 to 1993.He served two successful terms (1993-2005) as Director-General of the EuropeanMolecular Biology Laboratory (EMBL), the top leading molecular biology laboratory in Europepromoting new approaches to Biology and the development of research infrastructuresin Europe. In the 1960’s Kafatos was one of the scientists who introduced molecular biologyto the study of development. He helped develop fundamental techniques such as cDNAsynthesis, cloning and sequencing (the beta globin gene) and invented the dot-blot, theprecursor of DNA microarrays. He pioneered the analysis of gene families in developmentand evolution (chorion gene families), helped launch the Drosophila and Anopheles genomeprojects, and made important contributions to comparative and functional genomics. Hiscurrent scientific work is on malaria research with emphasis on mosquito genomics andimmunity of Anopheles to the Plasmodium parasite. He is active in efforts to promoteresearch and scientific education in the developing world. His professional activities includeservice on the advisory boards of distinguished scientific centres and organisations, in severalcountries of Europe and abroad. He is the recipient of numerous honours including fivehonorary doctorates. He is a Foreign Member of the Royal Society of London and the FrenchAcademy of Sciences, and Member of the US National Academy of Sciences, the AmericanAcademy of Arts and Sciences, the Pontifical Academy of Sciences, EMBO and AcademiaEuropea. In 2005, he was elected as Chairman of the ERC Scientific Council.

Comparative Genomics and our Current Understanding of Pathogen Control in Mosquitoes Fotis Kafatos Professeur d'immunogénomique, Faculté des sciences naturelles, Imperial CollegeLondres, R.-U.

Fotis C. Kafatos est né à Crête, en Grèce, où il a fait ses études primaires et secondaires. Il aobtenu un baccalauréat avec mention très bien à l’Université Cornell et poursuivi ses études demaîtrise et de doctorat (1965) en biologie à Harvard. Il est devenu le plus jeune professeur deHarvard en 1969, où il a enseigné jusqu’en 1994. Parallèlement, il a fait la promotion de laformation et du perfectionnement des sciences de la vie en Grèce, où il a occupé des postesde professeur adjoint à l’Université d’Athènes (1972-1982) et à l’Université de Crête (1982jusqu’à maintenant, actuellement en congé). Parmi ses activités d’ordre institutionnel, il a fondéet dirigé, de 1992 à 1993, l’institut de biologie moléculaire et de biotechnologie au Centre derecherche de Crète. Il a été pendant deux mandats fructueux (1993-2005) directeur généraldu Laboratoire européen de biologie moléculaire (EMBL), le plus important laboratoire debiologie moléculaire en Europe qui préconise l’adoption de nouvelles approches en biologie etla mise en valeur des infrastructures de recherche européennes. À la fin des années 1960,M. Kafatos a été l’un des chercheurs qui a utilisé la biologie moléculaire pour étudier ledéveloppement. Il a aidé à mettre au point des techniques fondamentales comme la synthèsede l’ADNc, le clonage et le séquençage (gène de la globine bêta) et inventé la technique dot-blot, qui a précédé les puces à ADN. Il est un pionnier de l’analyse des familles de gènes dansle développement et l’évolution (familles du gène chorionique), il a aidé à lancer les projets dugénome de Drosophila et d’Anopheles, et largement contribué à la génomique comparative etfonctionnelle. Ses travaux scientifiques actuels portent sur le paludisme, en particulier lagénomique des moustiques et l’immunité de l’Anopheles au parasite Plasmodium. Il s’emploieactivement à promouvoir la recherche et l’enseignement scientifique dans les pays endéveloppement. Entre autres activités professionnelles, il participe à des comités consultatifs decentres et d’organismes scientifiques distingués, dans plusieurs pays d’Europe et de l’étranger. Ila également reçu de nombreuses distinctions dont cinq doctorats honorifiques. Il est membreétranger de la Royal Society of London et de l’Académie française des sciences, et membre dela National Academy of Sciences des États-Unis, de l’American Academy of Arts and Sciences,de la Pontifical Academy of Sciences, de l’EMBO et d’Academia Europea. En 2005, il a été éluprésident du Conseil scientifique de l’ERC.




Chair | PrésidentWilliam M. Gelbart Professor, Molecular and Cellular BiologyHarvard University USA


Models of Biology andDisease Control

The Insect Down Syndrome Cell Adhesion Molecule(Dscam) Gene:The Making and Function of38,000 IsoformsBrenton Graveley University of Connecticut,USA

Comparative Genomics of 12 Fly SpeciesManolis Kellis Massachusetts Institute of Technology,USA

Fish and Chips: An Integrative Approach toUnderstanding Social DominanceHans HofmannUniversity of Texas,USA

The Genomics of Olfaction and Host Selection inDisease Vector MosquitoesLaurence Zwiebel Vanderbilt University,USA

Session 5 14:00 – 16:30

14:00 – 14:30

14:30 – 15:00

15:30 – 16:00

16:00 – 16:30

Modèles de biologie et de luttecontre les maladies

Frontenac

11




Chair | PrésidentRobert FletterickDepartment of Biochemistry and BiophysicsUniversity of California USA


Systems Approaches in Structuraland Functional Genomics

Intracellular Calcium-signaling: the EF-handomeand Calmodulin’s IQ-testHans Vogel University of Calgary,Canada

Making Sense of Point Mutants that Impact Protein FunctionRachel Karchin Johns Hopkins University,USA

Directed Structural Genomics: Focus onHuman Protein FamiliesMichael Sundstrom University of Oxford,UK

Harvesting the Value from Structural Genomics:A Pharmaceutical Industry Perspective Rob M. CookeGlaxoSmithKline Research and Development,USA

Session 6 14:00 – 16:30

14:00 – 14:30

14:30 – 15:00

15:30 – 16:00

16:00 – 16:30

Approches systémiques en génomiquestructurelle et fonctionnelle

Bellevue

12



la diversité de la biosphèreBanquet 18:00 – 22:00

Salle de Bal

13

Genomics: Another Dimension of Preventive Technology in the Battle Against AIDS?Stephen LewisScholar-in-Residence 2006 McMaster University Canada

Stephen Lewis, recently named McMaster University’s first Social Science Scholar-in-Residence, has an outstanding history as a diplomat and a humanitarian. He has been theUnited Nations’ Special Envoy for HIV/AIDS in Africa since 2001. He is also a Commissionerfor the World Health Organization’s Commission on the Social Determinants of Health, anda Senior Advisor to the Mailman School of Public Health at Columbia University in New York.In addition, Mr. Lewis is a director of the Stephen Lewis Foundation, which is dedicated toeasing the pain of HIV/AIDS in Africa. For eight years in the 1960s and 1970s he led theOntario New Democratic Party during which time he became leader of the OfficialOpposition. He later served as Canadian Ambassador to the United Nations, and as theDeputy Executive Director of UNICEF in New York. Mr. Lewis is a Companion of the Orderof Canada, the 2004 recipient of the Pearson Peace Medal for outstanding achievement inthe field of international service and understanding from the United Nations Association inCanada and in 2005, was named by TIME magazine as one of the 100 most influentialpeople in the world. In 2006, Mr. Lewis’ best-selling book, Race Against Time, received theCanadian Booksellers Association’s Libris Award for non-fiction book of the year.

Genomics: Another Dimension of Preventive Technology in the Battle Against AIDS?Stephen LewisProfesseur-résident en sciences sociales 2006Université McMasterCanada

M. Stephen Lewis, récemment nommé premier professeur-résident en sciences sociales àl’Université McMaster, a une expérience exceptionnelle de la diplomatie et de l’actionhumanitaire. Depuis 2001, il est envoyé spécial des Nations Unies pour le VIH/SIDA enAfrique. Il est également commissaire de la Commission des déterminants sociaux de la santéde l’Organisation mondiale de la santé, et conseiller principal auprès de la Mailman School ofPublic Health à l’Université Columbia à NewYork. M. Lewis est en outre administrateur de laStephen Lewis Foundation, qui a pour but d’atténuer les souffrances causées par le VIH/SIDAen Afrique. Pendant huit ans dans les années 1960 à 1970, il a dirigé le Nouveau PartiDémocratique en Ontario, période au cours de laquelle il est devenu chef de l’oppositionofficielle. Il a ensuite été ambassadeur du Canada aux Nations Unies, puis directeur exécutifadjoint de l’UNICEF à NewYork. M. Lewis est compagnon de l’Ordre du Canada, lauréat en2003 de la Médaille Pearson pour la paix, décernée par l’Association canadienne pour lesNations Unies, parce qu’il a contribué toute sa vie durant à l'amélioration de la qualité de vieet au mieux-être de l'humanité toute entière. En 2005, il a été cité par le magazine TIMEparmi l’une des cent personnes les plus influentes dans le monde. En 2006, le livre à succèsde M. Lewis, Race Against Time, a reçu le prix Libris de la Canadian Booksellers Associationdans la catégorie livre non romanesque de l’année.

Keynote Speaker Conférencier d’honneur

Friday, October 27Prospects, Challenges,and Issues

Vendredi, 27 octobreLes perspectives, les défis et les

enjeux de la génomique

14

Moving (Slowly) from Promise to Benefit Wylie Burke Professor and Chair of the Department of Medical History and EthicsUniversity of Washington Washington, USA

Wylie Burke is Professor and Chair of the Department of Medical History and Ethics at theUniversity of Washington (UW), and Director of the University of Washington Center forGenomics and Healthcare Equality. She received a PhD in Genetics and an MD from UW,completed a medical residency in Internal Medicine in 1981 and was a Medical GeneticsFellow from 1981 to 1982. She is an Adjunct Professor in the Departments of Medicine andEpidemiology. Her academic work addresses the ethical and policy implications of the use ofgenetic information in medicine and public health. Dr. Burke served on the Secretary’s AdvisoryCommittee on Genetic Testing from 1999 to 2002 and the National Human Genome AdvisoryCouncil from 1999 to 2003. She is currently President-elect of the American Society ofHuman Genetics.

Moving (Slowly) from Promise to Benefit Wylie Burke Professeure et maître de conférences, Département d'histoire médicale et d'éthiqueUniversité de WashingtonWashington, É.-U.

Mme Wylie Burke est professeure et titulaire d’une chaire au Département d’histoire médicaleet d’éthique de l’Université de Washington, et directrice du Center for Genomics andHealthcare Equality à la même université. Elle a obtenu un doctorat en génétique et undoctorat en médecine à l’Université de Washington, effectué sa résidence en médecine interneen 1981; elle a en outre été boursière en génétique médicale de 1981 à 1982. Elle estprofesseure adjointe aux Départements de médecine et d’épidémiologie. Ses travauxuniversitaires portent sur les répercussions sur le plan éthique et politique de l’utilisation desrenseignements génétiques en médecine et en santé publique. Mme Burke a fait partie duComité consultatif du Secrétaire sur les tests génétiques de 1999 à 2002 et du Conseilconsultatif national sur le génome humain de 1999 à 2003. Elle est actuellement présidentedésignée de l’American Society of Human Genetics.

Keynote Speaker Conférenciere d’honneur

Breakfast 7:30 – 8:45 Petit déjeuner

Salle de Bal


Vendredi, 27 octobreLes perspectives, les défis

et les enjeux de la génomique

Out of the Genomics Box:Applications for 2020

Session 7 9:00 – 12:00

Du génie de la génomique :applications en 2020

Frontenac

15

Chair | PrésidentMartin GodboutPresident and CEO, Genome Canada Canada


Patents, Material Transfers and Access toBiomedical Research ToolsJohn Walsh Georgia Institute of Technology,USA

Decoding the Vertebrate RegulomeTimothy Hughes University of Toronto,Canada

Bringing Society Back into Science: Opportunitiesand ChallengesEdna Einsiedel University of Calgary,Canada

9:00 – 9:30

9:30 – 10:00

Metagenomics will be to Genomics what Genomicshas been to GeneticsFord Doolittle Dalhousie University,Canada

10:00 – 10:30

10:30 – 11:00

11:00 – 11:30 Haystacks with DrugsRobert Fletterick University of California,USA

Genetic and Chemical-Genetic Interactions Networks RevealGene and Drug FunctionCharles Boone University of Toronto,Canada

11:30 – 12:00

Vendredi, 27 octobreLes perspectives, les défis et les

enjeux de la génomique

16


Drug Development with Pharmacogenetics in 2006Allen D. Roses Senior Vice-President of Genetics Research, GlaxoSmithKline (North Carolina, USA)

Allen D. Roses, MD, FRCP (Hon) was appointed as Senior VP for Genetics Research atGlaxoSmithKline in 2000. In 1997, Dr. Roses joined Glaxo Wellcome and was charged withorganizing genetic strategies for susceptibility gene discovery, pharmacogenetics strategy andimplementation, and integration of genetics into medicine discovery and development. In theGSK R&D structure, genetics, genomics, proteomics and bioinformatics are part of GeneticsResearch and support the entire R&D pipeline. His group recently published the proof ofprinciple experiments for using linkage disequilibrium mapping to identify susceptibility loci fordrug adverse events. In 1997 when he left Duke University Medical Center, Dr. Roses was theJefferson Pilot Professor of Neurobiology and Neurology, Director of the Joseph and KathleenBryan Alzheimer’s Disease Research Center, Chief of the Division of Neurology, and Director ofthe Center for Human Genetics. Dr. Roses was one of the first clinical neurologists to applymolecular genetic strategies to neurological diseases. His laboratory at Duke reported thechromosomal location for more than 15 diseases, including several muscular dystrophies andLou Gehrig’s disease. He led the team that identified APOE as a major, widely-confirmedsusceptibility gene in common late-onset Alzheimer’s disease.Translation of these findings topathway analyses, drug discovery and development has continued at GSK.


Salle de BalKeynote Speaker Conférencier d’honneur

Drug Development with Pharmacogenetics in 2006Allen D. Roses Vice-président principal, Pharmacogénétique, GlaxoSmithKlineCaroline du Nord, É.-U.

Allen D. Roses, MD, FRCP (Hon.) a été nommé vice-président principal de la Recherche engénétique chez GlaxoSmithKline en 2000. En 1997, le Dr Roses a joint les rangs de GlaxoWellcome où on lui a confié la responsabilité de l’organisation des stratégies génétiques pour ladécouverte de gènes de prédisposition, la stratégie de pharmacogénétique et sa mise en ?uvre,de même que l’intégration de la génétique aux découvertes et au développement enmédecine. Dans la structure de R-D de GSK, la génétique, la génomique, la protéomique et labioinformatique font partie de la Recherche en génétique et tous ces domaines appuient lepipeline de R-D dans son ensemble. Le groupe du Dr Roses a récemment publié desdémonstrations du principe de l’utilisation des cartes des déséquilibres de liaison pourdéterminer les loci de prédisposition concernant divers effets indésirables des médicaments. En1997, lorsqu’il a quitté le centre médical de l’Université Duke, le Dr Roses était le professeurde neurobiologie et de neurologie de la chaire Jefferson Pilot, directeur du Joseph and KathleenBryan Alzheimer Disease Research Center, chef de la Division de neurologie, et directeur duCenter for Human Genetics. Le Dr Roses a été l’un des premiers neurologues cliniciens àappliquer les stratégies de la génétique moléculaire aux affections neurologiques. Sonlaboratoire à l’Université Duke a fait connaître l’emplacement chromosomique de plus de 15maladies, notamment de plusieurs dystrophies musculaires et de la maladie de Lou Gehrig. Il adirigé l’équipe qui a identifié le gène de l'apolipoprotéine E (APOE), un gène de prédispositionimportant et largement confirmé dans les cas courants tardifs de la maladie d’Alzheimer. Latraduction de ces constatations pour les analyses des voies critiques, les découvertes desmédicaments et leur mise au point se poursuit chez GSK.

17

Klaus Ammann Towards Organo-transgenic Crops? . . . . . . . . . . . . . . . . . . . . 18Manuel Ares Applications of Splicing-Sensitive Microarrays . . . . . . . . . . . . 20Benjamin J. Blencowe Global Analyses of Alternative Splicing in Mammals . . . . . . 21Charles Boone Genetic and Chemical-Genetic Interactions Networks

Reveal Gene and Drug Function . . . . . . . . . . . . . . . . . . . . . . . 22Jean Bousquet Genomic Strategies for Identifying SNPs of Adaptive

Significance in Undomesticated Non Model Species . . . 23Laurent Bracco Investigation of Splice Variants Provides New Resolution

in Gene Expression Profiling: Applications to Drug and Biomarker Discovery and Development . . . . . . . . . . . . . . . . . 25

Tom Bureau Molecular Mechanisms Shaping the Rice Genome . . . . . 26Wylie Burke Moving (Slowly) from Promise to Benefit . . . . . . . . . . . . . . . . 28David Castle Population Genetics and Ethics of Difference . . . . . . . . . . . . 29Rob M. Cooke Harvesting the Value from Structural Genomics:

A Pharmaceutical Industry Perspective . . . . . . . . . . . . . . . . . . 30Ford Doolittle Metagenomics will be to Genomics what Genomics

has been to Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31Joe Ecker Systems Biology and the Virtual Plant . . . . . . . . . . . . . . . 32Edna Einsiedel Bringing Society Back into Science:

Opportunities and Challenges . . . . . . . . . . . . . . . . . . . . . . . . 33Ahmed El-Sohemy Genetic Variation in Caffeine Metabolism

and Sensitivity and Risk of Myocardial Infarction . . . . . . . . . 34Barbara Evans Regulatory Barriers to Clinical Introduction of

Genetically Targeted Therapies . . . . . . . . . . . . . . . . . . . . . 35Robert Fletterick Haystacks with Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36Brenton Graveley The Insect Down Syndrome Cell Adhesion Molecule

(Dscam) Gene:The Making and Function of 38,000 Isoforms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Michael Hayden Genetics and Drugs: How Genetic Variations Leads to New Approaches to Therapy . . . . . . . . . . . . . . . . . 38

Robert Hegele Genomics of Metabolic Disease in Vulnerable Familiesand Communities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Hans Hofmann Fish and Chips: An Integrative Approach to Understanding Social Dominance . . . . . . . . . . . . . . . . . . . 40

Thomas J. Hudson Bridging Genomes and Medicine . . . . . . . . . . . . . . . . . . . 41Timothy Hughes Decoding the Vertebrate Regulome . . . . . . . . . . . . . . . . . 42Fotis C. Kafatos Comparative Genomics and our Current

Understanding of Pathogen Control in Mosquitoes . . . . 43Rachel Karchin Making Sense of Point Mutants that Impact

Protein Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44Jane Kaye Networking and Sharing Genomic Resources—

A Legal Quagmire? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45Manolis Kellis The Comparative Analysis of Insect Genomes . . . . . . . . . . . . 46Juha Kere The NPS-NPSR1 Pathway in Asthma:

From Positional Cloning to Mechanisms . . . . . . . . . . . . . . . . . 47Stephen Lewis Genomics: Another Dimension of Preventive

Technology in the Battle Against AIDS? . . . . . . . . . . . . . . 48Cheng Lu Analysis of the Small RNA Component of the Rice

and Arabidopsis Transcriptomes . . . . . . . . . . . . . . . . . . 49Michael Phillips Pharmacogenomics: Paving the Way to Improved

Drug Development and Healthcare . . . . . . . . . . . . . . . . . 50Michael D. The Evolutionary Genomics of Domesticated Purugganan Asian Rice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51Allen D. Roses Drug Development with Pharmacogenetics in 2006 . . . . . . 52Stephen Scherer Genome Architecture in Autism Spectrum Disorder . . . . 54Michael Sundstrom Directed Structural Genomics: Focus on Human

Protein Families . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55Juan Valcárcel Mechanisms of Alternative Pre-mRNA Splicing Regulation . . 56Hans Vogel Intracellular Calcium-signalling:The EF-handome and

Calmodulin’s IQ-test. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57John Walsh Patents, Material Transfers and Access to Biomedical

Research Tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58Laurence Zwiebel The Genomics of Olfaction and Host Selection in

Disease Vector Mosquitoes . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Speaker Profiles and Abstracts Profils et abstraits des conférenciers

18

Klaus Ammann

Session 3

Curriculum VitaeBorn December 6, 1940Studied at University of Berne:Thesis on Vegetation History 1972,

summa cum laudeStudies at Duke University, NC, USA, Bergen, Norway and Kingston, JamaicaDirector of Botanical Garden, University of Berne since 1996Prof. hon. University of Berne since 2000

Teaching:Lecturing in Plant Systematics and Evolution, Biogeography Lectures on Air Pollution Biomonitoring at the Federal Institute of Technology

in Zurich

Committees, among others:Chairman European Group of Plant Specialists, IUCN Steering Committee of PLANTA EUROPA Project coordinator and member of executive board Euro+Med, Red List of

Threatened Plants of Europe Member of coordination group European Science Foundation: AIGM, Risk

assessment on transgenic crops Biosafety Committee of the Government of Switzerland GMO Expert Group European Commission Directorate General JRC—IPTS Chairman of the Section on Biodiversity of EFB European Federation

of Biotechnology Editor in Chief (Ecology) of Environmental Biosafety Research

Research Projects:Chemotaxonomy of macro-lichens, calibrated biomonitoring of air pollution with

lichens, molecular systematics with lichens, ecological monitoring, ethnobotany inJamaica, ecological monitoring in Bulgaria.

Ecological risk assessment of vertical gene flow in Switzerland 2 EU-Projects on Gene Flow and Plant Conservation of Europe1. Gene Flow of Brassicaceae in Europe, coordinator Swiss participation2. Euro+Med, coordinator work packages Atlas Florae Europaeae Helsinki,

Finland, Caryological Data Base Patras, Greece, European Red List and Websiteon Popularized Flora Europaea Contents, Botanical Garden, University of Berne,a joint venture with IUCN SSC Group European Plants, Planta Europa and theCouncil of Europe

2 Projects in collaboration with UNIDO (United Nations Industrial DevelopmentOrganisation:

a) Compendium on Risk Assessment Researchb) Global Initiative on Education in Biotechnology 1Website Project www.bio-scope.org, in collaboration with BioLinX in Frankfurt

His intention is to encourage the process leading to solutions concerning today’scrucial themes such as protection of biodiversity, risk assessment of geneticallyengineered crops and the public debate about biotechnology.

19

Organic farming is a heterogeneous agricultural management method.Thiscan be explained by its multiple origins, and by the fact that certification oforganic farming practices with follow-up inspections have been introducedover various decades and in many different places. Organic farming is nowgrowing rapidly away from its former association with backward-thinkingLuddites and becoming a veritable industry. Regulation has been imposed,more or less strictly, on all organic farms in states like California, bringing abasic shift towards top-down activities.The practice of organic farminginvolves not just regulation, but is also part of an overall marketing strategy.

