MEDICAL GENETICS-MEDICAL GENETICS-INTRODUCTIONINTRODUCTION

Brig Nuzhat Mushahid

March 2015

ALL DISEASE (WITH THE POSSIBLE EXCEPTION

OF TRAUMA)

ARE GENETIC!

Traditional category of genetic diseases represents only those conditions in which the genetic contribution is particularly marked

Importance of Genetics to MedicineImportance of Genetics to MedicineImportance of Genetics to MedicineImportance of Genetics to Medicine

• Globally 7.6 million children are born annually with severe genetic or congenital malformations

• 1 % of all newborn infants possess gross chromosomal abnormality

• 90% of these infants are born in mid- and low-income countries.

• In the developed world, genetic and congenital disorders are the second most common cause of infant and childhood death

• Serious disease with significant genetic component develops in approx 5% individuals younger than 25 years

• Life time frequency of genetics disease estimation 670 per 1000

Prevalence of more common conditions for referralPrevalence of more common conditions for referralPrevalence of more common conditions for referralPrevalence of more common conditions for referral

• Down syndrome (1/600 live births and increases with advanced maternal age)

• Cystic Fibrosis (1/2500 Caucasian Americans)• Fragile X syndrome (1/1,000 males and 1/800 female

carriers of which 30% will be mentally retarded)• Sickle cell disease (1/500 of African American births)• Hemophilia - Factor VIII Deficiency (48/100,000 male

births)• Duchenne muscular dystrophy (200/million male births)• Hemochromatosis (1/450 individuals)• Breast cancer (1/8 women of which 5-10% of will have a

genetic predisposition)

• If you were offered the “sequencing of whole of your genome”

• Would you consent for that?– YES

– NO

• Why??The Human Genome Project

Sequencing of first genome by Sequencing of first genome by Fredrick SangerFredrick SangerSequencing of first genome by Sequencing of first genome by Fredrick SangerFredrick Sanger

• 5,000 bases long and from a virus called phiX174 that infects bacteria

• Sanger’s team sequenced others including the DNA from human mitochondria

• Two important discoveries made Sangers work possible– PCR– Electrophoresis

technique

Born 13 August 1918[

Rendcomb, Gloucestershire, England

Died 19 November 2013 (aged 95)Cambridge, Cambridgeshire, England[

Nationality British

Fields Biochemistry

Institutions •University of Cambridge•Laboratory of Molecular Biology

Alma mater St John's College, Cambridge[

Robert SinsheimerRobert SinsheimerUniversity of CaliforniaUniversity of CaliforniaRobert SinsheimerRobert SinsheimerUniversity of CaliforniaUniversity of California

• Catalyst for scientists to start thinking about sequencing the human genome.

• By 1986• two of the organisation

provided considerable amounts of funding – the US Department of

Energy and – the National Institutes

of Health.• Launched in 1986 by

Charles DeLisi.• James Watson came on

board

• In 1989• support of the Prime

Minister Margaret Thatcher,

• Medical Research Council (MRC) released £11m towards the project for the next three years.

DefinitionsDefinitionsDefinitionsDefinitions

 GENETICS: a branch of biology that deals with the heredity and variation of organisms

GENOME – the whole hereditary information of an organism that is encoded in the DNA

HEREDITARY: Derived from one’s parents

FAMILIAL: derived from one’s parents and are transmitted in the germ line through the generations

CONGENITAL: “born with” Some congenital diseases are not genetic

Aims of the project:Aims of the project:Aims of the project:Aims of the project:

to identify the approximate 100,000 genes in the to identify the approximate 100,000 genes in the human DNA.human DNA.

determine the sequences of the 3 billion bases that determine the sequences of the 3 billion bases that make up human DNA.make up human DNA.

store this information in databases.store this information in databases.

develop tools for data analysis.develop tools for data analysis.

address the ethical, legal, and social issues that arise address the ethical, legal, and social issues that arise from genome research. from genome research.

