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Mother of GreenPhylogenomics of the P. falciparum Apicoplast
Indiana Center for Insect GenomicsAn International Center of Excellence
University of Notre DamePurdue UniversityIndiana University
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Mother of Green
Malaria causes 1.5 - 2.7 million deaths every year 3,000 children under age five die of malaria every day Plasmodium falciparum causes human malaria Drug resistance a world-wide problem Targeted drug design through phylogenomics
P. falciparum
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Mother of Green P. falciparum has three genomesNuclear, mitochondrial, plastid
Animals and insects have only two Target the third genome No harm to animals New antimalarial drug High risk, high tech, high payoff
J. Romero-SeversonDepartment of Biological SciencesGreg MadeyDepartment of Computer Science
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Mother of GreenPlastids are the third genomeIntracellular organellesTerrestrial plants, algae, apicomplexansFunctions in plants and algae
PhotosynthesisOxidation of waterReduction of NADPSynthesis of ATPFatty acid biosynthesisAromatic amino acid biosynthesis
Functions in apicomplexans ?
Chloroplast in plant cell
Plastid in Toxoplasma sp.
Apicoplast in P. falciparum
plastid
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Mother of Green
The apicoplast appears to code for
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Find the ancestors of the apicoplast Identify genes in the ancestors Determine gene function Look for these genes in the P. falciparum nucleus Then study regulatory mechanisms in candidate genes
Mother of Green
Phylogenomics
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Phylogenomics of plastids Very old lineage (> 2.5 billion years) Cyanobacterial ancestor Three main plastid lineages
GlaucophytesGroup of freshwater algaeChloroplast resembles intact cyanobacteria
ChlorophytesGreen plant lineageChloroplast genome reducedMany chloroplast genes now in nuclear genome
RhodophytesRed algal lineage
Chloroplast genome bigger than in green plantsOomycetesApicomplexans
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Phylogenomics of plastids One cyanobacterial ancestor ? Many? Lineages are not linear
One plastid origin
Multiple plastid origins
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The process ofendosymbiosis.
Horizontal GeneTransfer (arrows)from the plastid tothe nucleus.
The nucleomorph is aremnant of theoriginal endosymbiontnucleus.
Primitive eukaryote
Endosymbiontplastid
Secondaryendosymbionts
Secondeukaryote
Secondarynonphotosyntheticendosymbiont
Cyanobacteria
Nucleus
Nucleus
Nucleomorph
Plastiddisappears
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Secondaryendosymbiont
Tertiaryendosymbionts
Third eukaryote
Tertiarynonphotosyntheticendosymbiont
Plastid disappears
Tertiary endosymbiosis.Horizontal Gene Transfer
P. falciparum
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The information gathering problem
Rapid accumulation of raw sequence information~100 sequenced chloroplast genomes~55 sequenced cyanobacterial genomesRate of accumulation is increasingInformation accumulates faster than analyses finishInformation in forms not readily accessible
SolutionSemi-automated web-servicesSmart web -services
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The computational problemPhylogenetic trees
NP-hardPoisoned by information conflictPhylogenies based on individual genes
Maximum likelihood models exist
Processes are parallelizableAccess to compute farms inadequateRAW number-crunching powerGreedy
Similar genealogies may be mergedConvergence not possible for all
Makes computational problem more daunting
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The synthesis of ATP
Candidate genes for deep phylogeny
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Light-dependent ATP synthesis (photophosphorylation)
Hypothesis:Evolution of ATP synthaseseverely constrained
Candidate for ascertainment ofdeep phylogeny
1st : Individual subunit genealogy
2nd: Merge the data, reanalyze
ATP synthaseThe wheel that powers life
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Phylogenomics of the P. falciparum Apicoplast
Extract data from public and private databasesWeb services
Choose a metric for sequence comparisonMegablast and others
Choose a method to infer genealogy
Maximum Likelihood (ML) Develop a strategy to use ML that is feasiblefastDNAml and others
Create a computational infrastructureCompute farmsDedicated chunks of compute farms
Deal with management issues Solve band width problems Convince someone to fund this!
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Indiana Center for Insect Genomics
MissionCreate genomics tools for high impact arthropods lacking such tools
Develop integrated bioinformatics programs for arthropod genomics
Develop specific projects with potential practical application
Foster high risk ideas with mini-grants
Jeanne Romero-Severson, Director
Frank Collins, Co-PI at University of Notre DamePeter Cherbas, Co-PI at Indiana UniversityJeff Stuart, Co-PI at Purdue University
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