It is time to forget about ideological warfare, since the biotech cropindustry has also learned how to deal with environmental problems. Indeed,there has been dramatic progress in this area. For the most-commonlyplanted GM crops, like maize and cotton, the environmental advantages aremanifested in numerous scientific papers.

A close look at the molecular level reveals that the novelty of geneticengineering is restricted to the possibilities of jumping over the specieslevel, but a closer look at the processes indicates that nature and molecularengineering follow exactly the same strategies; there is simply no difference.The results of expanding this perspective to include what classic breedinghas done to the genomes of the most widespread crops are astounding.Chromosome number manipulation, handling fragments of chromosomes,and inverting and transposing sections of DNA have become routine ashave other questionable methods such as triggering mutations for breedingpurposes using gamma radiation and toxic substances.While certainly lesstargeted and elegant than genetic engineering, such manipulative techniquesare, nevertheless, being used. So – in essence – we should learn to worktogether and plan for organo-transgenic crops.

Session 3

Klaus Ammann (cont’d)

Towards Organo-transgenic Crops?

20

Manuel Ares

Our laboratory is interested in capturing changes in gene expression at thelevel of pre-mRNA splicing.We have developed splicing sensitivemicroarrays that are designed to capture estimates both of overallexpression of RNA from a set of genes, as well as information concerningthe amounts of distinct RNA isoforms produced from each gene byalternative RNA processing events, such as alternative splicing, alternativepolyadenylation, and promoter-specific alternative splicing events.We areparticularly interested in identifying important splicing events that may have

been invisible or overlooked in the study of diseases such as cancer,schizophenia, autism, or myotonic dystrophy and that may now be visible. Iwill present results from our laboratory concerning how we approach thequestion of detecting and measuring splicing changes focusing on work inmouse model systems, and how to apply some simple design and analysisprinciples to these questions that can be implemented by fairlystraightforward extensions of existing microarray technology.

Manny Ares is Professor of Molecular, Cell, and Developmental Biology at the University of California, Santa Cruz. He received a B.S. in Genetics and Development atCornell University (1977), and a Ph.D. from the University of California, San Diego (1982). After postdoctoral work at Yale University School of Medicine on thetranscription of human small nuclear RNA (snRNA) genes with Alan Weiner, he was hired by the Biology Department at Santa Cruz in 1987, became a full professorin 1998, and was the founding chairman of the Department of Molecular, Cell, and Developmental Biology from 2000 to 2002. Manny has published on the structureand function of the spliceosomal RNAs, developed splicing sensitive microarrays for yeast and mammalian cells, and uses a combination of computational and wet labmethods to study the regulation of splicing and the roles of RNA in genome function and evolution.

Applications of Splicing-Sensitive Microarrays

Session 2

21Session 2

Benjamin J. Blencowe

The regulation of exon inclusion in transcripts by alternative splicing (AS)represents a powerful mechanism underlying the generation of proteomicand regulatory complexity in higher eukaryotes. However, the full extent ofAS complexity in any one organism is not known. Moreover, the functionalroles of the vast majority of sequence-defined splice variants are also notknown.We have developed custom microarrays and computational toolsfor the quantitative profiling of AS in mammalian cells and tissues. Oursystem generates estimates for the inclusion levels of thousands ofindividual exons. Using this system, we have discovered hundreds of newcell- and tissue-specific AS events. Many of these AS events are

concentrated in sets of functionally linked genes, indicating that coordinationof gene regulation at the level of AS is important for cell and tissue-specificactivities. Analyses of these data have also resulted in the identification ofsequence elements in exons and introns that correlate with AS in specificcells and tissues. Consequently, we have begun to decipher aspects of thesequence “code” that underlies regulated splicing events.We have also usedour microarray system to compare AS patterns between different species,including humans and chimpanzees. Insights from these experiments willbe presented.

Dr. Benjamin Blencowe obtained a BSc (hons) in Microbiology from Imperial College of Science and Technology, University of London in 1988. He was awarded a PhDin Biochemistry in 1991 from the University of London, after working at the European Molecular Laboratory in Heidelberg, Germany from 1988-1991. He was aPostdoctoral Fellow (1992-1996) and a Research Fellow (1996-1998) in the Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, USA. Hewas appointed an Assistant Professor in the Banting and Best Department of Medical Research and Department of Medical and Molecular Genetics at the Universityof Toronto in 1998, and was promoted to Full Professor in these departments this year. Dr. Blencowe’s research focuses on mechanisms underlying the regulation ofgene expression at the post-transcriptional level. He has made numerous important contributions to the study of factors that regulate pre-mRNA splicing and recently,together with his collaborators, has developed new tools for the global analyses of alternative splicing. Dr. Blencowe is the recipient of several national and internationalresearch awards and is among the top 1% most highly cited researchers is his field.

Global Analyses of Alternative Splicing in Mammals

22 Session 7

Charles Boone

We are applying synthetic genetic array (SGA) analysis to the large-scalemapping of genetic interaction networks in yeast. Connectivity of a gene inthe network is predictive of function because query genes tend to interactwith genes of related function. Moreover, subsets of genes displaying similarpatterns of genetic interactions often encode components of the samepathway or complex. Comparison of genetic and protein-proteininteraction networks revealed that most genetic interactions are orthogonal

(not overlapping) with protein-protein interactions. In an application of thegenetic network analysis, we showed that clustering chemical-geneticprofiles and genetic interaction profiles identifies target pathways orproteins, providing a powerful means of inferring mechanism of drug action.Similar networks employing RNAi approaches will extend these conceptsto more complex cells and metazoans.

In 1989, Dr. Boone received his Ph.D. in molecular biology from McGill University, Montreal, Canada. He then did postdoctoral research in yeast genetics at theUniversity of Oregon in Eugene and, in 1993, began work at the Institute of Molecular Biology and Biochemistry in Burnaby, Canada. In 1999, he received the Premier’sResearch Excellence Award from the Province of Ontario government. He is also a recipient of the William E. Rawls Award for Research Excellence of the NationalCancer Institute of Canada, the 2003 Merck Frosst Award of the Canadian Society of Biochemistry, and the 2006 Ira Herskowitz award for yeast genetics. He iscurrently Professor at the University of Toronto’s Banting and Best Department of Medical Research and the Department of Medical Genetics and Microbiology. Dr.Boone’s lab developed an automated form of yeast genetic analysis and they are studying large-scale mapping of genetic interaction networks in yeast as a means ofdefining gene and cellular function.

Genetic and Chemical-Genetic Interactions Networks Reveal Gene and Drug Function

23Session 3

Jean Bousquet

Jean Bousquet is leader of the Canada Research Chair (Level I) in Forest and Environmental Genomics and scientific director of the Centre for Bioinformatics andComputational Biology at Laval University. He has also been director of the Forest Biology Research Centre and vice-dean for research and graduate studies of theFaculty of Forestry and Geomatics. He is currently the co-leader of a large-scale genomic project on conifers. He is one of the most productive young scientists of hisgeneration, with over 100 peer-reviewed publications including papers in Nature, Proceedings of the National Academy of Sciences, Molecular Biology and Evolution andGenetics. About 15 years ago, he has been among the first ones to incorporate molecular biology and PCR into forest genetics, a field where the perennial nature oftrees requires researchers to persevere for many years before obtaining concrete results. .After graduate studies at Laval University , the Petawawa National ForestResearch Institute and the University of Alberta, Jean moved to Oregon State University as a postdoctoral fellow in plant evolutionary genetics. He moved back to LavalUniversity at the beginning of the ‘90 to establish a strong research program in fungi and plant phylogenetics and evolution.

Professor Bousquet has already several scientific breakthroughs to his credit, notably in the area of molecular evolution. His was among the first ones to show theheterogenous nature of evolutionary rates, to establish dating methods relying on statistically constant molecular clocks and multi-gene approaches, and dated theorigin of important groups of organisms such as the symbiotic fungi, the gymnosperms and the monocots. He has moved in the area of tree genomics about 10 yearsago, and was among the first ones to apply genomic approaches to the development and application of gene markers in plant population genetics and phylogenomics.His current work and that of his collaborators involves the study of molecular adaptation at the genome-wide level, including genome scan approaches in domesticatedand natural populations t o elucidate the molecular nature of adapation.The ability of his laboratory to attract researchers is probably the best indication of hisgrowing reputation. He has supervised over 15 postdoctoral fellows and 15 doctoral students since becoming a professor and has welcomed many foreign students andpostdoctoral fellows to his laboratory. For Prof. Bousquet, genomic research is a mean to innovate, but it must also serve to educate and train highly qualified scientistsand professionals.

24 Session3

Jean Bousquet (cont’d)

Undomesticated non model species pose great challenges for theapplication of large-scale genomic, and more generally «’omic» strategies,whether for accelerating their domestication or improving the conservationof their genetic resources. For most plant species, little is known aboutgenome organization and the shear size of many plant genomes is suchthat any whole-genome sequencing effort with current or predictablesequencing technologies is financially prohibitive. Conifers are part of thegymnosperms, which are considered the most primitive of seed plants.Theunderstanding of genome organization in conifers can thus provide awindow in the past, permitting to better apprehend the evolutionarytrends affecting the plant genome. Conifers are also amongst the mostreforested species in the world, with well over 10 billion seedlings plantedevery year. Any marginal increment in breeding value can rapidly translateinto hundreds of millions of dollars per year in Canada alone. Genomics-assisted molecular breeding is seen as an environmentally more acceptablestrategy of tree improvement than the deployment of GMOs, whichenvironmental inocuity remains to be documented in forestry. But withconifer genome sizes anywhere between 3 to 10 times than of the humangenome and 30 times that of Arabidopsis or rice, and with a large array ofspecies to tackle worldwide, traditional genomic approaches includingwhole-genome sequencing are unrealistic and may actually be counter-productive.Transferring information from completely sequenced plantgenomes such as that of Arabidopsis, rice or poplar also proves difficult, as

conifers are phylogenetically remote from angiosperms. Furthermore, as formany undomesticated plant species, conifer natural populations are highlydiverse with large effective population sizes and high recombination rates.In such conditions, linkage disequilibrium may decrease rapidly, renderingdifficult the finding of positive associations between anonymous markeralleles and phenotypes over large genomic distances.The best strategy tocircumvent these numerous limitations is to target coding regions of thegenome, which should result in a higher rate of return per unit of newgenomic information, and which should facilitate the transfer of genomicinformation between species. Recently, we have focused our efforts on thetranscontinental North American white spruce, which is by far the mostreforested species in Canada.These efforts have focused on sequencingand mapping of the expressed component of genome, the transcriptome,with well over 15,000 distinct transcripts identified. Current efforts aimedat identifying thousands of SNPs located in expressed regions and linkingthem to adaptive variation through various genome scan strategies.Theseinclude QTL mapping in pedigree-structured populations, associationstudies in unstructured populations, and genome scans for identifyingoutlier loci among natural populations differentiated for adaptive characters.Because of the conserved nature of ESTs, transfer of some genomicinformation with sizeable economy of scale is possible between species.Such examples of ongoing transfer will be presented.

Genomic Strategies for Identifying SNPs of Adaptive Significance in Undomesticated Non Model Species

25Session 2

Laurent Bracco

Laurent Bracco is one of the co-founder of ExonHit Therapeutics and serves as an Executive VP of Research/Technology. ExonHit Therapeutics’ mission is to identifynovel therapeutics and diagnostics products via the study of alternative RNA Splicing. Prior to founding the company in 1998, Laurent Bracco worked for 9 years atRhône Poulenc Rorer (now Sanofi-Aventis) where he led projects in therapeutic targets identification in Oncology. Laurent Bracco is a Graduate from the EcoleNationale Supérieure de Chimie de Paris (1981) and has a PhD in Chemistry and Biochemistry from the University of Colorado, USA (1989). He also conducted post-doctoral training at the Institut Pasteur in Paris.

Investigation of Splice Variants Provides New Resolution in Gene Expression Profiling:Applications to Drug andBiomarker Discovery and Development

Aletrnative RNA Splicing is a key process that is responsible for theobserved diversity of gene expression in humans. Until recently, there wereno high–throuput tools to quantify splice variant expression and expand onexperimental data describing how alternative splicing can functionally impactgene products and how it gets deregulated within various pathologies.

Splicearrays represent a new generation of microarrays that can monitorthe expression of every transcript generated by the human genome.Theresearch community can freely access a web portal(http://portal.splicearray.com) and query their favourite genes for splicevariant analysis and custom microarray design.

We now have the ability to robustly and thoroughly study completetranscriptomes.This enhanced resolution will provide a higher likelihood ofdelivering novel drugs as well as diagnostics/pharmacogenomics biomarkers.

I will describe how our gene expression technologies have been applied tothe discovery of innovative biomarkers in the field of cancer detection andof potentially novel therapies for Alzheimer’s disease.

26 Session 3

Tom Bureau

Born and raised in California (USA),Thomas (Tom) Bureau completed his B.Sc. in Biology at the University of California at Irvine (UCI). He went on to do his doctoralthesis at the University of Texas (UT) at Austin in cell and structural biology and later changed fields while a postdoctoral research fellow in molecular biology at theUniversity of Georgia at Athens (UGA). In 1996, he landed a full-time faculty position in the Biology Department at McGill University.Tom is now an Associate Professorand a prestigious William Dawson Scholar. He is the coordinator of the largest course on McGill campus, Molecular Cell Biology (enrollment >1000 students) and hastaught courses in molecular evolution, cell biology, and applied tropical ecology.Though his primary research area is plant molecular evolution and bioinformatics, he hasgradually returned to his roots and applies his expertise to address research questions using cell, developmental, molecular and evolutionary biology approaches.

Tom’s laboratory research interests involve the characterization of transposable elements and their role in gene and genome evolution.Transposable elements ortransposons are so-called “jumping genes” and have been previously thought of as parasitic or junk DNA. In the genomic era, it is clear that for most eukaryoticorganisms, including humans, their genomes contain far more transposable elements than host genes. In fact, >50% of the human genome consists of transposableelements. It is therefore not surprising that researchers have reconsidered the role of transposable elements from “junk” to fundamental players in gene and genomeevolution.Tom’s research uses bioinformatics, genomics and conventional “wet bench” approaches to dissect the potential evolutionary contribution of transposableelements. His research has revealed new transposable elements and insights into their interactions with host genes. Many of the finds have been published in prestigiousscientific journals such as Nature, Genome Research, Proceedings of the National Academy of Sciences (PNAS), Molecular Biology and Evolution,Genetics, Journal of Biological Chemistry, Plant Cell, and Plant Journal. His laboratory was involved in the completion and annotation of the two primarymodel plant genomes, Arabidopsis thaliana and Oryza sativa (domesticated rice). In fact, his laboratory was the only Canadian contributor in these multinationalefforts. Both publications are considered to be among the most important papers in plant sciences and helped launch the plant genomics research field. In addition, hisother publications represent major contributions to the field. For example, a 2005 Genome Research article documenting the unusual behavior of transposableelements duplicating host gene segments, earned a “9.0” or exceptional rating by the Faculty of 1000 – an organization that highlights publications of merit.Tom’slaboratory continues to participate in the international consortiums targeting Arabidopsis and rice functional and comparative genomics.

27Session 3

Tom Bureau (cont’d)

Transposons (i.e. transposable elements) have traditionally been viewed as“junk DNA” or as the ultimate genomic selfish parasites. Far from being raregenomic entities, they can constitute a large fraction of eukaryotic genomes.Recently, several lines of evidence now suggest that transposons may beimportant players in the evolution of the host. (1) Transposon insertionscan provide cis-regulatory elements or conversely insulate pre-existing cis-regulatory elements to adjacent cellular (i.e. host) genes. (2) Transposonscan mediate exon-shuffling leading to cellular proteins with novelcombinations of domains or motifs with unique functions. (3) Transposonscan participate in ectopic recombination and have been implicated in geneand segmental genome duplication. (4) Some transposon insertions into

coding or non-coding regions can provide coding capacity to pre-existingcellular genes. (5) Repetitive transposons play a role in the establishmentand maintenance of heterochromatin. (6) Transposons can capture cellulargene fragments influencing the regulation of their cellular gene counterpartsthrough RNA-mediated gene silencing or provide a reservoir of geneconversion donor sequences. (7) Lastly, mobility-related genes have been“domesticated” providing a source of novel coding capacity.Thesemechanisms may lead to novel, developmentally-important functions andagronomically-important traits.Therefore, in order to fully understand themechanisms shaping the rice and other eukaryotic genomes, fine resolutionof the transposon repertoire is essential.

Molecular Mechanisms Shaping the Rice Genome

28

Wylie Burke

Completion of the Human Genome Project was accompanied by greatexpectations, but the benefits have been slow to emerge. Given thecomplexity of biological systems, slow progress in delineating moleculardisease processes is to be expected. In particular, understanding thecomplex diseases that represent the largest burden to public health willrequire innovative strategies for evaluating gene-gene and gene-environment interactions. Despite the discovery of many gene variantsassociated with disease outcomes or drug response, however, the era of

“personalized medicine” has not yet arrived. A careful look suggests threeproblems to be overcome: (1) the intuitive appeal of genetic susceptibilityinformation; (2) barriers to acquiring clinically relevant evidence; and (3)the complexities of pleiotropy. Ultimately, understanding disease biologymay provide more benefit than predicting risk. In the meantime, slowprogress allows time to unravel the potential burdens of discrimination,stigma, and marginalization that may accompany a health system based ongenetic prediction.

Wylie Burke is Professor and Chair of the Department of Medical History and Ethics at the University of Washington (UW), and Director of the University ofWashington Center for Genomics and Healthcare Equality. She received a PhD in Genetics and an MD from UW, completed a medical residency in Internal Medicinein 1981 and was a Medical Genetics Fellow from 1981 to 1982. She is an Adjunct Professor in the Departments of Medicine and Epidemiology. Her academic workaddresses the ethical and policy implications of the use of genetic information in medicine and public health. Dr. Burke served on the Secretary’s Advisory Committeeon Genetic Testing from 1999 to 2002 and the National Human Genome Advisory Council from 1999 to 2003. She is currently President-elect of the American Societyof Human Genetics.

Moving (Slowly) from Promise to Benefit

Breakfast: Friday, October 27 | Petit déjeuner : Vendredi, 27 octobre

29Session 4

David Castle

Population genetic studies are used to identify polymorphisms that couldunderlie important differences between individual responses to toxins,drugs and nutrients. In the field of nutritional genomics, population geneticstudies are used to identify candidates for nutrient-gene association studies,which can be used in the personalization of nutrition. Equally, these studies

can be used to identify sub-populations that share commonpolymorphisms. Different ethical and legal issues arise in these two uses ofpopulation genetics, and controversies associated with each may haveimportant bearing on the development and application of a field likenutritional genomics.

David Castle’s research addresses the interaction between science and technology innovation and society, particularly the ethical and legal issues posed bynew biotechnology.

He is a principal investigator on the Genome Canada funded Canadian Program on Genomics and Global Health, an investigator on the Social Sciences andHumanities Research Council of Canada supported Legal Models of Biotechnology Intellectual Property Protection:A Transdisciplinary Approach, andis the principal investigator on the Social Issues in Nutritional Genomics: the Design of Appropriate Regulatory Systems and Issues of PublicRepresentations and Understanding which is supported by the Advanced Foods and Materials Network.

Castle’s publications include Genetically Modified Foods: Debating Biotechnology, Science, Society and the Supermarket: Opportunities andChallenges for Nutrigenomics, and Aquaculture, Innovation and Social Transformation. He has also published in Postgraduate Medical Journal,Biology and Philosophy, Dialectica, American Journal of Bioethics and Trends in Biotechnology, and Public Affairs Quarterly.

Population Genetics and Ethics of Difference

30 Session 6

Rob M. Cooke

Structural studies of specific drug discovery targets have been a fruitfulactivity in many Pharma and Biotech for 1-2 decades, but the continuingrequirement to improve the yield from research investment has fuelledefforts to obtain information about a wider range of proteins as early aspossible. As the number of known protein structures has increased in recentyears, the number of drug discovery projects which benefit has expanded,particularly where the increased availability of reagents allows timelyexperimental determination of protein-ligand complexes. New ways inwhich the structural information can provide impact have also sprouted and

grown. In addition to visualising protein-ligand interactions, the structures areincreasingly also used to understand function, decide whether a protein willmake a good drug target or not, identify common modes of molecularinteractions, and predict which compounds will interact with which proteins.The latter two aspects are particularly significant for families of relatedproteins, where extensive structural coverage provides a comprehensiveview of the basis of ligand recognition, providing a firm foundation fordrug discovery.

Rob Cooke received his BSc and PhD from the University of Sydney, and after post-doctoral work at Oxford using NMR to determine protein structures, joined Glaxo in1989. Whilst there Rob has been responsible for a number of areas including structural biology, biophysics, protein production, analytical sciences and computationalchemistry, and is currently Director of Structural and Computational Sciences for GlaxoSmisthKline in the UK. Rob is the Honorary Secretary of the British BiophysicalSociety, and a member of the Molecules Genes and Cells funding committee for the Wellcome Trust. He initiated the proceedings which led to the creation of theStructural Genomics Consortium.

Harvesting the Value from Structural Genomics:A Pharmaceutical Industry Perspective

Session 7

Ford Doolittle

Genomics has been transformative. It has, as anticipated, answered verymany of the gene-level and protein-level questions that geneticists,biochemists and other biomedical scientists had been wrestling withthrough much of the latter part of the last century. But much moreimportantly it has redefined the terms in which those questions are askedand given birth to a host of new “omic” disciplines, focused at higherintegrative levels and addressing new and more challenging questions aboutwhole organism form and function. In the end, genomics will be understoodas the systems biology of organisms.

There are systems yet more complex than individual organisms, of course –communities. Metagenomics will be their systems biology. Indeed, it is multi-species communities that are the relevant level of focus for understanding

the essential services microbes perform in the biosphere and the complexand sometimes subtle roles they play in the maintenance of our ownhealth. Most microbes are unculturable and many ecosystems containhundreds of species, so omic approaches directed at individuals must giveway to experimental methods that sample a community or an environmentbroadly and computational analyses that can make sense of such data.Thechallenges are daunting but the enthusiasm of the microbiologists,genomicists and computer scientists who now call themselves“metagenomocists” is extraordinarily high.The relevance of this new scienceto areas of human concern – health and disease, pollution and itsremediation and climate change and the biota’s response to it – is obvious. Iwill use several recent metagenomic projects as exemplars.