• $3 billion over 13 years

• the ‘International Human Genome Sequencing Consortium’,

• scientists from 20 institutions in six countries:

• France, Germany, Japan, China, the UK and the USA

• ‘G5’ were:

– Broad Institute/Whitehead Institute for Biomedical Research (MIT) in Cambridge, USA

– Washington University in St Louis, USA

– Baylor College of Medicine in Houston, USA

– Department of Energy’s Joint Genome Institute in Walnut Creek, USA

– Wellcome Trust Sanger Institute (previously known as the Sanger Centre) in Cambridge, UK

Prof John Sulston &Prof John Sulston &Robert H. WaterstonRobert H. WaterstonProf John Sulston &Prof John Sulston &Robert H. WaterstonRobert H. Waterston

• During the 1990s, Fred Sanger’s sequencing method was automated

• used successfully, to sequence the genome of the nematode worm, Caenorhabditis. Elegans.

• This work acted as a test project for sequencing the human genome

DNA sequencing is the process of working out the order of DNA sequencing is the process of working out the order of the bases, A, C, G and T, in a strand of DNA.the bases, A, C, G and T, in a strand of DNA.DNA sequencing is the process of working out the order of DNA sequencing is the process of working out the order of the bases, A, C, G and T, in a strand of DNA.the bases, A, C, G and T, in a strand of DNA.

‘ ‘Chain Termination MethodChain Termination Method ‘ ‘Chain Termination MethodChain Termination Method

Sangers sequencingSangers sequencingSangers sequencingSangers sequencing

• DNA sequencing by hand was a long and laborious process for scientists,

• mistakes were often made and using radioactively-labelled bases could be dangerous.

• improvements and changes had to be made, • particularly if scientists were going to eventually

sequence the DNA of larger organisms, such as humans!

• They needed a technique that was safe, easily scaled-up and efficient.

Automated Sequencing :80’sAutomated Sequencing :80’sAutomated Sequencing :80’sAutomated Sequencing :80’s

• Automatic sequencing machines became commercially available

• It was easier to avoid making mistakes. • Fragments of DNA were still separated by size • DNA bases were now labelled with coloured dyes (A =

Green, C = Blue, G = Yellow and T = Red). • All four DNA bases could be loaded in the same lane. • Automated sequencing

– Cost to sequence 1 million bases: £10,000

– Time to sequence a human genome: 600 years

• Capillary sequencing• 1990s• Cost to sequence 1 million bases: £3,457• Time to sequence a human genome: 12 years

Whose genome is being sequenced?Whose genome is being sequenced?Whose genome is being sequenced?Whose genome is being sequenced?

- the first reference genome is a composite genome from several different people.

- generated from 10-20 primary samples taken from numerous anonymous donors across racial and ethnic groups.

Ethical, legal and social implications of the Ethical, legal and social implications of the Human Genome ProjectHuman Genome ProjectEthical, legal and social implications of the Ethical, legal and social implications of the Human Genome ProjectHuman Genome Project

How is each area benefited specifically by the How is each area benefited specifically by the Human Genome Project?Human Genome Project?How is each area benefited specifically by the How is each area benefited specifically by the Human Genome Project?Human Genome Project?- Improvements in medicine:

improved diagnosis of disease.- Microbial research: new energy

sources, bio fuels.- DNA forensics: identifying

potential suspects at a crime scene.

- Agriculture: more nutritious produce.

- Evolution and human migration: study migration of different population groups based on female genetic inheritance.

- Risk assessment: reduce the likelihood of heritable mutations.

Medical GeneticsMedical GeneticsMedical GeneticsMedical Genetics

Application of genetic principlesto medical practice.

Includes studies of inheritance, mappingdisease genes, diagnosis and treatment,and genetic counseling.