Dr. Doolittle is the Director of the Program in Evolutionary Biology of the Canadian Institute of Advanced Research, holds a Canada Research Chair in ComparativeMicrobial Genomics, and is Professor in the Department of Biochemistry and Molecular Biology at Dalhousie University. He is a Fellow of the Royal Society of Canadaand a member of the US National Academy of Sciences. He received his B.A. in Biochemical Sciences from Harvard College and his Ph.D. from Stanford University. Heundertook postdoctoral work with Sol Spiegelman (University of Illinois) and Norman Pace (National Jewish Hospital and Research Center, Denver). Dr. Doolittle joinedthe Department of Biochemistry at Dalhousie in 1971. Over the years, he has contributed to proof of the endosymbiont hypothesis, development of archaeal genetics,many aspects of prokaryote and eukaryote phylogeny, and the “introns-early” and “selfish-DNA” theories. His laboratory currently employs culture-dependent (multi-locus-sequence-typing) and culture-independent (fosmid-based metagenomic) methods to study recombination and lateral gene transfer in natural populations ofhyperthermophilic bacteria and halophilic archaea.These microevolutionary studies are complemented with phylogenomic bioinformatics approaches to assessing therole of lateral gene transfer in microbial macroevolution and its implications for phylogenetic reconstruction and classification.

Metagenomics will be to Genomics what Genomics has been to Genetics

31

32 Breakfast:Thursday, October 26 | Petit déjeuner : Jeudi, 26 octobre

Joe Ecker

Joseph Ecker earned his Ph.D. in Microbiology at the Pennsylvania State University College of Medicine. He served on the faculty at the University of Pennsylvania (1987-2000) before joining The Salk Institute for Biological Studies (2000) where he is a Professor in the Plant Biology Laboratory and Director of the Salk InstituteGenomic Analysis Laboratory. His research on the gaseous plant hormone ethylene has yielded basic insights into the mechanisms of plant growth control and itsapplication has resulted in technologies that delay fruit ripening and disease processes. His laboratory participated in mapping and sequencing of genome ofArabidopsis thaliana and his group continues to explore the encyclopedia of DNA elements in Arabidopsis through the development and application of technologiesfor genome-wide analysis of plant gene function. In 2006, Professor Ecker was elected to the National Academy of Science and he currently serves as President of theInternational Society for Plant Molecular Biology.

33Session 7

Edna Einsiedel

The production of knowledge is entering a new phase.This is particularlytrue of such areas as genomics which embraces a suite of applications thatembed a host of potential socio-ethical, economic or political-legalproblems.These issues pose challenges for traditional modes of ‘doingscience’. Even before scientific research produces commercializable products

or therapies, such research becomes subjected to social forces andinterests.This evolution of knowledge production in turn challenges thenotion of scientists doing work outside society, dispensing their gifts ofknowledge and wisdom.This presentation will address the implications forscientific work in this new terrain.

Edna Einsiedel is University Professor and Professor of Communication Studies in the Faculty of Communication and Culture at the University of Calgary. Her researchinterests are in the social issues around genomics and biotechnology. She has investigated approaches to public engagement and participation on these technologiesand public representations of science and technology. She is currently co-leader on a GE3LS project (Genomics, Ethics, Economic, Environmental, Legal and Socialstudies) on Genomics Knowledge Translation in Health Systems, supported by Genome Canada. Her research has also been funded by the Social Sciences andHumanities Research Council and the Alberta Heritage Foundation for Medical Research. Her publications have appeared in diverse journals such as Science, NatureBiotechnology, Public Understanding of Science, Science Communication, and Science and Engineering Ethics. She is current editor of the international journal PublicUnderstanding of Science published by Sage.

Bringing Society Back into Science: Opportunities and Challenges

34 Session 4

Ahmed El-Sohemy

Coffee is a major source of caffeine and has been implicated in thedevelopment of cardiovascular diseases. Caffeine is metabolized bycytochrome P450 (CYP)1A2, and the physiological effects of caffeine aremediated through blockade of adenosine receptors (AR). A geneticpolymorphism of CYP1A2 (-163C>A) decreases enzyme inducibilityresulting in slow caffeine metabolism, and a polymorphism in ADORA2A(1083C>T) has been associated with caffeine-induced anxiety. Our objectivewas to determine whether genetic differences in caffeine metabolism andsensitivity modify the association between coffee consumption and risk ofmyocardial infarction (MI). Cases with a first acute non-fatal MI andpopulation-based controls matched for age, sex and area of residence weregenotyped by RFLP-PCR, and caffeinated coffee consumption wasdetermined by food frequency questionnaire. Coffee consumption wasassociated with an increased risk of MI only among those with the low

inducibility CYP1A2 genotype, corresponding to slow caffeine metabolism,suggesting that caffeine plays a major role in this association. AlthoughADORA2A genotype did not modify the association between coffeeconsumption and risk of MI, individuals with the TT genotype for ADORA2Awere found to limit their caffeine intake.These findings suggest that geneticvariation in caffeine metabolism modifies the risk of MI associated withcoffee consumption. Incorporating genetic polymorphisms that affectcaffeine metabolism into nutritional epidemiological studies provides a betterassessment of exposure and helps to improve consistencies among studies.The observed association between genetic variation in caffeine sensitivityand habitual caffeine consumption suggests that ADORA2A genotype may bea genetic confounder in previous studies relating caffeine to various healthoutcomes.

Ahmed El-Sohemy earned is PhD in Nutritional Sciences from the University of Toronto in 1999.After completing his doctoral research in the area of diet and cancer, hereceived a postdoctoral fellowship to study nutritional and molecular epidemiology at the Harvard School of Public Health where his studies focused on the role ofbiomarkers of antioxidants in heart disease. In January 2000 he joined the faculty at the University of Toronto to establish a research program in the area of gene-dietinteractions and chronic disease.The goal of his research is to identify molecular targets of nutrient action and to elucidate the genetic basis for variability in nutrientresponse and selection. He has published several peer-reviewed articles and has given many invited talks on nutrigenomics and molecular nutrition. Dr. El-Sohemy hasconsulted for both industry and government agencies and serves as an ad hoc reviewer for a number of journals, granting agencies and international expert advisorypanels. He also teaches undergraduate courses in Nutritional Toxicology and Functional Foods & Nutrigenomics and supervises several graduate and undergraduatestudents. Dr. El-Sohemy leads the Functional Foods and Nutraceuticals theme of the Advanced Foods and Materials Network, which is one of the Networks of Centres ofExcellence. His research has been funded by the CIHR, NSERC, CFI, OIT and NCE. Dr. El-Sohemy is currently Chair of the Canadian Nutrigenomics Committee ofGenome Canada, and holds a Canada Research Chair in Nutrigenomics.

Genetic Variation in Caffeine Metabolism and Sensitivity and Risk of Myocardial Infarction

35Session 1

Barbara Evans

Genetically targeted drug and biologic therapies place a number of strainson the existing regulatory paradigm for development, validation, approval,clinical introduction, and use of new medical technologies. Many nations relyon pharmaceutical and medical device regulatory frameworks that tracetheir roots to the mid-20th century.These frameworks were designed toaccommodate the therapeutic products, and the primitive science andinformation technology, of that day.This talk explores key problems which, ifnot addressed, may impede the timely development and clinical introductionof genetically targeted therapies. Examples include: (1) legal, regulatory, and

commercial barriers to “successive improvement” of existing drugsthrough improved targeting; (2) legal barriers to cooperative, multi-partydevelopment of targeted therapies; (3) problems assessing the incrementalbenefit of an improved targeting strategy, using traditional drug regulatoryrisk/benefit methodologies; (4) limitations of product labeling as a mediumfor communicating timely, clear information about drug targeting to clinicians;and (5) difficulties defining the appropriate line between regulation ofmedical products and regulation of medical practice, in the case oftargeted therapies.

Dr. Barbara Evans is Director of the Program in Pharmacogenomics, Ethics, and Public Policy at the Indiana University Center for Bioethics. She teaches Law andGenetics and Administrative Law at the IU Law School.

She came to Indiana University in 2004 after a fellowship in clinical ethics at the University of Texas M.D.Anderson Cancer Center. She holds a Ph.D. in earth sciences,with emphasis on natural resource economics, from Stanford University; a J.D. from Yale Law School; and an LL.M. from the Health Law and Policy Institute at theUniversity of Houston Law Center.

As an economist at the World Bank and later as partner in a large international law firm, Dr. Evans has participated in numerous projects to restructure regulatedindustries and create new market structures, both in the U.S. and internationally. She is experienced in pricing and market analysis, design of new service offerings, anddrafting of regulations and contractual agreements to manage the use of shared resources such as electric power pools, data resources, and tissue repositories.

Dr. Evans is licensed to practice law in NewYork and, in addition to her work at IU, she practices law with a focus on U.S. Food and Drug Administration regulatorymatters; regulation of clinical trials and research with human tissues and health data; federal privacy law; and legal issues in protecting and commercializing newmedical discoveries. She currently is a Member of the American Bar Association Special Committee on Bioethics and the Law; a Corresponding Member of the MedicalTechnology Policy Committee of the Institute of Electrical and Electronics Engineers; and a Member of an American College of Medical Genetics committee that isdeveloping practice guidelines for the use of pharmacogenomic information in prescribing decisions.

Regulatory Barriers to Clinical Introduction of Genetically Targeted Therapies

36

The goal of proteomics is to learn protein partnerships in the life of a cell. If thesurfaces of two proteins interact,they are part of a larger macromolecule networkthat may decide cell fate. If a cell has ten thousand active proteins, it may have 10,000active sites but 100,000 interaction surfaces critical to the normal and disease states.Can compounds be found that bind to these surfaces and affect cell fate? If so, thepharmaceutical discovery haystack is vastly greater than is currently searched inResearch and Discovery laboratories.

The male sex steroid, dihydrotestosterone (DHT), regulates the transcription ofhundreds of genes in prostate, brain and muscle.The androgen receptor (AR) is thefirst in a network of proteins that change cell fate according to DHT presentation.AR’s role in prostate development is crucial, and in prostate carcinogenesis, AR is themaster control switch making it the clinical target for treating prostate cancers.

AR is a compelling example of a protein whose surface is its active site. It regulatestranscription of target genes by assembling coregulator proteins on its DHT bindingdomain (LBD) surfaces. DHT binding to the LBD induces structural changes needed

for forming interactions with coactivators and release from corepressors orchaperones. Once bound to AR, coactivators continue assembly of the networkby aiding the formation of multi-protein complexes that link to the transcriptionmachinery.

Three dimesional structures of AR with DHT and coactivators bound defined the ARcoactivator interaction surface, called AF-2. AF-2, is dimorphic.These two versions ofthe interaction site bind to two classes of coactivtors, the first containing thesequence LXXLL, and the second containing the sequence FXXLF.

Two screening technologies were used to search for compounds that bind andcompete with AR coactivator binding.The first, a competition assay, used afluorescent coregulator peptide interacting at the AF-2 site of AR, and the secondused X-ray crystallography to visualize organic molecules that bind at the AR LBDsurface. Seven compounds bind to AF-2, and a new site called BF-3. Competitionassays and biochemistry suggest that the BF3 site may function to loosen binding atthe AF-2 surface which is 10 Å away. All compounds are specific, not binding, to therelated receptor for estrogen and one weakens AR transcription in cell assays.

Haystacks with Drugs

Session 7

Robert Fletterick

Dr. Fletterick received his Ph.D. in physical chemistry from Cornell University, Ithaca, New York.This was followed by an NIH postdoctoral fellowship at Yale in theLaboratory of Professor Thomas Steitz. For the next five years, he taught in the Biochemistry Department of the University of Alberta in Edmonton, during which timehe was a member of the Medical Research Council Group in Protein Structure and Function. Since moving to the University of California at San Francisco in 1979, Dr.Fletterick has taught in the department of Biochemistry and Biophysics and served as Chair from 1982-1985 and Vice-Chair from 1998-2000.As part of the part ofthe UCSF Macromolecular Structure Group, Dr. Fletterick’s lab focuses on structural biology, studying the structure function of nuclear receptors, including those forthyroid hormone and androgen through X-ray crystallography, mutagenesis, cell, biochemical and biophysical assays, and chemistry.The author of numerouspublications, since 1991, Dr. Fletterick has also served on a number of federal and public scientific advisory boards for Spain, Canada, and Taipei. From 1993-1997, hewas a member of the Scientific Advisory Committee of the Cancer Research Fund, Damon Runyon-Walter Winchell Foundation. Sine 1994, he has served on the ProteinS Society Nominating Committee and from 1997-200, he served on the University of California Biotechnology Star Program.

37

Brenton Graveley

Alternative splicing is an important means by which eukaryotes regulate geneexpression and is the primary means of enhancing the diversity of proteins encodedin the genome. One project in my laboratory is aimed at understanding howalternative splicing of the Drosophila Down Syndrome Cell Adhesion Molecule(Dscam) gene is regulated. Dscam encodes a transmembrane receptor that functionsas an axon guidance receptor and plays a role in the immune response of the animal.Amazingly, Dscam can generate over 38,000 different isoforms by virtue of extensivealternative splicing. In fact, the number of proteins generated by this gene is ~2.5times the number of genes in the entire Drosophila genome! We have been makingextensive use of comparative genomics to understand the mechanisms by which thealternative splicing of this intriguing gene is regulated.We have discovered that many

of the alternative splicing events are regulated by the formation of RNA secondarystructures. In one case, we have found that a stem-loop structure we call the iStem isrequired for any of a set of 12 exons to be included.

More interestingly, we have identified a number of intronic sequences that areconserved in all insects, and perhaps all arthropods, that play a key role in ensuringthat only one of 48 exons is included in a strictly mutually exclusive manner.This isthe first case in which comparative genomics alone has led to the discovery of anovel mechanism involved in gene regulation. It was made possible solely by theavailability of the multitude of insect genome sequences. Finally, we have beenextending these analyses to study the evolution and function of this gene.

Brenton R. Graveley is an Associate Professor of Genetics and Developmental Biology at the University of Connecticut Health Center in Farmington, CT USA. Dr. Graveleyobtained his B.A. in Molecular, Cellular and Developmental Biology at the University of Colorado, Boulder where he performed research in the laboratory of Dr. David M.Prescott on DNA rearrangements in the hypotrichous ciliate Oxytricha nova. Dr. Graveley went on to obtain his Ph.D. in the Department of Microbiology andMolecular Genetics at the University of Vermont (Burlington,VT) under the direction of Dr. Gregory M. Gilmartin in the area of mRNA 3’ end formation. For postdoctoralresearch, Dr. Graveley trained under Dr.Tom Maniatis in the Department of Molecular and Cellular Biology at Harvard University (Cambridge, MA) where he studiedthe mechanisms of pre-mRNA splicing regulation. Dr. Graveley’s current research interests include the regulation of alternative splicing in insects and the role ofmicroRNA-mediated gene regulation in regeneration in the planarian Schmidtea mediterranea.

The Insect Down Syndrome Cell Adhesion Molecule (Dscam) Gene:The Making and Function of 38,000 Isoforms

Session 5

38 Session 1

Michael Hayden

Objectives:

1. to understand how varieties in genes become disease

2. understanding approaches to drug development based on genetics

3. the importance of phenotype & the clinician in choice of trait to be studied

Michael Hayden is a full professor of Medical Genetics at the University of British Columbia and the Director of the Center for Molecular Medicine and Therapeutics inVancouver. Dr. Hayden has served as Chief Scientific Officer for Xenon Pharmaceuticals Inc. since March 1999 and been a member of the Board since November 1996.

Author of over 400 peer-reviewed publications and 150 invited submissions, Dr. Hayden focuses his research primarily on genetic diseases. Dr. Hayden played a key rolein the development of predictive testing for Huntington's disease (HD) and his research group was instrumental in the demonstration of proteolytic cleavage ofHuntington, contributing to the understanding of HD pathogenesis.

The recipient of numerous prestigious honors and awards, Dr. Hayden was elected to the American Society of Clinical Investigation in 1992, the Board of the AmericanSociety of Human Genetics in 1994 and the Royal Society of Canada in 1995.Among his most recent awards are the 2003 Henry Friesen Award of the Royal College ofPhysicians and Surgeons of Canada, the 2001 Award of Excellence of the Genetics Society of Canada and the Ottawa Life Sciences Award of Merit. He also received the1998 Distinguished Scientist Award of the Canadian Society of Clinical Investigation and the 2000 BC Biotechnology Alliance Award for Vision and Leadership.

Dr. Hayden received his medical training (1975) and his PhD in Genetics (1979) from the University of Cape Town. He completed a post-doctoral fellowship and furthertraining in Internal Medicine at Harvard Medical School.

Genetics and Drugs: How Genetic Variations Leads to New Approaches to Therapy

39Session 4

Robert Hegele

A well-worn aphorism in medicine is that “the zebra can teach you aboutthe horse”. Evaluation of rare monogenic forms of complex diseases canhelp to understand common “garden variety” phenotypes.We have usedthe candidate gene approach to solve the genetic basis of several metabolicdiseases that are associated with increased risk of atherosclerosis, whichleads to most cases of heart disease and stroke in Canada. For instance, wefound that heterozygous familial hypercholesterolemia in Ontario resultsfrom >50 mutations in the LDLR gene and that ~30% of these are of the“copy number variant” type; furthermore, the mutation type correlates withseverity of the clinical and biochemical phenotype.We also identifiedmutations in genes encoding intestinal sterol transporters in families withearly heart disease; identification of these pathways has helped to define

new molecular targets for drugs to lower blood cholesterol in the generalpopulation. Also, we have studied families with an inherited form of diabetescalled partial lipodystrophy. Because lipodystrophic patients have insulinresistance that progresses to type 2 diabetes, these disorders are monogenicmodels for the commonly occurring cardiometabolic syndrome of abnormalblood sugar, blood lipids and blood pressure.We found the causative genesfor three subtypes of partial lipodystrophy: two of these genes encodenuclear lamins while the third encodes the nuclear hormone receptorPPAR-gamma. Systematic phenomic evaluation of molecularly characterizedsubjects has helped to define distinct stages of disease evolution, which inturn has helped to understand the development of common “garden-variety” type 2 diabetes.

Dr. Hegele received his MD (Honours) in 1981 from the University of Toronto, with speciality training in Internal Medicine and certification in Endocrinology and Metabolism.After post-doctoral research fellowships at Rockefeller University (New York) and Howard Hughes Medical Institute (Salt Lake City), he joined the University of Toronto. In 1997he joined Robarts Research Institute, becoming Professor of Medicine and Biochemistry at the University of Western Ontario (London, Canada). He holds the E.S Vinet CanadaResearch Chair in Human Genetics and the Jacob Wolfe Chair in Functional Genomics at the Schulich School of Medicine, University of Western Ontario.

He directs a tertiary referral lipid clinic. His laboratory studies atherosclerosis and metabolic disorders in Canadian sub-populations, and has discovered the molecular geneticbasis of 9 human diseases, including hepatic lipase deficiency, Oji-Cree type 2 diabetes and 3 forms of partial lipodystrophy. He has published more than 270 original scientificarticles and 60 reviews and book chapters.

In 2001, he was elected to the American Society for Clinical Investigation and his studies of monogenic insulin resistance were judged a “Top 10 Scientific Advance” by theAmerican Heart Association. He has received the Joe Doupe Award from the Royal College of Physicians and Surgeons (Canada), the Canadian Diabetes Association Top ScientistAward, the Haynes and Moen Award from the Genetic Society of Canada and the American Heart Association’s JM Hoeg Award for Basic Science and Clinical Research.

Genomics of Metabolic Disease in Vulnerable Families and Communities

40 Session 5

Hans Hofmann

The work in my lab aims to understand the physiological and molecularunderpinnings of social behaviour and its evolution.We study cichlid fishesfrom Lake Tanganyika in Africa, using experimental approaches ranging fromobservations in the lake to functional genomic analyses in the laboratory.Because of their complex but tractable behaviour, diverse reproductivephenotypes and accessible physiology, cichlids are an excellent modelsystem for evolutionary neurobiology.

We have developed EST and microarray resources for cichlids and haveused expression profiling in the brain to characterize the molecularsubstrates of social organization within and across species. For example, inthe African cichlid fish Astatotilapia burtoni, transitions between dominancestates depend on social cues and are frequent, reversible and accompaniedby changes in behaviour, physiology and neural structure and function. By

analyzing the covariance structure between gene activity and phenotypictraits, we have found that numerous clusters of co-regulated genes areassociated in a modular fashion with specific phenotypic traits, such as socialdominance, reproductive maturity or stress response.

We are also applying this strategy to the species-rich and monophyleticgroup of Ectodini cichlids, where we have previously found significantdifferences in behavioural patterns and brain anatomy related to socialorganization. Ectodini have undergone several independent transitions frommonogamy (with biparental care) to polygamy (with maternal care) andtherefore, represent an ideal model system to study the molecular basis ofsocial evolution.

Supported by NIH-NIGMS and NSF.

Dr. Hans Hofmann studied biology at the University of Würzburg, Germany, and obtained an MS degree in animal physiology in 1993 from the University of Tübingen,Germany. His master’s thesis used a systems biological approach to analyze visual landmark orientation in mosquitoes. For his doctoral studies, which he conducted atthe Max-Planck-Institute at Seewiesen, Germany, and at the University of Leipzig, Germany, he examined the neural basis of aggression in insects and how the socialenvironment controls its occurrence. He was awarded a Ph.D. in biology in 1997 from the University of Leipzig. Dr. Hofmann spent then several years as a postdoctoralresearcher at Stanford University, where he conducted ground breaking work showing that social context regulates somatic growth in cichlid fishes and how theneuropeptide somatostatin might control both growth and social dominance behavior. In 2000, Dr. Hofmann was awarded a prestigious Grass Foundation Fellowship inNeuroscience, which allowed him to pursue his research at the Marine Biological Laboratory in Woods Hole, MA. From 2001 to 2006 Dr. Hofmann was a BauerGenome Fellow and principal investigator at Harvard University. During his time at Harvard, he created a multitude of genomic resources for cichlid fishes andpioneered the genomic and systems biological analysis of socially controlled behavior within an organismic framework. Dr. Hofmann is now an Assistant Professor ofIntegrative Biology at the University of Texas at Austin.

Fish and Chips:An Integrative Approach to Understanding Social Dominance

41Lunch :Wednesday, October 25 | Déjeuner : Mercredi, 25 octobre

Thomas J. Hudson

Dr.Thomas J. Hudson is founder and Director of the McGill University and Genome Quebec Innovation Centre and past Assistant-Director of the Whitehead Institute/MIT Center forGenome Research. Dr. Hudson is internationally renowned for his work in Genomics.At the Whitehead Institute, Dr. Hudson led the effort to generate dense physical and gene mapsof the human and mouse genomes. He is a leader in the development and applications of robotic systems and DNA-chip based methodologies for genome research. In June 1996,he founded the Montreal Genome Centre based at the McGill University Health Centre Research Institute. In 2003, this group expanded to become the McGill University andGenome Quebec Innovation Centre. Hudson and his team were founding members of the International Haplotype Map Consortium. Dr. Hudson’s interests in human genetic diseasesfocus on the dissection of complex genetic diseases. Ongoing disease projects in Dr. Hudson’s laboratory include the search for genes predisposing to lupus, inflammatory boweldisease, coronary artery disease, asthma, diabetes and colon cancer.The laboratory is also using the DNA-chip technology in order to characterize breast and ovarian cancer.

Dr. Hudson is editor-in-chief of the journal Human Genetics. Dr. Hudson teaches in the departments of Human Genetics and Medicine at McGill University and practices medicineat the McGill University Health Centre – Montreal General Hospital (Division of Immunology and Allergy). He has received numerous awards, including the 2005 Achievement of theYear in Healthcare from Maclean’s magazine, the 2005 Award for Research in Immunology by the Canadian Society for Allergy and Clinical Immunology, the André-Dupont 2002Young Investigator Award given by Quebec’s Clinical Research Club, an Investigator Award from the Canadian Institutes of Health Research, a Burroughs-Wellcome Clinician-ScientistAward,The 2002 Prix de la Santé from the Armand-Frappier Foundation, the 2001 Young Scientist Award by the Genetics Society of Canada, the 2000 Scientist of the Year by Radio-Canada, the 1999 Canada Top 40 Under 40, and more.

42 Session 7

Timothy Hughes

A central challenge in understanding how a genome functions is to explainthe causes of gene expression patterns in terms of specific combinations ofcis-regulatory elements and trans-regulatory factors.There are indications thatthis goal is attainable in yeast, which has ~200 transcription factors and one ora few conserved elements in the promoter of each gene. However,vertebrate genomes encode >1,500 DNA-binding transcription factors, andcontain roughly one million nonexonic elements that represent candidate cis-regulators – the total sequence of which exceeds that of all known exons.Precise binding specificity is known for only a minority of the transcriptionfactors.An even smaller minority of the conserved elements have beenassociated with a known or putative binding factor.Thus, we are unable toread the vast majority of the vertebrate genetic “code”.This problem isfurther compounded by the requirement that vertebrate transcription factorsgenerally must work in combination with each other to achieve specificity.Atpresent, it is extremely difficult to explain, on the basis of sequence, why somegenes are regulated in a certain way while others are not.

We are taking two general approaches towards generating new laboratorydata that we believe will aid in decoding the vertebrate “regulome”.The firstis a brute-force attempt to determine the DNA-binding specificity of asmany transcription factors as possible in the mouse, which we believe willenable us to classify potential cis-regulatory elements and determine whichcombinations are predictive of observed gene expression patterns.Thesecond approach is to examine the phylogeny of gene expression patterns,in an attempt to take advantage of the fact that both cis-regulatoryelements and gene expression patterns display varying degrees and varyingpatterns of conservation among vertebrate species, in order to formulaterules that dictate vertebrate gene expression. Although both of theseprojects are still in progress, both of them are feasible and productive,indicating that this work will greatly enhance our understanding of theactivity and evolution of vertebrate transcriptional regulatory networks.

Timothy R. Hughes is a Professor in the Banting and Best Department of Medical Research at the University of Toronto. He holds a Canada Research Chair inFunctional Genomics and was the recipient of the 2005 NCIC Terry Fox Young Investigator Award. Dr. Hughes studied engineering and music at the University of Iowa,and received his Ph.D. in Cell and Molecular Biology from Baylor College of Medicine. He did his postdoctoral work at Rosetta Inpharmatics (now Merck), where heplayed a key role developing ink-jet microarrays now marketed by Agilent Technology, and showed that microarray expression patterns can be used to correctly inferfunctions of novel genes. After moving to Toronto in 2001, Dr. Hughes has continued to pioneer techniques and applications in functional genomics, microarray analysis,RNA processing, and gene regulation. His laboratory is currently exploring genome function in organisms encompassing yeast, drosophila, frog, mouse, chicken,and pufferfish.

Decoding the Vertebrate Regulome

43Lunch :Thursday, October 26 | Déjeuner : Jeudi, 26 octobre

Fotis C. Kafatos

Fotis C. Kafatos was born in Crete, Greece, where he received his primary and secondary education. He graduated from Cornell University with a bachelor’s degree with high honoursand earned his Masters and PhD degrees (1965) in biology from Harvard. He became the youngest full Professor at Harvard in 1969, serving until 1994. In parallel, he promotedtraining and development of the life sciences in Greece, holding adjunct professorships at the University of Athens (1972-1982) and the University of Crete (1982—now, currently onleave). His institution-building activities included founding and directing the Institute of Molecular Biology and Biotechnology at the Research Centre of Crete from 1982 to 1993. Heserved two successful terms (1993-2005) as Director-General of the European Molecular Biology Laboratory (EMBL), the top leading molecular biology laboratory in Europepromoting new approaches to Biology and the development of research infrastructures in Europe. In the 1960’s Kafatos was one of the scientists who introduced molecular biology tothe study of development. He helped develop fundamental techniques such as cDNA synthesis, cloning and sequencing (the beta globin gene) and invented the dot-blot, the precursorof DNA microarrays. He pioneered the analysis of gene families in development and evolution (chorion gene families), helped launch the Drosophila and Anopheles genome projects,and made important contributions to comparative and functional genomics. His current scientific work is on malaria research with emphasis on mosquito genomics and immunity ofAnopheles to the Plasmodium parasite. He is active in efforts to promote research and scientific education in the developing world. His professional activities include service on theadvisory boards of distinguished scientific centres and organisations, in several countries of Europe and abroad. He is the recipient of numerous honours including five honorarydoctorates. He is a Foreign Member of the Royal Society of London and the French Academy of Sciences, and Member of the US National Academy of Sciences, the AmericanAcademy of Arts and Sciences, the Pontifical Academy of Sciences, EMBO and Academia Europea. In 2005, he was elected as Chairman of the ERC Scientific Council.

44 Session 6

Rachel Karchin

DNA variation that results in a single amino-acid residue change in theprotein product of a gene (missense mutant) may have a major impact onan individual’s susceptibility to disease and sensitivity to drugs. Many suchvariants occur at very low population frequencies, thus case/control andfamilial cosegregation studies are not sufficiently powered to discriminatebetween those which are pathogenic/high clinical significance and those ofneutral/low clinical significance. A promising alternative approach is tointegrate information derived from computational biology with clinicalpatient data and functional studies.

I will describe work that applies protein homology modeling, sequenceanalysis, and machine learning to predict and rationalize the impact ofmissense mutations on protein stability and function.These predictions cancomplement information from patient pedigrees and help make sense ofthe results of functional assays. I will also discuss how the process can beautomated and applied to large-scale datasets.

Making Sense of Point Mutants that Impact Protein Function

Positions2006-present Assistant Professor, Biomedical Engineering

Johns Hopkins, Baltimore, MD2003-2006 Postdoctoral Scholar, Biopharmaceutical Chemistry

University of California, San Francisco1999-2003 Graduate Research Assistant, Computational Biology

University of California, Santa Cruz1998-1999 Technical Scholar, Center for Applied Scientific Computing

LLNL, Livermore, CA

Education/TrainingUniversity of California, San Francisco Postdoc 2003-2006 Computational BiologyUniversity of California, Santa Cruz Ph.D. 2003 Computer ScienceUniversity of California, Santa Cruz M.S. 2000 Computer ScienceUniversity of California, Santa Cruz B.S. 1998 Computer Engineering

Honors/Awards1998 Highest honors and comprehensive honors in the majorChancellor’s and Dean’s Undergraduate Research AwardsUniversity of California, Santa Cruz1998-2003 National Physical Science Consortium Pre-Doctoral Fellowship2004-2006 NIH Ruth L. Kirschstein National Research Service Award

45Session 4

Jane Kaye

The developments in genomic analysis and computer technology have leadto a greater ability to process, interrogate and analyse DNA samples andpersonal data in large data-sets, have had considerable benefits forpopulation genetics.The scientific benefits of data sharing has lead toconsiderable investment by funding bodies, to establish new genomicresources that can be used by all, but also to develop the means to link andshare existing collections. Data sharing policies have been put in place bymajor funding bodies, such as the NIH, the European Commission, and theMRC (UK) as a requirement of funding.The rationale behind such initiativesis to utilize publicly-funded research data to its fullest extent, by opening upsuch collections to other researchers, thereby reducing unnecessary

duplication of data-sets, enabling new lines of enquiry and speeding up theprocess of knowledge production. However these requirements haveimplications for the present practices of scientists, such as how to protectthe privacy rights of the data providers, standardise procedures, ensuringtrust between researchers, publishing acknowledgements, andapportionment of intellectual property rights. Using Europe as a casestudy, the purpose of this paper is to outline some of the legal obstaclesand issues that arise out of the sharing of samples and data, in order to hi-light areas of the law that need development and require furtherpolicy consideration.

Jane Kaye is the Research Fellow in Law at the Oxford Genetics Knowledge Park (OGKP) based at the Ethox Centre, University of Oxford. She obtained her degreesfrom the Australian National University (B.A); University of Melbourne (L.L.B); and University of Oxford (D.Phil). She was admitted to practice as a solicitor/barrister bythe Australian Capital Territory Supreme Court in 1997. She is a member of the Faculty of Law, University of Oxford and has taught the Bachelor of Civil Law Masterscourse on Regulation at the University of Oxford.

Her research in the area of law and genetics focuses on the development of innovative technologies and the legal issues of privacy, confidentiality, data protection andnegligence, as well as the broader issues of the public interest, governance and regulation. Her socio-legal research is based on issues that have implications for practice,which is a result of working in a multi-disciplinary team consisting of clinicians, epidemiologists and other researchers. She has carried out research on the IcelandicHealth Sector Database; lead the Law Team of an EC Framework 5 project called ELSAGEN (The Ethical, Legal and Social Aspects of Human Genetic Databases: AEuropean Comparison); and has recently been awarded a Wellcome Trust grant (with Dr. Andrew Smart and Prof. Mike Parker of the Ethox Centre) for a project called‘Governing Genetic Databases’. She has been involved in a number of expert committees focusing on the issues surrounding biobanks within Europe.

Networking and Sharing Genomic Resources—A Legal Quagmire?

46 Session 5

Manolis Kellis

Manolis Kellis is a Distinguished Alumnus (1964) of the Massachusetts Institute of Technology and holder of a Career Development Professorship. He is an AssistantProfessor, at the MIT Department of Electrical Engineering and Computer Science (EECS), Principal Investigator, Computer Science and Artificial Intelligence Laboratory(CSAIL) and an Associate Member, Broad Institute of MIT and Harvard (Broad). His master’s thesis was on image interpretation and retrieval, with Patrick Winston andhe completed his Ph.D. on computational genomics, with Eric Lander and Bonnie Berger. His primary research interests are in Computational Biology. Currently, theKellis group is developing new algorithms and machine learning techniques for the interpretation of complete genomes, the understanding of gene regulation, and theelucidation of evolutionary mechanisms and embryo development. I In addition, he is involved in various research projects in Machine Learning, ComputationalGeometry, Robotics, and Information Retrieval.

The fruit fly Drosophila melanogaster provides an important model for animal biologyand development, combining the complexity of bilateral animals and the powerfulgenetics of small eukaryotes.The recent community effort to sequence, assemble, andalign 12 species of Drosophila is providing this model organism with the richestcomparative genomic dataset of any eukaryote, enabling unprecedented opportunity forcomputational signal discovery.

We have undertaken a comparative analysis of these genomes for the de-novodiscovery of genes, regulatory motifs, microRNAs, gene targets, and enhancer elements.By studying the conservation properties of known functional elements, we defineevolutionary signatures, specific to each type of functional element and dictated by theprecise selective constraints that it evolves under.We have used such signatures to refinethe annotation of existing elements, reveal hundreds of new functional elements, andstudy the evolutionary dynamics of gene families across the twelve species.

For gene identification, our comparative analysis has allowed us to pinpoint genes andexons with very high accuracy.This has allowed us to revisit the D. melanogaster genomeannotation with surprising results: hundreds of previously defined gene models appearspurious, reducing the overall gene count; at the other end of the conservationspectrum, we find thousands of new exons, representing novel multi-exon genes, novel

alternatively spliced gene forms, and many high-confidence isolated exons.We are usingRT-PCR to confirm these novel genes and exons. For proposed changes andinvestigation of dubious genes, we are collaborating with FlyBase curators to produced arevised fly gene catalogue.

To understand gene regulation, we searched for repeated, conserved sequence patterns,resulting in a dictionary of candidate regulatory motifs in the fly. Motifs in promoterregions overlap strongly with known bindings sites of developmentally importantregulators, and numerous novel motifs show enrichment in genes with coordinatedtissue-specific expression. Motifs in 3’-UTRs correlate strongly with known microRNAgenes, and led to the discovery of several novel microRNA genes. Moreover, with 12aligned fly genomes, we can pinpoint individual motif instances with high confidence,enabling us to reliably identify target genes, combinatorial patterns of motif usage, novelenhancer elements, and networks of gene regulation.

The combination of classical genetics, systematic experimentation, embryo visualization,and powerful genomics in the fly are bringing us closer than ever to a globalunderstanding of genome biology in an animal genome.These approaches are general,applicable to a wide range of species, and will likely prove invaluable in the understandingof the human genome.

The Comparative Analysis of Insect Genomes

47Session 4

Juha Kere

Asthma is defined as a reversible constriction of the airways, associated withlocal inflammation and chronically, permanent structural changes in thebronchial walls. Studying samples from families recruited in Kainuu, a largerural province in Eastern Central Finland, and in the Saguenay-Lac-St-Jeanregion in Northeastern Quebec (in collaboration with Dr.T. Hudson), wewere able to map a locus for asthma-related traits to chromosome 7p15(Laitinen et al. 2001) and then, by genetic association mapping, positionallyclone the gene (Laitinen et al. 2004).We implicated a new G proteincoupled receptor gene, named GPRA (now called NPSR1) in thepathogenesis of asthma. Association analyses employing the Finnish, theFrench Canadian and a second Finnish sample set supported the associationof risk-SNPs with high IgE or asthma in all three populations.Immunohistochemical stainings suggested that a specific protein isoform,

GPRA-B, was aberrantly expressed in asthmatic airways as compared tohealthy bronchus.Taken together, these results supported GPRA as a novelgene involved in pathogenetic processes in asthma, a finding now supportedby at least four independent replications in altogether six European and aChinese population. A peptide ligand, Neuropeptide S (NPS), was identifiedas a rat arousal and anxiolytic peptide activating GPRA (Gupte et al. 2004,Xu et al. 2004). More recently, we have excluded GPRA as a susceptibilitygene for atopic eczema, but implicated it in respiratory distress syndromeand inflammatory bowel disease. GPRA plays a role in several cell types,including macrophages and other immune system cells, and NPS stimulationcan modulate macrophage functions. Studies on cell models have allowed usto identify downstream target genes for the NPS-GPRA pathway, triggeringfurther gene-gene interaction studies.

Professor Juha Kere received his M.D. (1984), Ph.D. (1989) and specialty in clinical genetics (1994) from University of Helsinki, Finland. He holds currently the positionsof Professor of Molecular Genetics and Scientific Director of KI Biobank at Karolinska Institutet, Stockholm, Sweden. He has also appointments as Chief Physician ofMolecular Genetics at Karolinska University Hospital, Huddinge, and Investigator at Biocentrum Helsinki and Center of Excellence for Disease Genetics at University ofHelsinki. Dr Kere supervises research groups at both Karolinska Institutet and University of Helsinki. Prior to these positions, Dr Kere was the founding Director ofFinnish Genome Center at University of Helsinki (1998-2001), and served as Professor of Medical Genetics at the Universities of Helsinki and Turku, Finland. During1990-1993, Dr Kere was postdoctoral research associate at Washington University, St. Louis, Missouri. Dr Kere has coauthored over 200 original research articles. Hiscurrent research focuses on common, complex diseases.

The NPS-NPSR1 Pathway in Asthma: From Positional Cloning to Mechanisms

48 Banquet:Thursday, October 26 | Jeudi, 26 octobre

Stephen Lewis

Stephen Lewis, recently named McMaster University’s first Social Science Scholar-in-Residence, has an outstanding history as a diplomat and a humanitarian. He hasbeen the United Nations’ Special Envoy for HIV/AIDS in Africa since 2001. He is also a Commissioner for the World Health Organization’s Commission on the SocialDeterminants of Health, and a Senior Advisor to the Mailman School of Public Health at Columbia University in New York. In addition, Mr. Lewis is a director of theStephen Lewis Foundation, which is dedicated to easing the pain of HIV/AIDS in Africa. For eight years in the 1960s and 1970s he led the Ontario New DemocraticParty during which time he became leader of the Official Opposition. He later served as Canadian Ambassador to the United Nations, and as the Deputy ExecutiveDirector of UNICEF in New York. Mr. Lewis is a Companion of the Order of Canada, the 2004 recipient of the Pearson Peace Medal for outstanding achievement inthe field of international service and understanding from the United Nations Association in Canada and in 2005, was named by TIME magazine as one of the100 most influential people in the world. In 2006, Mr. Lewis’ best-selling book, Race Against Time, received the Canadian Booksellers Association’s Libris Award fornon-fiction book of the year.

49Session 3

Cheng Lu

Small RNAs play important regulatory roles in most eukaryotes, but only afew of these molecules have been identified. In collaboration with Solexa,Inc., we sequenced more than two million small RNAs from seedlings andthe inflorescence of Arabidopsis. Known and new microRNAs (miRNAs)were among the most abundant of the nonredundant set of more than75,000 sequences, whereas more than half of them represented lowerabundance small interfering RNAs (siRNAs). By applying this technology torice, we have found that the small RNA profile of this organism is far morecomplex. Nearly 150,000 different sequences were found in a small RNA

library made from rice flowers. Similar to Arabidopsis, the nonredundant setof rice seedling (leaf) small RNAs is much less complex than flowers.Further analysis of the rice small RNA sequences will be described.We willcompare our findings with rice to that of Arabidopsis to identify thefeatures that differ between, or are common to these plants.We will alsocompare the expression pattern of small RNAs across samples representingdiverse rice tissues and treatments based on the normalized data.This workshould provide insights about the importance of small RNAs relevant tocereal crops and plants in general.

After receiving his Masters degree in plant molecular biology at Peking University in China, Dr. Lu obtained his doctorate in plant physiology in 2002 from PennsylvaniaState University. Since then he has been a postdoctoral scholar working with Dr. Pam Green at the Delaware Biotechnology Institute of the University of Delaware onRNA aspects of the gene family in Arabidopsis. He has published a number of papers in various journals and been invited to speak at international conferences inthe United States and France.

Analysis of the Small RNA Component of the Rice and Arabidopsis Transcriptomes

50 Session 1

Michael Phillips

Dr. Michael S. Phillips, Ph.D. is the Director of Pharmacogenomics at Genome Quebec in Montreal. He is also an Associate Professor in the faculty of Medicine at theUniversity of Montreal and the Director of the Pharmacogenomics Centre at the Montreal Heart Institute.The Pharmacogenomics Centre is a cutting GLP clinicalgenotyping laboratory that is supporting clinical trial work and consists of two parallel components: a technology development platform and a clinical operationsplatform. His studies are concentrating on the development and the implementation of genomic technologies into healthcare. His main focus is in the area ofpersonalized medicine offering specialized pharmacogenomics services and technologically advanced tools to clinical, industrial and academic projects. Previously,Dr. Phillips was an associate director in the department of Pharmacogenetics at Orchid BioSciences, Inc. in Princeton NJ, a biotechnology company providing products,services and technologies for SNP scoring and genetic diversity analyses.While at Orchid, Dr. Phillips worked on pharmacogenomic screens for personalized medicine, ledOrchid’s contribution to The SNP Consortium (TSC) and produced the first detailed haplotype map of chromosome 19. Prior to joining Orchid BioSciences, Dr. Phillipsworked at Merck Research Laboratories,West Point, PA, with Dr. C.Thomas Caskey in the Department of Human Genetics, where he worked on Type 1 Diabetes andvarious pharmacogenetic projects. He obtained his Ph.D. from the University of Toronto, concentrating on the understanding and analysis of the gene responsible for theanesthetic induced pharmacogenetic condition of malignant hyperthermia.

It is commonly accepted in the medical community that no drug works well for allpatients. Some of the differences in how individuals respond to a drug are due topersonal characteristics such as their age, size and gender, however, it is estimatedthat half of all variation in drug response can be attributable to the geneticdifferences found within patient populations. Recent advances in pharmacogenomicsshow that screening patients for genetic biomarkers can significantly improvetherapeutic outcomes for specific medications. By integrating new technologies forpredictive biomarkers, specifically high throughput genotyping and proteomicmethods, into the clinical environment, physicians will have access to tools that will bepredictive of a person’s response to a drug. Ultimately, this will lead to new guidancefor physicians resulting in improved drug selection and dosing.

Increasingly, pharmaceutical companies are starting to integrate pharmacogenomicsinto their drug development pipelines.They are primarily studying the effects of genesand proteins involved in drug metabolism, transport, and response on the

effectiveness and safety of their new compounds.These investigations are intended toidentify, during early stage development, genomic and proteomic predictivebiomarkers that can be used to address optimal dosing, adverse events and drugselection for a given patient population.The promise of using genomic and proteomicsignatures to better evaluate a clinical trial population has the potential to optimizetrial designs by reducing the size of the phase III patient populations, to improveefficacy by targeting the right patient with the right dose, to reduce unwanted safetyconcerns by avoiding problematic patients and to bring back drugs that did not makeit to market because of efficacy and safety problems.These approaches are quicklygaining increased acceptance within the pharmaceutical and biotech communities andare being advocated by the FDA.The integration of pharmacogenomics into drugdevelopment can ultimately have the effect of saving on costs, producing safer andmore effective medications that will be targeted to the correct patient populations.

Pharmacogenomics: Paving the Way to Improved Drug Development and Healthcare

51

Michael D. Purugganan

Domestication is the most important human technological innovation, and canprovide insights into the origin of new species.We have conducted a genome-widesurvey of patterns of DNA sequence variation in domesticated Asian rice (Oryzasativa), one of the oldest and most widely cultivated crop species, and its wildancestor, O. rufipogon. This pattern allows us to reconstruct, in part, the evolutionaryhistory of domesticated rice and the dynamics of the evolutionary process. Moreover,

we are able to scan localized genome regions to identify signatures of positiveselection that may lead us to genes that were the targets of the domesticationprocess. Evolutionary genomics provides a powerful framework for dissecting theevolution of plant species, and provide key insights into the nature of theevolutionary forces that accompany species diversification.