Long history of GeneticsLong history of GeneticsLong history of GeneticsLong history of Genetics

http://wellcomelibrary.org/

Eugenic movementsEugenic movementsEugenic movementsEugenic movements• “Eugenics” comes from the Greek roots for “good”

and “origin,” or “good birth” and involves applying principles of genetics and heredity for the purpose of improving the human race

• Galton (1822-1911) advocated a selective breeding program for humans in his book Hereditary Genius (1869)

• 1910, Davenport founded the Eugenics Record Office (ERO) at Cold Spring Harbor Laboratory on Long Island “to improve the natural, physical, mental, and temperamental qualities of the human family”

• 920s and 30s. the American Eugenics Society was founded

• legislation for their forced sterilization•  forced sterilization of over 64,000 people in the

United States • Buck v. Bell (1927), the state of Virginia sought to

sterilize Carrie Buck for promiscuity • lose power in the 1940s and was completely

discredited following the horrors of Nazi Germany.

Terminology:Terminology:Terminology:Terminology:

• Gene

• Alleles

• Nucleotides

• Codon

• Genetic Code

GENE and ALLELEGENE and ALLELEGENE and ALLELEGENE and ALLELE

• Biological unit of heredity.• Gene hold the information to build and maintain their cells and

pass genetic traits to offsprings• In cells, a gene is portion of DNA• Allele

– Is one member of a pair or series of different forms of a gene.• Homozygous-an organism in which 2 copies of genes are identical

i.e. have same alleles• Heterozygous-an organism which has different alleles of the gene

• NUCLEOTIDE: group of molecules that when linked together, form the building blocks of DNA and RNA; composed of phosphate group, the bases:adenosine,cytosine,guanine and thymine and a pentose sugar(In case of RNA,thymine base is replaced by uracil)

• CODON: series of three adjacent bases in one polynucleotide chain of a DNA or RNA molecule which codes for a specific amino acid.

• GENETIC CODE: the sequence of nucleotides in a DNA or RNA molecule that determines the amino acid sequence in the synthesis of proteins.

Genes and dominanceGenes and dominanceGenes and dominanceGenes and dominance

• A trait is a specific characteristic that varies from one individual to another.

• The offspring of crosses between parents with different traits are called hybrids.

• Today, scientists call the factors that determine traits genes.

Gene (DNA)

RNA formation

Protein formation

Cell structure Cell enzymes

cell function

• Mutations:

Permanent changes in the DNA.

Those that affect germ cells are transmitted to the progeny.

Mutations in the somatic cells are not transferred to the progeny but are important in the causation of cancer and some congenital diseases.

Classification of genetic Classification of genetic disordersdisordersClassification of genetic Classification of genetic disordersdisorders

• Multifactorial

• Single gene

• Chromosomal

• Mitochondrial

• Somatic mutations (cancer)

Male

+ environment

Mandelian Disorders (single gene mutations)Mandelian Disorders (single gene mutations)Mandelian Disorders (single gene mutations)Mandelian Disorders (single gene mutations)

• Follow the classic Mandelian pattern of inheritance

• Disorders related to mutations in single gene with large effects

• Mutations cause the disease or predispose to the disease

• Typically not present in normal population

• Highly penetrant

• Very informative in medicine

• Generally rare

Chromosomal disordersChromosomal disordersChromosomal disordersChromosomal disorders

• Structural or numerical alteration in the autosomes and sex chromosomes

• Uncommon• High penetrance

Complex multigenic (polygenic) disordersComplex multigenic (polygenic) disordersComplex multigenic (polygenic) disordersComplex multigenic (polygenic) disorders

• Common• Interactions between multiple variant forms of genes and

environmental factors• Variant genes are called polymorphisms• Each variant gene confers a small increase in disease risk• Low penetrance• No single susceptibility gene is necessary or sufficient to

produce the disease• Several polymorphism are present when disease occurs

• Mutation in mitochondrial genes

• Mitochondrial genes• Inherited in different manner

• Somatic mutations• Not transmitted to progeny• Gives rise to cancers

• Mendel's first conclusion was that biological inheritance is determined by factors that are passed from one generation to the next.

• Mendel’s second conclusion is called the principle of dominance.

Mendel’s LawsMendel’s LawsMendel’s LawsMendel’s Laws

• Mendel’s Law of Segregation

• The alleles for each character segregate (separate) during gamete production (meiosis).

• Mendel’s Law of Independent Assortment

• The two pairs of alleles segregate independently of each other.