Dr. Michael Purugganan received his B.S. in Chemistry from the University of the Philippines (1985), an M.A. from Columbia University (1986) and a Ph.D. in Botanywith a Global Policy minor at the University of Georgia (1993). After obtaining his Ph.D., he did postdoctoral research as an Alfred P. Sloan Molecular Evolution Fellowat the University of California in San Diego, studying the evolution of development (1993-1995). Dr. Purugganan is a leader in the field of Evolutionary and EcologicalGenomics and his work focuses on identifying the molecular basis for evolutionary adaptations that occur in nature. Prior to joining the NYU faculty in 2006, he wasthe William Neal Reynolds Distinguished Professor of Genetics at North Carolina State University, where he also won the Outstanding Faculty Research Award and theSigma Xi Research Prize. He has authored over sixty peer-reviewed publications, including papers in Science, Nature, Genetics, and the Proceedings of the NationalAcademy of Science. He is the recipient of an Alfred P. Sloan Foundation Young Investigator Award (1997-2002), a Guggenheim Fellowship (2006-2007) and in 2005was elected a Fellow of the American Association for the Advancement of Science. He is the PI on several multimillion-dollar genome grants from NSF for his researchon rice and Arabidopsis genomics. He is a member of The Faculty of 1000, and Associate Editor of Molecular and Developmental Evolution and Molecular Ecology.

The Evolutionary Genomics of Domesticated Asian Rice

Session 3

52

Allen D. Roses

Allen D. Roses, MD, FRCP (Hon) was appointed as Senior VP for Genetics Research in GlaxoSmithKline in 2000. In 1997, Dr. Roses joined Glaxo Wellcome and wascharged with organizing genetic strategies for susceptibility gene discovery, pharmacogenetics strategy and implementation, and integration of genetics into medicinediscovery and development. In the GSK R&D structure, genetics, genomics, proteomics and bioinformatics are part of Genetics Research and support the entire R&Dpipeline. His group recently published the proof of principle experiments for using linkage disequilibrium mapping to identify susceptibility loci for drug adverse events.In 1997 when he left Duke University Medical Center, Dr. Roses was the Jefferson Pilot Professor of Neurobiology and Neurology, Director of the Joseph and KathleenBryan Alzheimer’s Disease Research Center, Chief of the Division of Neurology, and Director of the Center for Human Genetics. Dr. Roses was one of the first clinicalneurologists to apply molecular genetic strategies to neurological diseases. His laboratory at Duke reported the chromosomal location for more than 15 diseases,including several muscular dystrophies and Lou Gehrig’s disease. He led the team that identified APOE as a major, widely-confirmed susceptibility gene in common late-onset Alzheimer’s disease.Translation of these findings to pathway analyses, drug discovery and development has continued in GSK.

Lunch : Friday, October 27 | Déjeuner :Vendredi, 27 octobre

53

Allen D. Roses (cont’d)

Pharmacogenetic analyses at appropriate times for adverse events and efficacy areused throughout the R&D pipeline. Patients are consented for blood for PGX andbiomarkers in Phase I through Phase III clinical trials. Starting in 2006 all Phase IVVclinical trials will also be consented for PGX. Examples will be presented of mild AEanalyses during Phase I, IIA, generation of markers for efficacy in Phase IIA, safetyPGX during a Phase III clinical trial, and conformation of predetermined PGXbiomarkers in Phase IIB leading to a major affect on attrition of a drug to treat mildto moderate Alzheimer’s disease and conformational of a mitochondrial hypothesisfor AD.

Apolipoprotein E4 is associated with lowering the age of onset distribution ofcommon, late-onset Alzheimer’s disease [AD]. Originally identified by linkage onchromosome 19 and examined as a candidate gene, APOE4 has now been highlyassociated with AD [p < 3.8E-6] in a multi-candidate gene study of 1651 genes and5400 SNPs, involving 465 AD patients and 468 matched controls recruited from anine center Canadian consortium.This was the preliminary analysis of more than1,000 AD patients and controls recruited for genome-wide SNP linkagedisequilibrium association analysis. Similar clinical association studies are underway in18 complex diseases with greater than 1,000 patients and 1,000 controls in each. In1996-1998 we initially studied the role of apoE4 in brain metabolism using APOEknock-out and humanized APOE-transgenic mice to determine which metabolicpathways were affected in brain.We found that enzymes involved in glucoseutilization, particularly those involved in the Krebs cycle and those enzymesconstituted by using mitochondria coded sub-units were either over- or under-expressed in proteomic experiments with APOE knock-out mice. Using glucose-

stimulated thermogenesis we confirmed that brain homogenates of APOE KO andAPOE4 transgenic mice had a decreased glucose utilization that could be stimulatedby PPARÁ agonists in a dose-dependent manner.The emergence of positronemission tomography data demonstrating that patients with AD had decreased brainregion-specific glucose utilization and that this identical distribution was observed inyoung normal APOE4 carriers, decades before the age of onset of AD.These dataprovided the impetus for studying PPARÁ agonists. Rosiglitazone was approved as atreatment of type 2 diabetes mellitus in 1999 and is now widely prescribed. Becauseof its well established safety profile, clinical trials were initiated. In a 24 week doubleblind Phase IIB monotherapy trial of 511 patients, there was no demonstrated effectof rosiglitazone on the ADAS-cog or other clinical measures of cognitiveimprovement in mild to moderate AD patients.This was due to the heterogeneity ofAD patients and their responses.When these clinical trial data were stratified bypatients carrying one or two APOE4 alleles versus patients carrying no APOE4 allele,there was statistically significant improvement in the cognitive scores in the patientswho carried no APOE4 allele in all three doses tested. A possible dose effect wasalso observed in carriers of APOE4, with the lowest dose deteriorating and somepositive effect at the higher doses, although not to the level of improvementobserved in APOE4 non-carriers.Thus, what would have been a negative clinical trial[and another attrition statistic!] progressed to a Phase III registration program basedon the inheritance of a confirmed, associated susceptibility biomarker incorporatedinto a pharmacogenetic analysis of the clinical trial data.

Risner er at., Efficacy of Rosiglitazone in a Genetically Defined Population with Mild-to-Moderate Alzheimer’s Disease.The Pharmacogenomics Journal, 2006, in press.

Drug Development with Pharmacogenetics in 2006

Lunch : Friday, October 27 | Dejeuner :Vendredi, 27 octobre

54 Session 1

Stephen Scherer

Autism is a neurodevelopmental disorder characterized by impairments insocial-communication and by a preference for repetitive activities. Autism,which begins in early childhood and persists throughout adulthood, affectssome 105,000 individuals in Canada.With about 3,000 new cases identifiedeach year, it is more common than Down syndrome, cerebral palsy, andjuvenile diabetes. Moreover, the number of children receiving diagnosis hasrisen as much as 400% in the last decade. Autism research has consumedpublic interest of late, due to significant press around deficient diagnosticand treatment resources, insurance, environment-vaccination-diet, andsupport issues. Notwithstanding the public attention, the cause of autismremains a medical mystery.The only generally agreed-upon fact is that thereis a strong genetic basis underlying the condition, but none of the majorcontributing genes has been identified.

Progress from our Genome Canada-funded ‘Autism Genome Project’ willbe presented.This initiative brings together from across Canada leading

geneticists, clinicians, and genome scientists performing autism research, andlinks them with 170 other scientists from 50 institutions in 10 othercountries worldwide. In the first stage, the genomes from over 6000members of 1500 families were screened using the latest genome scanningtechnologies to find the regions of chromosomes that show the highestlinkage or association with disease. In the second phase, advanced genomicmethods are being applied to rapidly assess the DNA in thesechromosomal regions to identify the disease-susceptibility genes.

Already, several new candidate genes and candidate loci have beenidentified. Moreover, a significant number of chromosomal abnormalitieshave been found. Progress has also been made towards determining thebest methods of incorporating the genomic information generated into thestandard practice of health care delivery and health policy developmentfor autism.

Dr. Stephen Scherer, Ph.D., at The Hospital for Sick Children and University of Toronto, is one of Canada’s leading scientists making contributions towards understandingthe composition of the human genome for studies of genetic disease. His recent work characterizes structural variation in the human genome, and examines the rolegenetics has in autism. Long-standing endeavors include the study of human chromosome 7 as a model of the chromosomal basis of disease, and building genomicsinfrastructure to facilitate biomedical research. He has published over 200 peer-reviewed articles and won numerous awards including an Honorary Doctorate(University of Windsor), Canada’s Top 40 Under 40 Award, and the 2004 Steacie Prize in the Natural Sciences. He is an Investigator of the Canadian Institutes ofHealth Research, International Scholar of the Howard Hughes Medical Institute, and currently chairs Genome Canada’s Science and Industry Advisory Committee.

Genome Architecture in Autism Spectrum Disorder

Michael Sundstrom

Michael Sundstrom earned his PhD from the Dept.of Molecular Biology at the Uppsala Biomedical centre,Sweden, in 1992.After PostDoctoral training at the Centre for Structural Biochemistryat the Karolinska Institute,he started at the Pharmacia BioScience Centre in Stockholm as scientist in Protein Crystallography.He was later appointed head of the Protein Crystallography group aswell as Project Leader for a Drug Discovery Project in Diabetes. In 1998,he moved to the Pharmacia Oncology Research site in Milan, Italy,as Director of Structural Chemistry & ResearchInformatics and in addition served as Chairman for the Oncology Research Review Committee. In 2001,he became Research Director of Actar AB (a Stockholm-based start-up drug discoverycompany) and later joined Biovitrum AB as Director, In-Licensing (2002).He was appointed Chief Scientist for the Structural Genomics Consortium (SGC) at the University of Oxford in July 2003.The SGC is focused on determining three-dimensional structures of human proteins of medical relevance and to place them in the public domain without restriction.The Oxford site has ~65 staffmembers and efforts are focused on metabolic enzymes,phosphorylation dependent signalling and integral membrane proteins.Over the first 2 years of operation,SGC-Oxford deposited 125protein structures in the PDB, representing 102 novel human proteins.Overall, the SGC operations in Oxford,Stockholm and Toronto during 2005 contributed 16% of all novel human proteinstructures deposited in the public domain.

Session 6

The Structural Genomics Consortium (SGC) is a not-for-profit organizationthat determines the three dimensional structures of proteins of medicalrelevance and places them in the public domain without restriction.Theinitiative receives funding from Canadian and British sponsors, from boththe public and private sectors, including the Wellcome Trust,GlaxoSmithKline and a consortium of Canadian and Swedish fundingagencies.The SGC has three sites at the Universities of Oxford (UK) andToronto (Canada) as well as at the Karolinska Institute (Sweden).

Over the first three years, the SGC is attempting to structure determine~400 proteins that have relevance to human health and disease, such asproteins associated with diabetes, cancer, and infectious disease.Targets arechosen based on interest from the scientific community and we are largelyfollowing a target family approach with the aim to provide extendedexperimental structure coverage allowing comparative intra-family structuralanalysis.To date (22nd of June 2006) the SGC has determined thestructures of ~250 novel human and malarial proteins and made them

available in the public domain http://sgc.utoronto.ca/SGC-WebPages/ sgc-structures.php. On a monthly basis, the SGC consistently deposits 12-14 novel structures in the PDB.

The Oxford operations of the SGC are focused on generating structuralinformation of key proteins amongst Dehydrogenases and Reductases aswell as those involved in Membrane Receptor and PhosphorylationDependent Signaling. In addition to the structure determination of novelprotein structures of medical impact, we’re now dedicating resources toprovide the structures of key target classes (such as protein kinases) incomplex with representative inhibitors, natural ligands and protein partners.

The talk will focus on our approach structural genomics and to theidentification and validation of generic and specific ligands as well asstructure determination of such protein-inhibitor/ligand complexes topromote the understanding of specificity and selectivity determinants forprotein-ligand interactions and their utility to promote drug discovery.

Directed Structural Genomics: Focus on Human Protein Families

55

56

Juan Valcárcel

Juan Valcárcel Juárez received his PhD in 1990 from the Centro de Biología Molecular, Universidad Autónoma de Madrid (Spain), specializing in biomedical andmolecular biology. From 1991-1995 he was a postdoctoral fellow under Dr. Michael R. Green at the University of Massachusetts,Worcester, MA. Following this, Dr.Valcárcel was a group leader in the Gene Expression Programme.at the European Molecular Biology Laboratory, Heidelberg, Germany. Since 2002, he has been groupleader of the Gene Regulation Programme at the Centre de Regulacio Genomica, in Barcelona and Research Professor, (ICREA)Institució Catalana de Recerca i EstudisAvançats. His primary research areas are Postranscriptional regulation of gene expression and alternative splicing of mRNA precursors. In 2004, he was elected amember of the European Molecular Biology Organization (EMBO).

Session 2

As persuasively illustrated by the contributions of the other speakers in this session,alternative splicing plays an important role in regulating eukaryotic gene expression,and failure to properly regulate alternative splicing has significant impact in humanpathologies. Our laboratory is interested in understanding molecular mechanisms ofpre-mRNA splicing regulation, particularly those involving genes and regulatoryfactors relevant to cell proliferation and tumour progression.We currently focus onthree topics:

1) how splice sites are recognized and proofread: we have identified proteins thatfacilitate recognition of the rather short and degenerate splice site sequences bythe splicing machinery or that proofread these interactions; interestingly thesefactors include apoptosis regulatory factors and oncogene products.

2) how the use of particular alternative splice sites is regulated: we have identifiedfactors that modulate the use of alternative exons in the Fas receptor and Pax6genes.These alternative splicing events are relevant for the control of cellproliferation, differentiation and programmed cell death and their deregulationleads to various pathologies, including autoimmune disease and aniridia.Theregulatory factors identified include protein products of tumour suppressorgenes which act through a variety of mechanisms at different stages of thesplicing process.

3) how does the cell program coordinate changes in alternative splicing of multiplegenes: we are using splicing-sensitive microarrays to correlate changes inalternative splicing with changes in the expression of spliceosomal factors andregulators with the goal of finding general rules for cell type-specific splicing.Weare applying these arrays to a variety of biological problems, including tumourprogression, muscle differentiation and the activation of signaling pathways. Globalcorrelations between isoform expression and cell phenotypes can be readilymade, suggesting that appropriate splice site choices in numerous genes arebiologically relevant.While the arrays can reveal causal connections betweenindividual regulators and splicing events, no global correlations have been foundbetween the expression of splicing factors and global changes in splicing or cellphenotypes.This suggests that posttranscriptional regulation plays an importantrole in the function of splicing regulators and/or that key regulatory factorsremain to be identified.

Efforts along these lines are supported by the European Alternative Splicing Networkof Excellence (EURASNET), a consortium of over 30 laboratories funded by theEuropean Union to integrate multidisciplinary research on the biological and medicalimpact of alternative splicing and its underlying biochemical and cellular mechanismsfrom a functional genomics perspective.

Mechanisms of Alternative Pre-mRNA Splicing Regulation

57

Hans Vogel

Dr. Hans Vogel was born in the Netherlands and received his M.Sc. degree at the University of Groningen. He subsequently obtained his Ph.D. degree from theUniversity of Alberta and he did postdoctoral work at the University of Lund in Sweden. In 1985 he joined the University of Calgary where he has build up a successfulmultifaceted research group working in the area of structural biology and membrane proteins. As a member of its Board of Directors he has also played a role indeveloping the Canadian Light Source, Canada’s first synchrotron, in Saskatoon. Since his initial appointment in Calgary he has held Scholar and Scientist awards fromthe Alberta Heritage Foundation for Medical Research (AHFMR). Dr.Vogel’s main research tool is Nuclear Magnetic Resonance spectroscopy (NMR). However he alsomakes extensive use of other biophysical tools and molecular biology methods to study protein and peptide interactions. His current research interests encompass abroad range of biological problems. His research group actively studies antimicrobial peptides and they also publish regularly on bacterial iron uptake processes as atarget for the development of novel antibiotics. More recently he has been involved in establishing a metabolomics NMR research centre in Calgary, evaluating itspotential for clinical diagnosis and prognosis. Since joining the University of Calgary he has had an active research interest in the study of regulatory calcium-bindingproteins involved in human health (supported by CIHR) and plant stress (supported by NSERC). He has published nearly 300 scientific papers and is regularly invitedto speak at international meetings and symposia.

Session 6

The concentration of calcium in the cell is strictly regulated.At high levels, this metalion can become toxic, and hence, all eukaryotic cells have ATP-driven calcium pumpsthat secrete calcium to the outside or into intracellular storage organelles.As a result,the intracellular calcium concentration in a resting cell is around 10-7 M, while that ofthe extracellular milieu is around 1 mM. During activation, the cells can make use ofthis 10,000-fold concentration gradient by allowing calcium to flow into the cellthrough highly regulated calcium channels, where it then acts as a secondarymessenger.The transient increase in the calcium concentration is translated intophysiological and biochemical responses by a series of dedicated regulatory calcium-binding proteins.This group of intracellular proteins has characteristic helix-loop-helixcalcium-binding motifs, which are known as the ‘EF-hands’ after the E and the F-helix ofthe protein parvalbumin, in which this structural motif was first described.The humangenome contains about 250 genes that code for EF-hand proteins.The vast majorityof these proteins are relatively small proteins containing two, three, four, five or six EF-hands, but not all sites bind calcium, and some can bind magnesium as well. Several of

these proteins, such as calmodulin, are ubiquitously expressed, while others only occurin neurons or skeletal and cardiac muscle (recoverin and troponinC, respectively).Some EF-hand proteins have four genes and several isoforms (calcium-integrin-bindingproteins), others (e.g. caldendrin) have multiple alternative spliceforms, while forcalmodulin, there are three human genes, all expressing the same protein molecule.This class of proteins has been intensely studied over the last three decades andnumerous three-dimensional structures have been reported to date. It is now possibleto perform statistical analyses to highlight their main features.The next step will be toelucidate the ‘EF-hand interactome’ and to try to gain an understanding of therelevance of the various protein-protein interactions. In this talk, I will discuss threeexamples: the neuronal cytoskeletal targeting of caldendrin, transmembrane plateletsignaling by calcium-integrin-binding protein and the binding of calmodulin to ‘IQ-motifs’ in newly discovered smooth muscle proteins.These control learning processes,blood clot formation and smooth muscle contraction respectively and illustrate theenormous diversity of functions regulated by calcium signaling.

Intracellular Calcium-signalling:The EF-handome and Calmodulin’s IQ-test.

58

John Walsh

Concern over the impact of patenting and licensing on biomedical research hasgrown since the CAFC’s 2002 Madey v. Duke decision which visibly affirmed theabsence of any general research exemption shielding universities from infringementliability.This paper examines the impact of patents and licensing on access toknowledge and material inputs for academic biomedical research.

Our results suggest that commercial activity is widespread among academicresearchers. Patenting does not, however, appear to significantly restrict access to theintangible knowledge inputs that are essential to research. Only 1% of our randomsample report suffering a project delay of more than a month due to patents onknowledge inputs necessary for their research. None had stopped a project due tothe existence of third party patents on research inputs. Our respondents tend not tobe aware of relevant patents and few regularly look for relevant patents.

Access to tangible research inputs from others is more problematic and is morelikely to impede research. Nineteen percent of respondents did not receive theirmost recently requested material, and rates of refusal seem to have increased in

recent years. Eight percent of requests for a tangible research input led to theresearch having to stop for more than one month, as compared to 1% of caseswhere only a patent (no material) is involved. Scientific competition, business activityand the costs and effort involved are the main reasons for not fulfilling such requests.

When we focus on research in specific signal proteins where we expect higher ratesof problems due to patents, we find that those working on EGF and NF-kB showhigher rates of commercial activity, while CTLA-4 researchers are much closer to thenorm.While adverse effects from patents are still infrequent, they are somewhatmore common for these researchers than for the random sample. Material transfers,on the other hand, have much higher rates of adverse effects for those working onEGF and NF-kB (less so for CTLA-4).

The importance of scientific competition, transaction costs and commercial interestsfor limiting access to material research inputs suggests that policymakers shoulddevote their attention to alleviating these causes of friction in the flow of neededresearch materials.

Professor Walsh’s research focuses on the relations among work, organizations, institutional context and innovation. Recent studies include the impact of patents onresearch inputs for biomedical research, the role of patents and other appropriability mechanisms for firm R&D in the U.S. and Japan, and university-industry linkages inJapan and the U.S.His work has been published in Science, Research Policy, Management Science and Social Studies of Science.

Professor Walsh received his Ph.D. in Sociology from Northwestern University. He has heldvisiting positions at Carnegie Mellon University, University of Tokyo, HitotsubashiUniversity, and Japan’sNational Institute of Science and Technology Policy.

Patents, Material Transfers and Access to Biomedical Research Tools

Session 7

59Session 5

Laurence Zwiebel

Laurence J. Zwiebel, PhD, is a Professor of Biological Sciences at Vanderbilt University in Nashville TN USA. A native New Yorker, Dr. Zwiebel was educatedat the State University of New York (B.S.),The University of Michigan (M.S.), Brandeis University (PhD) and was a postdoctoral fellow at Harvard Universityand The European Molecular Biology Laboratory.

Dr. Zwiebel’s research specialty is the molecular genetics and neurobiology of olfaction in disease vector mosquitoes. His laboratory has pioneered theidentification and characterization of odorant receptors and other genes involved in olfactory processes in vector mosquitoes. Dr. Zwiebel is the principalinvestigator on several NIH funded projects as well as an international mosquito olfaction consortium that recently received a Grand Challenge in GlobalHealth grant from the Bill & Melinda Gates Foundation. Its role will be to apply the tools of bioinformatics and molecular biology to further analyze thesereceptors in the malaria vector mosquito—Anopheles gambiae—particularly the ones that respond to human odors.The researchers will use geneticengineering techniques to place mosquito smell receptors in immature frog eggs and grow them in cultures in order to test large numbers of differentchemical compounds for those that interact the most strongly with the receptors that the mosquito uses for many important behaviors, most particularlyto seek out human prey.

The ability to sense and discriminate a large collection of chemical and visual cues iscentral for several behaviours of insects that act as vectors for the pathogens that areresponsible for many important human diseases. In particular, olfaction plays a majorrole in host-seeking and selection behaviours of blood-feeding female mosquitoesincluding the principal Afrotropical malaria vector, Anopheles gambiae, whose strongpreference for human hosts (anthropophily) is largely responsible for its high vectorialcapacity. A long-term objective of our research is centered on an examination of themolecular genetics of the chemosensory system in anopheline and other mosquitoes,and its role in determining anthropophilic host preference in malaria vectormosquitoes. Data will be discussed concerning the characterization of representativesof several families of genes that together make up essential elements of theperipheral chemosensory signal transduction cascades in An. gambiae and theDengue virus vector mosquito, Aedes aegypti. These include arrestins, G-proteins andserpentine receptor proteins associated with olfactory and gustatory pathways. An

enhanced understanding of the olfactory systems of these disease vector insectscould provide opportunities for manipulating these sensory processes and thereby,provide alternative approaches to control olfactory-based behavioural choices, suchas host preference.

We have identified, and continue to characterize, the complete repertoire of odorantreceptor (OR) genes in An. gambiae and A.aegypti. Among these, is OR7, which isexpressed in most of the olfactory neurons in antenna, maxillary palp and theproboscis of female mosquitoes and is thought to be the mosquito ortholog for ahighly conserved non-conventional subfamily of insect Ors that play an importantrole in olfactory signal transduction.With this information in-hand, we are nowpoised to undertake efforts for the design of novel disease reduction programs thattarget chemosensory pathways and the behaviours they control in vectormosquitoes. Several approaches in this regard will be discussed.

The Genomics of Olfaction and Host Selection in Disease Vector Mosquitoes

Understanding Human DiseaseDenise Avard Les enjeux éthiques et sociaux du dépistage de l’anémie falciforme : développer des techniques d’enquête afin de connaître

les positions de la communauté sur ces enjeux . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62Zuhier Awan Homozygous Familial Hypercholesterolemia and Severe Premature Aortic Calcification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63Patrick Beaulieu An ENSEMBL/BIOMART- based Environment for the Analysis of Regulatory Regions Functional Assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64Joëlle Dionne Functional Impact of Regulatory Polymorphism (rSNP) in G1/S Cell Cycle Checkpoint Genes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65Scott Gurd Allelic Imbalance in the Human Genome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66Jasmine Healy Promoter SNPs in G1/S Checkpoint Regulators and their Impact on the Susceptibility to Childhood Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . 67Nina N’Diaye A Naturally Occurring Regulatory Haplotype Enhances BTN3A2 Expression In Vivo. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68Panagiotis Prinos Regulation of the Alternative Splicing of Apoptotic Genes by hnRNP Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69Jacqueline Schein Mapping Genome Rearrangements in Follicular Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70Hans J. Vogel Application of 1H NMR Metabolomics to a Murine Model of Inflammatory Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71Farah Zahir Genotype-phenotype Correlations for Submicroscopic Copy Number Variants detected by Array Genomic Hybridization

in Children with Mental Retardation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

Molecular Evolution and Biosphere DiversityJessica Alfoldi The Strangest Chromosome That You Have Ever Seen: Sequence of the Mouse Y Chromosome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73Shannon R. Escasa Gene Organization and Content of Malacosoma Californicum Pluviale Nucleopolyhedrovirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74Daniel J. Gaffney Selective Constraint and Deleterious Mutation in Murid Noncoding DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75JL Gifford EF-hand Mutants of CIB1 Reveal a Unique Function for the -Z metal Coordinating Residue on Ca2+, Mg2+ and Target Peptide Interactions 76Felix D. Guerrero Global Comparative Genomic Analysis of the Southern Cattle Tick . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77Yoonsoo Hahn Gene Inactivation by Exon Deletion in Human Evolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78Zhen Li Sequence Analysis of the Choristoneura Biennis Entomopoxvirus Genome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79Jason Maydan Copy Number Polymorphisms in Mutant and Natural C. elegans Isolates Detected by Oligonucleotide Array . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80Hans J.Vogel The Solution Structures of Two Soybean Calmodulin Isoforms and their Complex with a Vacuolar Calcium-ATPase Peptide . . . . . . . . . . . . . . . . . 81

Poster Abstracts Résumés d’affiches

60

61

Emerging TechnologiesDenise Avard Pharmacogenomics Ethical, Social and Legal Issues: Frequently Asked Questions on the Web . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82Brian E. Colton The Dual Use Dilemma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83Allison Guy Emerging Technologies and the Impact on the Ethical Use of Animals in Science . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84Wenqi Hu Aspergillus Fumigatus Essential Gene Identification and Antifungal Drug Target Prioritization using Conditional Promoter System. . . . . . . . . . . . 85Roscoe Klinck LISA: An Integrated System for Tissue-Specific Alternative Splicing Annotation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86Tony Kwan Using the Affymetrix Exon Array to Investigate Variation in Alternative Splicing in a Human Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87Mathieu Larivière Using the Biacore 3000 Biosensor for Detecting DNA-protein Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88Srini Perera Propagation of Amsacta Moorei Entomopoxvirus in Two Lepidopteran Cell Lines, IPLB-Ld652 and FPMI-Cf-70-clone B2 . . . . . . . . . . . . . . . . . . 89Jean Sharp Grade Nine Biotechnology Activity Kit: Benefits and Risks of Biotechnology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90Lorraine Sheremeta Genomics and Convergence: Developing Capacity for “E3LS” Research in Canada . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91Hans J. Vogel Developing Robust White Spruce Trees for Reforestation: Metabolic Footprinting By 1H NMR. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92Deming Xu Genome-wide Fitness Test of Heterozygotes and Studies of Mechanisms of Action of Inhibitory Compounds in Candida Albicans . . . . . . . . . . . 93

Poster Abstracts Résumés d’affiches

Understanding Human Disease

Author(s): Emmanuelle Lévesque, Béatrice Coly, Denise AvardAffiliation: Université de MontréalPresenter : Denise AvardE-mail: [email protected]

Contexte :Afin d’enrayer certaines maladies génétiques, les gouvernementsinstaurent de plus en plus des programmes de dépistage.Actuellement, le Québec réfléchit à la mise en place d’un programmede dépistage de l’anémie falciforme. Implanter un tel programmesoulève d’importants enjeux éthiques et sociaux. Par exemple, ladiscrimination, l’accès aux services de santé, les valeurs religieuses, etc.Ces enjeux ont un caractère particulier puisque l’anémie falciformetouche particulièrement des communautés culturelles minoritaires.Avant de mettre en place le dépistage, il est primordial de connaîtreles positions de cette communauté sur ces enjeux.

Notre projet vise à développer une méthode afin d’enquêter sur lesenjeux éthiques et sociaux du dépistage de l’anémie falciforme auprèsde la communauté touchée.

Méthode:Le projet s’articule autour de deux questionnements principaux :• Quels enjeux éthiques et sociaux préoccupent la communauté? • Comment faire participer la communauté à une telle enquête?

Dans ce poster, nous présentons les résultats d’une dizaine d’expertsde la recherche multiculturelle en santé ayant répondu à desquestionnaires téléphoniques semi-structurés.

Résultats :Les enjeux principaux sont les choix reproductifs pour les porteurs, lerisque de discrimination ainsi que le renoncement à certaines valeursreligieuses. Quant aux façons d’impliquer la communauté dans uneenquête, il est suggéré d'organiser de petits groupes de discussionreprésentatifs de la communauté. Le recrutement pourrait être facilitéen sollicitant dans les lieux de culte et les centres communautaires.

Conclusion:Les résultats obtenus permettent d’établir une méthode d’enquêtesur les enjeux éthiques et sociaux du dépistage génétique chez unecommunauté multiculturelle. Ces résultats démontrent l’importanced’adapter les techniques d’enquête lorsque les questions poséestouchent au dépistage génétique. Dans une étape ultérieure, nousmettrons en ?uvre la méthode dans le cadre d’une large enquête.

Les enjeux éthiques et sociaux du dépistage de l’anémie falciforme : développer destechniques d’enquête afin de connaître les positions de la communauté sur ces enjeux

62

63


Author(s): Awan Z, Marcil M, Genest J Jr, Gagné C, Couture P.Affiliation: Cardiovascular Genetics Laboratory, Division of Cardiology, Department of Medicine, McGill University Health Center/Royal

Victoria Hospital, MontrealPresenter: Zuhier AwanE-mail: [email protected]

Purpose:Patients with homozygous familial hypercholesterolemia (FH hmz)have shown a remarkable increase in survival over the last 20 years,due to new medication and extracorporeal LDL removal techniques.However, we are now facing a severe form of premature calcificationof the ascending aorta in patients with FH hmz on long termtreatment which merit attention and intervention.

Methids and Results:In a retrospective manner, we have examined 15 FH hmz patients (6males & 9 Females) from the province of Québec with a confirmedmolecular diagnosis (9 out of 15 patients carrying the French-Canadian mutation > 10 kb deletions in one or both genes).Themean age was 34 years (range between 12-54 years) and the initialaverage total cholesterol value prior to intensive treatment was 17.4± 4.4 mmol/l.The extra-calcification of the ascending aorta has beenconfirmed by CT scan. In one third of the patients aortic valve repairhas possessed a considerable challenge to surgeons operating incalcified aorta.

Summary:Although coronary atherosclerosis is markedly slowed down in FHhmz with advanced treatment, severe aortic calcification and valvulardisease appears to be significant and independent of in lipid values,therefore suggesting the possibility of a genetic link between theLDL-receptor dysfunction and vascular calcification. Of thoseidentified mutations the 10> kb deletion seems to be associated themost. Future studies of LDL-receptor knockout bone marrow-derived cells in animal will help confirm this association.

Homozygous Familial Hypercholesterolemia and Severe Premature Aortic Calcification


Author(s): Patrick Beaulieu, Alexandru Graziani, Robert Hamon,Vince Forgetta, Mathieu Blanchette, Ken Dewar, Eef Harmsen, Daniel SinnettAffiliation: Centre de recherche, Hopital Ste-Justine, Montréal, QC, CanadaPresenter : Patrick BeaulieuE-mail: [email protected]

Previous efforts to identify functional disease-causing DNA variantswere essentially oriented towards the coding regions of candidategenes since these variants have a direct impact on the structure andfunction of the affected proteins. However, abnormal expression offinely regulated genes can also lead to disequilibria in differentmetabolic pathways and/or biological processes.Thus, investigation ofthe functional impact of polymorphisms as well as the determinationof the importance of evolutionary conservation in the regulatoryregions of candidate genes should improve our knowledge ofcomplex disease aetiologies. As part of the Gene Regulators inDisease (GRID) project, we have to integrate layers of informationincluding gene structure, SNP content, genomic patterns (i.e. CpG

islands, conserved regions) and in-silico analysis together withexperimental results from electrophoretic mobility shift assays (EMSA)and several types of in vitro/vivo promoter activity assays.

We present a web-based environment to combine, analyse anddistribute the results generated by the GRID project. Our softwaretakes advantage of the ENSEMBL genome browser packagecombined with the BIOMART data management and query system.This allows an efficient integration of data collected from the variouswet-lab platforms and therefore a better functional annotation of theregulatory regions of human genes.

An ENSEMBL/BIOMART- based Environment for the Analysis of Regulatory Regions Functional Assays

64

65


Author(s): Joëlle Dionne, Manon Ouimet,Vincent Gagné, Damian Labuda, Daniel SinnettAffiliation: Université de MontréalPresenter : Joëlle DionneE-mail: [email protected]

G1/S transition in the cell cycle is a finely regulated biological process.Depending on the context, growth-control genes present in the G1/Scheckpoint can stop the cell cycle progression and activate survivalpathway in the cell.Then DNA repair process or cell death byapoptosis is initiated. Dysregulation of G1/S checkpoint genes isfrequently observed in complex disease, particularly like cancer.Indeed genes encoding components of cell cycle processes arefrequently mutated in human cancers.We hypothesize that functionalpolymorphisms located in the regulatory region of candidates genescould lead to variable level of transcript and thus predisposing theindividuals carrying these genetic variants to cancer. In this report weassessed the functional impact of rSNPs located in the proximalpromoter of 18 candidates genes encoding components of G1/Scheckpoint by combining in silico analysis and in vitro functional assays.

We identified 150 rSNPs including 123 with predicted impact onputative transcription factor binding sites.This information was used toconstruct promoter haplotypes. Following the subcloning of the majorpromoter haplotypes into a luciferase gene reporter vector (pGL3a),transient transfection assays were performed in 3 cell lines (Hela, Jeg3and HepG2).We found that at least 5 promoter haplotypesassociated with TGFβ1, CDKN2A and TFDP1 significantlyinfluenced transcriptional activity in an allele-specific manner. Furthervalidation by electrophoresis mobility shift assays (EMSA) to detectdifferential DNA-protein bindings is being done. Although, thebiological significance of these observations still remain to bedemonstrated, the expected variability of expression levels in key cellcycle components might influence individual’s risk of cancer.

Functional Impact of Regulatory Polymorphism (rSNP) in G1/S Cell Cycle Checkpoint Genes


Author(s): Scott Gurd, David Serre, Bing Ge, Robert Sladek, Donna Sinnett, Eef Harmsen, Marina Bibikova, Eugene Chudin, David Barker,Todd Dickinson, Jian-Bing Fan and Thomas J. Hudson

Affiliation: McGill University and Genome Quebec Innovation CentrePresenter: Scott GurdE-mail: [email protected]

Several recent studies have shown that the two alleles of a gene areoften differentially expressed. Here we describe a robustmethodology to rapidly investigate a large number of genes usingIllumina Allele-Specific Expression Bead Arrays and validation byquantitative sequencing of RT-PCR products.We show that thisapproach allows reliable identification of differences in the relativeexpression of the two alleles larger than 1.5-fold (i.e., deviations largerthan 60:40). Additionally, we show that immortalized cell lines are notsignificantly affected by tissue culture factors and are a suitablematerial for the investigation of cis-acting mechanisms of geneexpression regulation. Our analysis of than 80 individuals for2,968 SNPs located in 1,380 genes confirms that differential allelic

expression is a common phenomenon affecting the expression of,roughly, one out of five genes in the human genome and that it resultsfrom mechanisms including epigenetic and genetic cis-actingregulation. Using extensive genotype information from the HapMapproject we are able to map, for some of the genes, the cause of thedifferential allelic expression to a regulatory haplotype and to validatethese associations using independent gene expression data. Our studyprovides a list of genes with low and high expression haplotypes thatcan now be tested for their association with cancers or otherhuman diseases.

Allelic Imbalance in the Human Genome

66

67


Author(s): Jasmine Healy, Hélène Bélanger, Patrick Beaulieu, Mathieu Larivière, Damian Labuda, and Daniel SinnettAffiliation: Sainte-Justine Hospital Research CenterPresenter : Jasmine HealyE-mail: [email protected]

Mutations leading to alteration of cell cycle checkpoint functions are acommon feature of most cancers. Because of the highly regulatednature of the cell cycle, it seems likely that variation in gene dosage ofkey components due to functional regulatory polymorphisms couldplay an important role in cancer development. Here we provideevidence of the involvement of promoter SNPs (pSNPs) in cyclin-dependent kinase inhibitor genes CDKN2A, CDKN2B, CDKN1A andCDKN1B, in the etiology of childhood pre-B acute lymphoblasticleukemia (ALL). A case-control study conducted in 240 pre-B ALLpatients and 277 healthy controls combined with a family-based

analysis using 135 parental trios, all of French-Canadian origin, wereused to evaluate single site genotypic as well as multilocus haplotypicassociations for a total of ten pSNPs. Using both study designs, weshowed evidence of association between variants CDKN2A -222A,CDKN2B -593A and CDKN1B -1608A and an increased risk of ALL.These findings suggest that variable expression levels of cell cycleinhibitor genes CDKN2A, CDKN2B and CDKN1B due to regulatorypolymorphisms could indeed influence the risk of childhood pre-BALL and contribute to carcinogenesis.

Promoter SNPs in G1/S Checkpoint Regulators and their Impact on the Susceptibility to Childhood Leukemia


Author(s): Nina N’Diaye,Tomi Pastinen, Alan Paterson, Mathieu Larivière, Damian Labuda,Thomas Hudson, Daniel SinnettAffiliation: Department of Hematology-Oncology, Sainte-Justine Hospital Research Center, University of Montreal, Montreal, QC, CanadaPresenter : Nina N’DiayeE-mail: [email protected]

A growing number of studies report allelic-specific gene expression,suggesting that allelic imbalance (AI) might be a common mechanismin the regulation of the human genome expression. However, fewexamples of well-defined regulatory SNPs or haplotypes (rSNPs,rHap) can be found in the literature. In the present study, wecharacterized the molecular mechanism underlying the unequal allelicexpression of BTN3A2 gene.The initial in vivo measurement ofBTN3A2 AI previously led to the identification of a putative rHap thatspans a 15kb region bearing 11 candidate functional SNPs.Transgenicmice were generated with two 5kb-constructs harboring the putativepromoter, and the first 2 exons of BTN3A2 gene (rHap¯ and rHap+).A strong AI (3 to 4-fold increase) was observed and confirmed withtransiently transfected HeLa cells.We generated 2 chimericconstructs, Hapa: rHap+(– 2103 -+300)–rHap¯(301-2812) and itscounterpart Hapb: rHap¯(– 2103 -+300)– rHap+(301-2812) thatshowed a 1.8–fold difference in promoter activity (Hapa>Hapb).Thissuggests that the XhoI(–2103) – NdeI(+300) fragment retains thedifferential expression pattern.We then subcloned the 2kb promoter

region flanked by the first exon and intron (XhoI(–2103) –NcoI(+818)), both constructs sharing the same BglII(–587) –NcoI(+818) region from rHap+. A 1.5 to 2-fold differential expressioncould still be observed, inferring the putative functional SNPs to the 3promoter SNPs (pSNPs) C/T– 1771,T/C– 939, and A/C– 831.Transfection with the chimeric constructs C–1771-C– 939-C– 831and T–1771-T– 939-A–831 resulted in a complete loss of differentialexpression.This indicates that at least 2 pSNPs (C/T– 1771 and C/T–939 or C/T– 1771 and A/C– 831) are needed for the haplotype-specific expression illustrating the fact that gene regulation is indeed acomplex trait.We also performed electrophoretic mobility shift assays(EMSA) and observed allele-specific binding for A/C– 831 andG/A–1771 probes but not for T/C– 939. In conclusion, BTN3A2 geneprovides a good example of an experimentally characterized rHapunderlying the involvement of regulatory linkage between rSNPs thatcould define a regulatory module.This work is supported by GenomeQuebec/Canada.

A Naturally Occurring Regulatory Haplotype Enhances BTN3A2 Expression In Vivo

68

69


Author(s): Panagiotis Prinos, Ulrike Froehlich, Elvy Lapointe, Sonia Couture, Eric Paquet, Sherif Abou-Elela and Benoit ChabotAffiliation: Laboratoire de Génomique Fonctionnelle de l’Université de Sherbrooke, Centre de développement des biotechnologies (CDB)

de Sherbrooke, Sherbrooke, Québec, J1E 4K8 CanadaPresenter: Panagiotis PrinosE-mail: [email protected]

Regulation of alternative splicing is mediated to a large extent byRNA-binding proteins.The majority of the genes encoding the morethan 200 pro- and anti-apoptotic proteins involved in apoptoticcontrol are alternatively spliced. Regulatory proteins of opposingfunctions are often produced from a common pre-mRNA.Thus,alternative splicing of apoptotic genes is of a crucial importance for

apoptotic regulation.Very little is known about the molecularmechanisms regulating splice site selection of apoptotic genes.Wehave undertaken a large-scale systematic analysis of the effects of RBPprotein knock-down on the alternative splicing of a panel of humanapoptotic genes. Analysis of the data supports an intricate regulatoryRBP network of apoptotic splicing units.

Regulation of the Alternative Splicing of Apoptotic Genes by hnRNP Proteins


Author(s): Jacqueline Schein, Martin Krzywinski, Inanc Birol, Readman Chiu, Matthew Field, Carrie Mathewson, Lindsey Johnson,Darlene Lee, Johar Ali, Agnes Baross, Ian Bosdet, Susanna Chan, Allen Delaney, Irene Li,Trevor Pugh, Rene Warren, Kim Wong,George Yang, Nathalie Johnson,Thomas Relander, Robert Holt, Steven Jones, Randy Gascoyne, Douglas Horsman,Joseph M. Connors and Marco A. Marra.

Affiliation: Genome Sciences Centre, BC Cancer Agency,Vancouver, BCPresenter : Jacqueline ScheinE-mail: [email protected]

With the aim of identifying and sequencing mutations in follicularlymphoma genomes, we have begun a project to generate 24sequence-ready Bacterial Artificial Chromosome (BAC)-based wholegenome maps, each from a different individual’s lymphoma. BAC-arrayCGH and Affymetrix 500K SNP arrays will be used together with themaps to identify genomic amplifications and losses in the lymphomas.Results from the mapping and array studies will identify BAC clones forsequence analysis.This approach facilitates targeted sequencing of tumorDNA in genomic regions of interest, including those containing genesrelevant to cancer.

Our mapping strategy employs deeply redundant BAC librariesconstructed from primary lymphomas and high throughput restrictionenzyme fingerprinting of individual BACs. Using the fingerprints, we willalign the BACs to the reference human genome to assess genomecoverage and to identify candidate genome rearrangements. In parallel,we will assemble the fingerprints into genome maps, looking for larger-scale genome variations between the lymphomas and the referencegenome sequence.

To test the feasibility of our approach, restriction digest fingerprints wereobtained from BACs sampled from a 6.5-fold redundant library created

from a primary follicular lymphoma, and the clones assembled into amap.Alignment of the fingerprints to the reference human genomesequence indicated that the fingerprint map represents at least 94% ofthe lymphoma genome.These alignments establish a correspondencebetween sequence position in the reference genome, and the tumorfingerprint map clones and contigs.

We identified two BACs that capture the canonical t(14;18)translocation characteristic of follicular lymphomas, and sequenced oneof these to precisely characterize the BCL2/IGH fusion gene in oursample.We also identified 3 BACs spanning the breakpoint of a novelcandidate inversion of 365 kb on chromosome 16, and are conductingexperiments to validate this discovery.

We have also identified 693 candidate deletions, 90% of which are lessthan 10.8 kb in size. In total, these affect 306 genes, 27 of which overlapwith recently published deletion polymorphisms.We are studying thefine structure of 100 of these microdeletions to refine our methods foridentification of alterations at the resolving level of a few restrictionfragments.

Mapping Genome Rearrangements in Follicular Lymphoma

70

71

Author(s): Aalim M Weljie, Reza Dowlatabadi, B. Joan Miller, Frank R. Jirik and Hans J.VogelAffiliation: Metabolomics Research Centre, University of Calgary, Calgary, Alberta, CanadaPresenter : Hans J.VogelE-mail: [email protected]

Metabolomics is the newest branch on the ‘omics’ tree where the fullcomplement of metabolites in human biofluids is measured.Thistechnology is believed to have great potential for disease diagnosisand prognosis. Both NMR spectroscopy and mass spectrometry canbe used to measure the metabolome.We are currently evaluating thepotential of this approach in various mouse models of human disease.Rheumatoid arthritis, a debilitating, systemic inflammatory joint diseaseimpacting almost 2% of the population, may be accompanied byalterations in specific metabolites. As an initial approach to investigatingthis possibility in a well-defined system we selected a murine model ofrheumatoid arthritis, the KBxN mouse. Sera from arthritic populationsof KBxN mice that are genetically-predisposed to arthritis (N=14), aswell as healthy parent strain population (N=21) were analyzed using1H NMR spectroscopy. A “Targeted Profiling” approach was used to

identify and quantify 54 metabolites and several unknowns.Subsequent multivariate analysis was performed to build a highlypredictive model based on cross-validation that was not influence bygender. Specific markers were identified relating to nucleotidesynthesis, fatty acid metabolism, protein synthesis, inflammation, andmethylation.The results attest not only to the complexity of systemicinflammatory responses, but also to the power of the experimentalapproach in being able to reveal such a wide variety of markers.Theimplication of monitoring a spectrum of metabolic eventssimultaneously is discussed with respect to the potential for newtreatments and individualized medicine. (Supported by GenomeAlberta/Canada and the Arthritis Society of Canada)

Understanding Human DiseaseApplication of 1H NMR Metabolomics to a Murine Model of Inflammatory Arthritis

Author(s): Farah Zahir, Agnes Baross, Allen D Delaney, Patrice Eydoux, Helen V Firth,WilliamT Gibson, Sylvie Langlois, Marco Marra,Sui-Li Yong, Barbara McGillivray, Jan M Friedman

Affiliation: Friedman Lab, Genetics Graduate Program, University of British ColumbiaPresenter: Farah ZahirE-mail: [email protected]

The cause of mental retardation (MR) in at least half of all affectedchildren is unknown.We have identified potentially pathogenic denovo submicroscopic gains or losses of genomic material in 10 of 100children studied with idiopathic MR using Affymetrix GeneChip®100K Whole Genome Sampling Analysis.These copy number variants(CNVs) include 8 deletions ranging in size from 178 kb to 11.1 Mband two duplications (1.1 and 3.6 Mb). In order to establish thepathgenicity of these CNVs for MR, we performed genotype-phenotype correlations by detailed comparisons of dysmorphicfeatures and genomic alterations in the affected children.

Six of our cases have CNVs that overlap with other cases inDECIPHER (http://www.sanger.ac.uk/PostGenomics/decipher/), an international repository for information on pathogenicCNVs detected in array genomic hybridization.Two of our patientsand DECIPHER case CAM126 show overlapping deletions of14q11.2, and all three patients exhibit similar facial features withwidely-spaced eyes, prominent epicanthic folds, a very short nose with

flat nasal bridge, long philtrum, prominent Cupid’s bow, full lower lip,and an unusual malformation of the auricle. Our patient BCC996 andDECIPHER case GHE883 both have overlapping deletions of12q14;q15, and they both have short stature and osteopoikilosis inaddition to their delay. Another of our patients with a 3.6 Mbduplication of 16p13.3 exhibits a striking phenotypic resemblance toDECIPHER case CHG237, who has an overlapping duplication.Twoother cases in our series have deletions of 22q12 and 7p21,respectively. In each instance, another patient with an overlappingCNV has been reported to the DECIPHER database.

The fact that 6/10 of our de novo CNVs show overlaps with othercases reported in DECIPHER and the common phenotypic featuresobserved among patients with similar submicroscopic genomicchanges underline the ability for high resolution array CGH to detectand define novel chromosomal abnormality syndromes.Theseobservations also show that these CNVs are likely to be pathogenicfor MR.

Understanding Human DiseaseGenotype-phenotype Correlations for Submicroscopic Copy Number Variants detected by Array Genomic Hybridization in Children with Mental Retardation

72

73

Molecular Evolution and Biosphere Diversity

Author(s): Jessica E. Alfoldi, Helen Skaletsky,Tina Graves, Patrick J. Minx, Steve Rozen, Richard K.Wilson, and David C. PageAffiliation: MIT/Whitehead Institute for Biomedical ResearchPresenter : Jessica AlfoldiE-mail: [email protected]

The mouse Y chromosome consists almost entirely of a large array ofsegmental duplications, named the Huge Repeat, which has nohomology to the human Y chromosome and which makes up 3% ofthe haploid mouse genome.This array is composed of three differentrepeat units of approximately 100kb that are euchromatic, gene-containing, and 98-99.999% identical within each repeat unit family.There are 3 gene families found in the Huge Repeat array: Ssty (Y-linked spermiogenesis specific transcript), Srsy (Serine-rich, secreted,Y-linked) and Sly (Sycp3-like,Y-linked). Of these 3 genes, Ssty and Sly areknown to be exclusively expressed in round spermatids, and Srsy isexpressed somewhere in the testis.These gene families are found in200-1000 copies across the mouse Y chromosome.The purpose of

this segmental duplication is unknown, but we suspect that the Y maybe using the genes of the Huge Repeat array to promote its sperm atthe expense of X-containing sperm.

We also know of 3 Mb of non-Huge Repeat sequence on the mouseY chromosome, found in two contigs.This sequence shows homologyto the mouse X and the human X and Y. It also includes gene-containing palindromes, which are analogous but not homologous tothe human Y’s palindromes. However, there is nothing to be found onthe human Y chromosome that is similar in sequence, copy number, orscale to the Huge Repeat array.

The Strangest Chromosome That You Have Ever Seen:Sequence of the Mouse Y Chromosome


Author(s): Shannon R. Escasa1,2 and Jenny S. Cory1,2Affiliation: 1Laboratory for Molecular Ecology, Great Lakes Forestry Centre, Sault Ste. Marie, ON, P6A 2E5, 2Algoma University College,

Sault Ste. Marie, ON, P6A 2G4Presenter: Shannon R. EscasaE-mail: [email protected]

The western tent caterpillar, Malacosoma californicum pluviale, is acommon defoliator of deciduous trees in British Columbia.The insectsfeed mostly on alder, ash, birch and fruit trees. Larvae are gregariousand spin a large silk tent on a branch from which they feed on newleaves.Tent caterpillars follow a cyclic population pattern every 6-10years; these cycles are thought to be driven by a baculovirus,Malacosoma californicum pluviale nucleopolyhedrovirus (McplNPV).Understanding the interplay between host resistance and virusvirulence over temporal and spatial scales is of key importance indisease epidemiology and evolution. Part of this process is elucidatingthe role of genetic diversity in host and pathogen populations. NPVpopulations can be genetically very diverse: here we present data onthe gene organization and content of McplNPV, which will produce abasis for studying genetic variation. Baculoviruses form a large family ofoccluded viruses composed of two genera: nucleopolyhedroviruses

(NPVs) and granuloviruses (GVs) that are differentiated by size, shape,and virion occlusion. NPVs are further subdivided into group I andgroup II NPVs. Data analysis suggests that McplNPV is most similar tothe group II NPVs. McplNPV has been sequenced, resulting in twocontigs with a total of 133,109bp and 130 open reading frames(ORFs). Preliminary analysis shows that the first contig is 107,905bpwith 106 ORFs, and an A+T content of 58.2%.The second contig is25,204bp with 24 ORFs and an A+T content of 57.8%. Gene parityplots, phylogenetic trees and gene alignments are important analysistools used to show relationships between baculoviruses. Genecontent, gene organization, and the comparison of McplNPV genomewith other baculoviruses will give a better understanding of how thegenome functions and how it relates to its host.

Gene Organization and Content of Malacosoma Californicum Pluviale Nucleopolyhedrovirus

74

75


Author(s): Daniel J. Gaffney and Peter D. KeightleyAffiliation: McGill University and Genome Quebec Innovation CentrePresenter : Daniel J. GaffneyE-mail: [email protected]

Selective constraint is defined as the proportion of new mutationsoccurring at a site which are strongly deleterious and are removed bypurifying selection.

Recent work has suggested that there are many more selectivelyconstrained, functional noncoding than coding sites in mammaliangenomes. However, relatively little is known about how selectiveconstraint varies from one region of the mammalian genome toanother.We estimated the selective constraint in a large dataset ofmouse-rat gene orthologues and their surrounding noncoding DNA.Our analysis indicates that there are more than three times as manyselectively constrained, nonrepetitive sites within noncoding DNA asin coding DNA in murids.The majority of these constrainednoncoding sites appear to be located within intergenic DNA, atdistances greater than 5kb from known genic regions. Surprisingly, ouranalysis also suggests that selective constraint in murid introns isdependent upon their length. Intron length, in turn, is strongly

negatively correlated with ordinal number.Thus, low ordinal numberintrons tend to be longer and contain the most putatively functionalsites.We also investigated how selective constraint of noncodingDNA varies with gene function.We find that genes involved indevelopment and neuronal processes contain the largest numbers ofselectively constrained intronic bases, suggesting that these genesrequire complex transcriptional control.This result indicates that suchgenes are more likely to be involved in genetic disease because theypresent larger mutational targets. Combining our estimates of thetotal number of constrained coding and noncoding bases we calculatethat over twice as many deleterious mutations have occurred inintergenic regions as in known genic sequence and that the totalgenomic deleterious point mutation rate is 0.91 per diploid genome,per generation.This is over twice as large as a previous estimatein murids.

Selective Constraint and Deleterious Mutation in Murid Noncoding DNA


Author(s): Yamniuk AP, Gifford JL,Vogel, HJAffiliation: University of CalgaryPresenter : JL GiffordE-mail: [email protected]

Calcium integrin binding protein (CIB1) is an EFhand protein withimportant roles in hemostasis, apoptosis, and several other biologicalprocesses. Unlike the inactive N-terminal EFhands, EFIII is a mixedCa2+/Mg2+ site that binds Ca2+ with a weaker affinity than theCa2+ specific EFIV. Since five of the six Ca2+ coordinating residueswithin EFIII and EFIV are identical, we hypothesized that the lastchelating position, the -Z residue of EFIII (D127) and EFIV (E172),might confer these different metal-binding characteristics. Genomeanalysis of EFhand proteins reveals that Glu is highly favored at thisposition (> 90%) over Asp (<10%), and biochemical/biophysicalstudies show that the –Z residue is important for determining metalaffinity, specificity and mediating conformational changes.We havegenerated and studied CIB1 mutants with neutral –Z residues(D127N or E172Q) or acidic –Z residues with different side chainlength (D127E or E172D) to investigate the importance of the –Zresidue identity. Our data shows that D127N and E172Q mutantshave reduced Ca2+ and Mg2+ affinity at the mutated site, whileD127E has increased Ca2+ and Mg2+ affinity at EFIII, and E172D has

decreased Ca2+ affinity and like wild type CIB1 was unable to bindMg2+ at EFIV.The D127N, E172Q and E172D mutants retained theability to bind to a target peptide derived from the alphaIIbcytoplasmic domain of platelet integrin alphaIIb-beta3, however,peptide binding to D127E was severely compromised. Additionalexperiments performed using a D127Q mutant showed similarCa2+/Mg2+ binding properties to D127N, but no peptide binding,suggesting that the longer Glu/Gln side chain replacing D127 distortsthe alphaIIb binding site. 3D NMR spectroscopy studies subsequentlyrevealed that the helices of EFIII indeed form the central region of thealphaIIb binding site.Therefore we suggest that the ancestral Glu atthe –Z position of EFIII was replaced with Asp during evolution tofacilitate the interaction with its biological target, the alphaIIbcytoplasmic domain.The D127 residue is also strictly conserved in theother CIB isoforms suggesting a common and important biologicalfunction for this residue in this protein family. (Supported by CIHR)

EF-hand Mutants of CIB1 Reveal a Unique Function for the -Z metal Coordinating Residue on Ca2+, Mg2+ and Target Peptide Interactions

76

77


Author(s): Minghua Wang and Felix D. GuerreroAffiliation: US Department of Agriculture, Agricultural Research Service, Knipling-Bushland US Livestock Insects Research Lab, 2700

Fredericksburg Rd., Kerrville,TX 78028, USAPresenter: Felix D. GuerreroE-mail: [email protected]

The southern cattle tick, Rhipicephalus (Boophilus) microplus, is aneconomically important parasite of cattle and transmits severalpathogenic microorganisms to its cattle host during the feedingprocess. Understanding the biology and genomics of R. microplus iscritical to developing novel methods for controlling these ticks.Wepresent a global comparative genomic analysis of a gene index of R.microplus comprised of 13,643 unique transcripts derived from42,512 expressed sequence tags (ESTs), representing approximately athird of the complement of R. microplus genes. Functional annotationusing RPSblast analysis identified conserved protein domains in theconceptually translated gene index and assigned GO terms to those

database transcripts which had informative BlastX hits. Blast ScoreRatio and SimiTri analysis compared the conceptual transcriptome ofthe R. microplus database to other eukaryotic proteomes and ESTdatabases, including those from 3 ticks.The most abundant proteindomains in BmiGI2 were also analyzed by SimiTri methodology. Alarge fraction of BmiGI entries have no homologs in other sequencedgenomes. Sets of genes were identified which had closer homologuesto mammalian genes than to insect genes. Members of these groupswould likely be poor choices as targets for development of novel tickcontrol technology.

Global Comparative Genomic Analysis of the Southern Cattle Tick


Author(s): Yoonsoo Hahn, Sangkyun Jeong, Karl Pfeifer, Byungkook LeeAffiliation: Laboratory of Molecular Biology, National Cancer Institute, NIHPresenter : Yoonsoo HahnE-mail: [email protected]

Humans have acquired many distinct phenotypic features since thedivergence of humans and chimpanzees. Gain of such human-specifictraits must be consolidated by genetic changes and subsequentnatural selection of the variants. Possible genetic modifications includealteration of gene expression pattern, accelerated protein evolution,novel gene formation, and gene inactivation.We developed abioinformatics method for systematic identification of putative human-specific gene inactivation instances caused by an exon-deletionmutation. First, we extracted chimpanzee genome regions each ofwhich is apparently missing in the corresponding orthologous humangenome locus.Then, we checked if the region matches one or moreregions of homologous non-human gene mRNAs. Finally, weperformed manual in-depth analysis to collect a small number ofhighly plausible candidates.These included the CMAH gene, whichwas previously known to be inactivated in humans by exon deletion.

Exon deletions in two novel cases involving MOXD2 and S100A15genes were experimentally verified. In both cases, all human genomicDNAs sampled from 6 different geographical locations had thedeletions while none of 6 non-human primate DNAs did.The proteinsequences of both genes are highly conserved in mammals includingprimates, mouse, dog, and opossum, implying that the function of thegenes is important for mammalian biology. Inactivation of MOXD2gene which encodes a monooxygenase in olfactory epithelia might beinvolved in altered smell sensitivity in humans. S100A15 gene isexpressed in skin of which loss-of-function may confer unknownstructural or physiological difference of the skin between the twospecies. Functional inactivation study of these genes using mice willprovide clues on phenotypic modification in humans caused by thehuman-specific functional loss of the genes.

Gene Inactivation by Exon Deletion in Human Evolution

78

79


Author(s): Zhen Li, Misha E. Coppens, Hilary A. M. Lauzon, Peter J. Krell, Christopher J. Lucarotti and Basil M. ArifAffiliation: Laboratory for Molecular Virology, Great Lakes Forestry CentrePresenter : Zhen LiE-mail: [email protected]

The two-year-cycle spruce budworm, Choristoneura biennis, harboursa number of viruses including an entomopoxvirus (CbEPV) that hasbeen previously isolated and characterized with respect to a numberof its genes and proteins.The viral genome is approximately 280 kb insize, and typical of EPVs, contains approximately 80% A+T residues.The genome was nebulized, cloned and partially sequenced.To date,contigs that cover in excess of 60% of the total genome weregenerated. Almost all the genes related to functions such as DNAreplication, repair, nucleotide metabolism, transcription, RNAmodification and protein modification that have been previously foundin the Amsacta moorei entomopoxvirus (AmEPV) have homologues

in the CbEPV genome. Indeed, the sequence so far indicates that theCbEPV genome aapoptosis, p35, was also found in the CbEPVgenome. Homologues of 6 gene families of AmEPV have been foundin CbEPV: 17K ORF family, which contains KilA-N domain (conservedDNA-binding domain), has 6 members in CbEPV (5 in AmEPV);methionine-threonine-glycine (MTG ) motif gene family has 6members in CbEPV (3 in AmEPV); alanine-leucine-isoleucine (ALI-like)gene family has 5 members in CbEPV (same as in AmEPV); AMV176gene family(function unknown),Tryptophan repeat gene family andleucine-rich repeat (LRR) gene family each have one homologuefound in CbEPV.

Sequence Analysis of the Choristoneura Biennis Entomopoxvirus Genome


Author(s): Jason Maydan, Stephane Flibotte, Joanne Lau, Mark Edgley, James Thomas and Donald MoermanAffiliation: University of British ColumbiaPresenter : Jason MaydanE-mail: [email protected]

We are using array comparative genomic hybridization (array CGH)to locate copy number polymorphisms (CNPs) in Caenorhabditiselegans.We have designed high-density (385,000 features)oligonucleotide microarrays that probe both the whole genome andspecific chromosomes. Using this approach we detect single-gene,heterozygous deletions with exon-specific resolution of the deletionbreakpoints.We have detected deletions as small as 141 bp, withbreakpoint resolution to within fewer than 50 bp in someexperiments.This approach is being used by the C. elegans GeneKnockout Consortium as a method of screening for mutagen-inducedknockout mutations.

We have also used array CGH to detect extensive natural genecontent variation in wild C. elegans isolates.The degree of variationwe observe in C. elegans has also been found in the human genome[1, 2].The nematode arrays consist of probes tiled across 98 percentof annotated exons in the genome. Some of the more divergentisolates carry deletions in roughly 2% of the genes in the canonicalN2 genome. CNPs are non-randomly distributed within and betweenchromosomes, occurring frequently on autosome arms and rarely intheir centers or on the X chromosome. Deletions are stronglyenriched in clustered unstable gene families.

Previous phylogenetic studies in C. elegans have indicated that rareinstances of outcrossing were important in the evolution of thespecies [3, 4]. Due to the limited number of markers used it has notbeen possible to specify which portions of the genome have beenexchanged between strains through recombination.We have detectedhaplotype blocks of shared CNPs and should be able to infer specificoutcrossing events that have occurred between strains.This researchshould greatly increase our understanding of the natural history andevolution of C. elegans.

1. Sebat, J., et al. Science, 2004. 305(5683): p. 525-8.

2. Sharp, A.J., et al. J Hum Genet, 2005. 77(1): p. 78-88.

3. Denver, D.R., K. Morris, and W.K.Thomas. Mol Biol Evol, 2003. 20(3):p. 393-400.

4. Haber, M., et al. Mol Biol Evol, 2005. 22(1): p. 160-73.

Copy Number Polymorphisms in Mutant and Natural C. elegans Isolates Detected by Oligonucleotide Array

80

81


Author(s): Hiroaki Ishida, Hao Huang, and Hans J.VogelAffiliation: Structural Biology Research Group, Department of Biological Sciences, University of Calgary, Calgary, CanadaPresenter : Hans J.VogelE-mail: [email protected]

Calmodulin (CaM) is one of the most extensively studied calcium-binding proteins due to its central role in calcium signaling pathways.The unique structure of CaM consists of two similar globular domains,the N- and C-domain, that are connected by a highly mobile centrallinker.The latter plays a critical role allowing the two domains of CaMto accommodate various CaM binding domains (CaMBDs) byrearranging the position of the domains. CaM is a highly conservedprotein and the amino-acid sequence is 100% conserved amongstvertebrate species. On the other hand, higher plant species havedeveloped a unique CaM regulatory system, compared with animals,in which several CaM isoforms are found to control different targetproteins. For example, soybean has five known CaM isoforms(sCaM1-5), three of which, sCaM1-3 are highly similar to mammalianCaM with more than 90% sequence identity, while sCaM4 and 5 aredivergent with ~78% sequence identity. Enzyme activation studiesshow that some CaM-target proteins are activated by both sCaM1and 4 while others are only activated by sCaM1 or 4, suggesting that

those isoforms are specifically used for controlling particular targetproteins. Here, we describe the solution structures of two differentisoforms, sCaM1 and 4. In addition, we have also solved the structureof sCaM4 in complex with the CaMBD from vacuolar calcium-ATPaseas the first reported structure for a plant CaM-target complex.

Vacuolar calcium-ATPase (a calcium-pump) has its CaMBD at its N-terminal region.The amino-acid sequence of the CaMBD does notbelong to any previously reported classes of CaMBD.The structure ofsCaM4 complexed with the synthetic peptide corresponding to theCaMBD revealed a novel CaM-target binding mode in which thebound peptide forms a unique helix-beta-turn-helix structure.Thetwo hydrophobic anchoring residues on the peptide are separated by16 residues and sCaM4 binds in an antiparallel orientation.Theresulting domain orientation of the two domains of sCaM4 in thiscomplex is distinct from those found in other previously determinedCaM-target complexes. (supported by AHFMR and CIHR.)

The Solution Structures of Two Soybean Calmodulin Isoforms and their Complex with a Vacuolar Calcium-ATPase Peptide

Emerging Technologies

Author(s): Guillaume Sillon,Yann Joly, Denise AvardAffiliation: Directrice de recherche, Centre de recherche en droit public, Université de Montréal, MontréalPresenter : Denise AvardE-mail: [email protected]

Research in pharmacogenomics is a growth area and the researchfindings are gradually being implemented into clinical practice.However, this new area of research also raises important ethical, socialand legal issues. For example research participants inpharmacogenomics need to know what benefits they could expectfrom this kind of research, if and how they should know aboutresearch results, or what social implications their participation in theresearch could have.

There is presently an unmet need for brief answers to commonethical and social questions emerging in this area.We hope to addressthis unmet need by developing FAQs, since they are considered atrustworthy method of communication and an effective means ofcommunicating key messages in a succinct fashion.

Method:Topics were identified through a review of the literature. Key subjectswere identified and evaluated by various audiences, in particularduring interviews with researchers from the “Pharmacogenomics of

Drug Efficacy and Toxicity in the Treatment of Cardiovascular Disease”project initiated by Genome Quebec/Canada. Draft FAQs werevalidated by the “Genetics and Society Project” team at theUniversité de Montreal.The feedback obtained during these pre-testing sessions was used to revise the questions and answers prior toposting them on the HumGen website (www.humgen.umontreal.ca).

Conclusion:Health professionals, policy makers, researchers and ethics committeesneed more information about the ELSI issues in pharmacogenomicresearch.The FAQ module stimulates communication and is animportant reference tool for a broad audience of stakeholders.Thepharmacogenomics FAQ section of our website will evolve basedon new scientific developments and their applications, and will beupdated frequently.

The poster will demonstrate features from the website and willinclude evaluation questions.

Pharmacogenomics Ethical, Social and Legal Issues:Frequently Asked Questions on the Web

82

83


Author(s): Brian E. Colton and Eric R. Stephen Affiliation: Departmental Biotechnology Office—Health CanadaPresenter : Brian E. Colton E-mail: [email protected]

Dual Use refers to the risks associated with the potential for misuseof legitimate scientific research for malicious purposes.The risks maybe associated with specific biological agents, or the knowledge ortechnologies resulting from research. Misuse of agents or knowledgecould be unintentional (inadvertent applications of experimentalresults) or intentional (state-level bioweapons programs orbioterrorism).

On March 1-2, 2006 a Health Canada and Defence Research andDevelopment Canada, co-sponsored a National Forum on Dual UseBiotechnology which was held in Ottawa.The purpose of the Forumwas to initiate a Canadian dialogue on Dual Use biotechnology issuesin order to begin to build a broad understanding of the nature andextent of the issue.

Forum participants took part in a facilitated discussion, supported byexpert presentations, designed to open and advance dialogue on theDual Use issue.

A list of issues to be considered in more detail over time as theDual Use issue is explored more thoroughly as a Canadian approachwas developed. Issues identified by participants include some ofthe following:

• Pathogen control, resources and knowledge – There is a need forclear understanding and a distinct approach to manage both thepathogen resources used in the research and the knowledge flowresulting from research.

• Science culture – the culture of awareness, acceptance andaccountability in the science community regarding Dual Use.

• Funders’ obligations – to address the funders’ potential obligations,one starting principle could be to demand that all proposals havebeen reviewed for Dual Use risk prior to submission to funders.

• Publishers’ obligations – need to address the publisher rolethrough potential development of guidelines/codes of conduct.

• A preliminary list of overarching principles and goals for a federalpolicy on Dual Use was also created.They identified potential rolesand responsibilities of stakeholders for implementing a Canadianapproach to Dual Use.

• Over the next 12-24 months, consultations will likely beundertaken to provide input into the dialogue culminating in asynthesis session and a report outlining cogent advice to thefederal government on a policy direction for Canada.

The Dual Use Dilemma


Author(s): Guy, A., Griffin, G. & Gauthier, C.Affiliation: Canadian Council on Animal CarePresenter : Allison GuyE-mail: [email protected]

The Canadian Council on Animal Care (CCAC) is the nationalorganization responsible for overseeing the care and use of animals inscience. Like most other national oversight systems, whether legislatedor not, the CCAC system is based on the Russell and Burch tenet ofthe Three Rs (Replacement, Reduction and Refinement). Publication ofthe mouse and human genome sequences and the ability tomanipulate an animal’s genome has led to a rapid increase in thenumbers of animals being “designed” to answer questions concerninghuman disease.There are underlying ethical challenges and animalwelfare problems associated with the use of these animals, includingthe large numbers of animals that are used in the pre-experimentalproduction phase, as well as the potential pain and distress associatedwith the procedures used and with the disease models themselves.The CCAC is in the process of developing guidelines on: geneticallyengineered animals, in particular to address these ethical issues and toimprove the welfare of the animals.

The development of high-throughput genomics, proteomics andmetabolomics technologies are resulting in simultaneous monitoringof the expression of large numbers of individual genes and proteins,permitting a more detailed study of disease processes. It may be tooearly to say what effect this will have on the overall pattern of animaluse in science. However, the potential of genomics technology as aThree Rs tool has already been recognized.The emergence of thesetechnologies, and the elucidation of biological mechanisms they mightprovide, may allow the identification of opportunities to replaceanimal use with in vitro alternatives. In addition, the ability to examinethe sub-clinical effects of smaller quantities of chemicals holds thepromise to minimize pain and distress and to reduce the numbers ofanimals involved as the examination of earlier and multipleexperimental endpoints within one animal becomes possible.Thechallenge will be to ensure that these emerging technologies areharnessed appropriately to support sound science, including theethical use of animals.

Emerging Technologies and the Impact on the Ethical Use of Animals in Science

84

85


Author(s): Wenqi Hu1, Susan Sillaots1, Sebastien Lemieux1, John Davison1, Anouk Breton1, Annie Linteau1, Chunlin Xin1, Sarah Kauffman 2,Jeff Becker 2, Bo Jiang1, and Terry Roemer1

Affiliation: 1 Merck Frosst Canada & Co. Center of Fungal Genetics, Montreal, Quebec, Canada, H2X 3Y8 and 2 Department ofMicrobiology, University of Tennessee, Knoxville, 37919

Presenter : Wenqi HuE-mail: [email protected]

Aspergillus fumigatus has become the most prevalent airbornefilamentous fungal pathogen in humans, causing severe and often fatalinvasive infections in immunocompromised patients. Current availableantifungal drugs clinically used to treat Invasive Apergillosis (IA) havelimited modes of action and few are safe and effective. Conservedessential genes offer new antifungal drug targets, and a comprehensivedetermination of all the essential genes has been achieved inSaccharomyces cerevisiae and Candida albicans.To identify andprioritize novel essential A. fumigatus drug targets, we have employeda promoter replacement (PR) strategy in which the endogenouspromoter of the target gene was replaced with a conditionalpromoter.Thus, gene essentiality could be directly determined byevaluating its conditional phenotype under repressing conditions. Inthis way, we have undertaken a large scale analysis of essential gene

identification in this clinically relevant fungal pathogen.We furtherdemonstrate that cidal/static terminal phenotypes could bedetermined using the conditional mutants constructed.We also showthat the conditional mutants constructed could be validated in animmuno-compromised mouse model of systemic aspergillosis. Finally,we show that ERG11 conditional mutant under repressing conditionsdisplayed a 10-fold MIC shift to its cognate inhibitor, fluconazole,suggesting that A. fumigatus conditional mutants provide sensitizedtarget-based whole cell assays suitable for compound screening.Collectively, the promoter replacement strategy offers methodologiesto directly identify, prioritize, and screen A. fumigatus essential genesfor cognate antifungal inhibitors.This project was cosponsored byGenome Canada/Genome Quebec and Merck & Co., Inc.

Aspergillus Fumigatus Essential Gene Identification and Antifungal Drug TargetPrioritization using Conditional Promoter System


Author(s): Roscoe Klinck, Anne Bramard, David Brunelle, Geneviève Dufresne-Martin, Julien Gervais-Bird, Lyna Inkel, Richard Madden,Panagiotis Prinos, Benoit Chabot, Sherif Abou Elela

Affiliation: Laboratoire de Génomique Fonctionnelle de l’Université de SherbrookePresenter: Roscoe KlinckE-mail: [email protected]

While it is now generally accepted that the majority of human genesundergo alternative splicing (AS), access to experimentally validatedtissue-specific annotation of these AS events has been difficult.Toaddress this, we have developed the LISA, (Layered and Integratedsystem for Splicing Annotation), a bioinformatics and experimentalplatform for RT-PCR based annotation of AS in human tissues and celllines.The system comprises automated in silico primer and PCRexperiment design, high throughput execution of PCR reactions onhuman total cDNA, capillary electrophoretic quantitation ofamplicons, data analysis and data filtering modules.The LISA usespublicly available mRNA and EST-based transcript compilations as astarting point for the annotation process. All proposed events areclassified by type and their existence and relative abundance areassessed in each RNA source.The system also allows the detection ofnovel AS events.

We have tested the LISA on 86 genes associated with apoptosis in 6to 12 human RNA sources. 89% of the 1025 AS events predicted forthese genes could be validated in at least one of the RNA sourcesanalyzed. One quarter of the genes showed strong evidence for novelAS events, 10 of these were selected and confirmed by sequencing.An in silico data filter was developed and applied to our database toidentify AS-associated differences between tumor and normal tissues.For the 86 gene set, this filter yielded an 11 gene subset harboring keyAS events which were subsequently evaluated for their functionalrelevance and potential as candidate AS-based cancer markers.

LISA:An Integrated System for Tissue-Specific Alternative Splicing Annotation

86

87


Author(s): Tony Kwan, David Benovoy, Christel Dias, Scott Gurd, David Serre, Harry Zuzan,Tyson A. Clark, Anthony Schweitzer, Hui Wang,Michelle K. Staples, John E. Blume,Thomas J. Hudson, Rob Sladek, and Jacek Majewski

Affiliation: Department of Human Genetics, McGill UniversityPresenter: Tony KwanE-mail: [email protected]

The sequencing and annotation of the human genome revealed anunexpectedly low number (~25000) of protein coding genes.Recent hypotheses postulate that alternative pre-mRNA splicingmay be an important mechanism for regulation of gene expressionand increasing the complexity of the mammalian transcriptome.Furthermore, variation in alternative splicing (AS) among individualsmay be responsible for phenotypic diversity and differentialsusceptibility to genetic disorders.

Microarray-based studies promise to provide new insights intogenome-wide splicing patterns; however, large-scale AS studies havegenerally been carried out using custom chips designed for specificexperimental purposes, and/or were limited by the amount ofsplicing-related genome annotation.The recently released AffymetrixExon Array relies on sets of probes targeted to individual exons,allowing independent measurement of expression levels of over 1million known and predicted human exons.

Here, we demonstrate the effectiveness of the Exon Array forinvestigating variation in AS among individuals. Our approach isbased on comparing lymphoblasts from the CEPH population, which

provides easy access to large amounts of mRNA, as well as highresolution (1kb) information on individual genotypes from theHapMap project.We used lymphoblasts (n=15) from two individualsto select candidate exons with differential levels of inclusion,followed by validation using RT-PCR. Confirmed true positives weretested for genetic effects by following their transmission in families(linkage) and significant genotype association within the CEPHHapMap panel (60 unrelated individuals).

We show that the Exon Array is a valuable discovery tool, allowingus to detect both known (EST-based) and novel (previouslyunannotated) cases of AS. Several of these cases are furthersupported by linkage and/or association analyses, suggesting thatthey have underlying genetic causes. Candidate genetic differencesare currently being investigated in order to elucidate themechanisms of splicing variation.The microarray coverage is alsobeing extended to the entire CEPH panel of 60 unrelatedindividuals, in order to assess the amount of splicing variation in thepopulation and identify its underlying genetic basis.

Using the Affymetrix Exon Array to Investigate Variation in Alternative Splicing in a Human Population


Author(s): Mathieu Larivière, Gregory de Crescenzo, Daniel SinnettAffiliation: Division of Hematology-Oncology, research center, Ste. Justine Medical University Center, University of Montreal,

Montreal, CanadaPresenter: Mathieu LarivièreE-mail: [email protected]

PurposeThe gel shift assay is the most simple and most common methodused for detecting DNA-protein interactions. However this technique,which requires stringent experimental conditions to promote DNA-protein binding, does not always allow for the detection of weakinteraction effects, particularly not in a dynamic environment. It is alsodifficult to determine the association and dissociation constants forthe proteins assayed by gel shift, and precise, accurate values arealmost impossible to measure. Surface Plasmon Resonance (SPR)-based biosensors allow bio-molecular interactions to be assessed inreal-time and in a dynamic cellular context which is an importantadvantage when compared to the use of gel shift assays. Still, fewstudies have used the biosensor technique to investigate DNA-protein interactions. In the preliminary study shown here, we used theBiacore 3000 to examine interactions between the Sp1 transcriptionfactor and its consensus sequence using nuclear extracts.

MethodsNuclear extracts were obtained from Hep G2 cells and the Biacore3000 was used to assess bio-molecular interactions.Two biotinylatedoligonucleotides were immobilized on two distinct streptavidin-coatedsensorchips; one corresponds to the Sp1 consensus sequence and theother, to a mutated version. An HBS buffer solution containing 50ng/ulof poly [d(I-C)] was used to dilute nuclear extracts and injectionswere performed at a constant rate of 10ul/minute for 3 minutes.Results were confirmed by gel shift assays.

ResultsWe showed that it is indeed possible to study the impact of amutation in a transcription factor consensus sequence on DNA-protein binding using the Biacore 3000. Furthermore, the differentialbinding results obtained using the biosensor technique were perfectlycorrelated with those obtained by gel shift.The greater sensitivity ofthe Biacore 3000, the fact that nuclear extracts were used in adynamic setting, and the speed at which we were able to produceaccurate results using minimal sample quantities, render the biosensorthe technique of choice for studying the functionality of regulatorypolymorphisms in gene promoter regions.

Using the Biacore 3000 Biosensor for Detecting DNA-protein Interactions

88

89


Author(s): Srini Perera, Philip Wong, Kathleen Rossi, Peter Krell and Basil ArifAffiliation: Great Lakes Forestry Centre, Sault Ste. Marie, Ontario, CanadaPresenter : Srini PereraE-mail: [email protected]

The Amsacta moorei entomopoxvirus (AmEV) has been shown toestablish a successful infection in the gypsy moth (Lymantria dispar)cell line IPLB-Ld652.We have compared the infectivity of AmEV inLd652 cells and in FPMI-Cf-70-B2 cells which is a clonal cell linederived from the spruce bud worm, Choristoneura fumiferana.Virusinfection was assayed by microscopic observations, and bydetermining budded virus titers and occlusion body production at aninitial multiplicity of infection (moi) of 1 and 10 pfu/cell. Both cell linessupported high levels of budded virus production as determined byTCID50 assays. However, occlusion body production was lower inCf70-B2 cells. At 5 days post infection (dpi) 80% and 60% of Cf70-B2cells contained occlusion bodies when infected at 10 and 1 moirespectively. In contrast, approximately 100% of Ld652 cells supported

occlusion body production at both 10 and 1 moi. Subsequentpassaging (up to four passages) showed a gradual decline in buddedvirus titers in both cell lines. Despite the high levels of budded virusproduction, Cf70-B2 cells underwent apoptosis as a result of AmEVinfection. At late stages of infection, cell membrane blebbing andformation of apoptotic bodies were visualized by light microscopy.Preliminary experiments showed increased levels of caspase-likeactivity in Cf70-B2 cells infected with AmEV as compared touninfected cells.We are currently investigating if Cf-70-B2 cells showother features of apoptosis such as cellular DNA fragmentation andchromatin condensation.The expression of anti-apoptotic genes P35and IAP is also being investigated.

Propagation of Amsacta Moorei Entomopoxvirus in Two Lepidopteran Cell Lines,IPLB-Ld652 and FPMI-Cf-70-clone B2


Author(s): Jean Sharp, CWC Inc., Andrea Hallendy-MallonAffiliation: Health CandaPresenter : Jean Sharp, Public Awareness Analyst/Project OfficerE-mail: [email protected]

Health Canada’s Departmental Biotechnology Office (DBO) hasdeveloped a Grade Nine Biotechnology Activity Kit , as a pilot project,in the Ottawa region.The Kit is designed to give grade nine studentsthe opportunity to explore many aspects of biotechnology through:research; writing; oral presentations; and creative arts.

The students are asked to write a magazine article for a fictitiousCanadian science journal using information gathered from varioussources, including electronic and print resources, community resourcesand personally collected data. Essentially intended to spark teenagers’interest in biotechnology, it will also inform them of Health Canada’sregulatory process for products made with biotechnology. Additionalactivities include holding a debate on the benefits and risks of usingbiotechnology products; the use of genetically modified crops indeveloping countries; and the way Health Canada regulatesnew products.

From the very start of this project, DBO sought input from teachersby setting up a booth at the Science Teachers’ Association of Ontarioannual conference, surveying the teachers for activity ideas and

format. An education consultant with the Ottawa-Carleton DistrictSchool Board was instrumental in developing the evaluation criteria,providing the teachers with the tools to grade their students on thevarious activities contained within. Once the Kit was in a draft form itwas focus tested by science teachers and principals. It received highpraise and was endorsed for its usefulness and suitability.

The plan is to provide Kits to English Public High Schools in theOttawa region during the fall of 2006 and at the end of the schoolyear evaluate their usefulness as a teaching tool. If modifications arerequired they will be made, the Kits translated and offered to all highschools in Ontario for the 2007-08 school year. At the same time wewill be reaching out to Science Teachers’ Associations in all Provincesand Territories with a view to adapting the Kit to meet their curricula,hopefully in time for distribution for the 2008-09 school year.

Once finalized, the Kit will be posted on Health Canada’s Web siteunder the theme Biotechnology.

Grade Nine Biotechnology Activity Kit: Benefits and Risks of Biotechnology

90

91


Author(s): Lorraine SheremetaAffiliation: Health Law Institute, University of AlbertaPresenter : Lorraine SheremetaE-mail: [email protected]

Convergent technologies, employing nanotechnology, biotechnology,information technology, and cognitive science are expected to effectprofound societal change; increasingly they are challenging existingresearch funding, policy, and regulatory frameworks in Canada.Vexingchallenges will continue to arise as convergence implicates genomics.

E3LS research is that focuses on the Ethical, Environmental, Economic,Legal and Social issues of new technologies.The purpose of E3LSresearch is to facilitate the responsible research and development,commercialization and public acceptance (or non-acceptance) of newtechnologies in and by society. Genome Canada’s research fundingmodel which demands integration of GE3LS research at the earlystage of scientific project development is one that warrantsconsideration by Canada’s national research funding agencies –including the Canadian Institutes of Health Research (CIHR), theNational Science and Engineering Research Council (NSERC) and theSocial Sciences and Humanities Research Council (SSHRC) – in thecontext of convergent technologies.

Whilst recognizing that Genome Canada’s efforts to engage GE3LSresearch have not escaped criticism, the model stands as the exemplarof interdisciplinary E3LS research in Canada.The purpose of thispresentation is to examine the evolution of GE3LS research inCanada and to argue that GE3LS researchers hold the necessaryexpertise to develop appropriate collaborations and new capacity toproactively evaluate the E3LS implications of convergent technologies.

As Canada moves towards the development of a nationalnanotechnology strategy, the proactive consideration of “NE3LS”issues is of critical importance. As a matter of priority, there is a needto expand capacity of Canadian researchers, from a variety ofdisciplines, who can lead these E3LS outside of the traditional field ofgenomics. NE3LS research will be highlighted as a particular exampleof the downstream value of Genome Canada’s GE3LS researchinitiatives.

Genomics and Convergence: Developing Capacity for “E3LS” Research in Canada


Author(s): Reza Dowlatabadi, Aalim M.Weljie,Trevor A.Thorpe, Hans J.Vogel, and Ed C.YeungAffiliation: Metabolomics Research Centre, University of Calgary, Calgary, Alberta, CanadaPresenter : Hans J.VogelE-mail: v [email protected]

White spruce is an important commercial species for reforestation.The success in its propagation through somatic embryogenesis is welldocumented. In order to improve the quality of the somatic embryosgenerated, a better theoretical understanding of this system is stillneeded.The variable quality embryos generated in vitro suggestscontrol at the protein and metabolite level. In order to probemetabolic changes, we have adopted a metabolic profiling or‘metabolomics’ approach referred to as “Metabolic footprinting”.

Metabolomics allows one to study the full complement of metabolitesin biofluids or tissue extracts of various organisms by NMRspectroscopy or MS spectrometry. Metabolite footprinting is a uniquetechnique whereby culture media from growing cells is analyticallyanalyzed to determine which metabolites are consumed andexcreted. Such experiments are advantageous in that there is no needto quench cellular metabolism or extract intracellular metabolitesthrough time-consuming protocols. Here we demonstrate the

application of this footprinting assay to somatic embryo cells of whitespruce tree (Picea glauca) using 1D 1H NMR spectroscopy.We havesurveyed embryogenesis metabolism in two types of media,maintenance (MN) and maturation (MT). MN media does not resultin shoot apical meristem (SAM) formation, while MT media inducesthe necessary changes preceding germination.The two types of mediawere easily distinguished using metabolomics analysis, namelymultivariate pattern recognition statistics (partial least squaresdiscriminatory analysis). From this analysis, we have identifiednumerous compounds involved with branch-chained amino acidpathways such as valine and isoleucine, as well as proline- associatedcompounds.These results are explained on the basis of knownmetabolic pathways implicated in plant and animal developmentalprocesses.We aim to further enhance this analysis through the use ofLC-NMR techniques to characterize further specific plant metabolites.(Supported by Genome Alberta/Canada).

Developing Robust White Spruce Trees for Reforestation:Metabolic Footprinting By 1H NMR

92

93


Author(s): Deming Xu1*, Bo Jiang1*,Troy Ketela2, Sebastien Lemieux3, Catherine Bachewich4, Karynn Veillette1, Nick Martel1, John Davison1,Susan Sillaots1, Steve Trosok1, Howard Bussey5, Phil Youngman6, and Terry Roemer1

Affiliation: * These authors have contributed equally, 1Merck Frosst Canada & Co., Center of Fungal Genetics, Montreal, Quebec, Canada,2Infinity Pharmaceuticals, Cambridge, MA, USA, 3University of Montreal, Montreal, Quebec, Canada, 4Department of Biology, Conco

Presenter : Deming XuE-mail: [email protected]

Candida albicans is the principal fungal pathogen of humans causing aspectrum of disease ranging from superficial skin and mucosalinfections to life threatening nosocomial infections. Continueddiscovery of more efficacious antifungals is required to address thisunmet medical need.The completion and annotation of the C.albicans genome has provided the foundation and opportunity fornovel drug discovery strategies.Taking advantage of the results of aGenome Canada Competition II project (1), we have constructed agenome-wide fitness test platform in a project (2) co-sponsored byMerck & Co., Inc. and Genome Canada/Quebec.

The fitness test relies on chemically induced haploinsufficiency, whichhas been demonstrated in S. cerevisiae to be highly specific for target-specific inhibitors, and provides an efficient genomic approach toelucidating the mechanisms of action (MOA) of small-moleculeinhibitors.The first version of the C. albicans fitness test (CaFT)contains ~3000 heterozygous deletion strains, representing ~45% ofthe genome. Each of these strains is tagged with two unique DNAbarcodes at the deleted allele so that the effect of an antifungalinhibitor on individual strains in the mixed population can be

monitored with DNA microarrays.The specific responses of strains,hence the corresponding genes, can then be assessed in relation topotential mechanisms of inhibitory compounds.

The effectiveness of the CaFT is demonstrated in a series of proof-of-concept experiments with ~25 reference compounds.The CaFTresults reveal unambiguously the targets and/or the MOAs of all butone known inhibitors. Furthermore, we adopted the CaFT as ascreening strategy in drug discovery and identified a class of novelantifungal molecules that are predicted by the CaFT to affectmicrotubule dynamics.The MOA of these compounds has beenindependently verified by genetic and biochemical means. Ourresearch represents the first such demonstration of applying agenome-wide fitness test strategy directly in the fungal pathogen toelucidating MOAs of antifungal molecules.

(1). Genome wide essential gene identification in Candida albicans andapplications to antifungal drug discovery.

(2). Chemogenomics-driven drug discovery in the human fungalpathogen, Candida albicans.

Genome-wide Fitness Test of Heterozygotes and Studies of Mechanisms of Actionof Inhibitory Compounds in Candida Albicans

www.genomecanada.ca

program 2020 vision - genomecanada.ca€¦ · laboratory include the search for genes predisposing...

Documents