Mother of Green Phylogenomics of the P. falciparum Apicoplast Indiana Center for Insect Genomics An...
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Mother of GreenMother of Green
Phylogenomics of the Phylogenomics of the P. falciparumP. falciparum ApicoplastApicoplast
Indiana Center for Insect GenomicsIndiana Center for Insect GenomicsAn International Center of ExcellenceAn International Center of Excellence
University of Notre DameUniversity of Notre DamePurdue UniversityPurdue UniversityIndiana UniversityIndiana University
Mother of GreenMother of Green
• Malaria causes Malaria causes 1.5 - 2.7 million deaths every year1.5 - 2.7 million deaths every year
• 3,000 children under age five die of malaria every 3,000 children under age five die of malaria every
dayday
•Plasmodium falciparum Plasmodium falciparum causes human malariacauses human malaria
• Drug resistance a world-wide problemDrug resistance a world-wide problem
• Targeted drug design through phylogenomicsTargeted drug design through phylogenomics
• Malaria causes Malaria causes 1.5 - 2.7 million deaths every year1.5 - 2.7 million deaths every year
• 3,000 children under age five die of malaria every 3,000 children under age five die of malaria every
dayday
•Plasmodium falciparum Plasmodium falciparum causes human malariacauses human malaria
• Drug resistance a world-wide problemDrug resistance a world-wide problem
• Targeted drug design through phylogenomicsTargeted drug design through phylogenomics
P. falciparumP. falciparum
Mother of GreenMother of Green
• P. falciparumP. falciparum has three genomes has three genomesNuclear, mitochondrial, plastidNuclear, mitochondrial, plastid
• Animals and insects have only twoAnimals and insects have only two• Target the third genomeTarget the third genome• No harm to animalsNo harm to animals• New antimalarial drugNew antimalarial drug• High risk, high tech, high payoffHigh risk, high tech, high payoff
J. Romero-SeversonJ. Romero-SeversonDepartment of Biological SciencesDepartment of Biological SciencesGreg MadeyGreg MadeyDepartment of Computer ScienceDepartment of Computer Science
J. Romero-SeversonJ. Romero-SeversonDepartment of Biological SciencesDepartment of Biological SciencesGreg MadeyGreg MadeyDepartment of Computer ScienceDepartment of Computer Science
Mother of GreenMother of Green
•Plastids are the third genome•Intracellular organelles •Terrestrial plants, algae, apicomplexans•Functions in plants and algae
PhotosynthesisOxidation of water Reduction of NADPSynthesis of ATPFatty acid biosynthesisAromatic amino acid biosynthesis
•Functions in apicomplexans ?
•Plastids are the third genome•Intracellular organelles •Terrestrial plants, algae, apicomplexans•Functions in plants and algae
PhotosynthesisOxidation of water Reduction 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
Mother of GreenMother of Green
•The apicoplast appears to code for <30
proteins.
• Repair, replication and transcription
proteins
•Why is the apicoplast essential?
• 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 GreenPhylogenomicsMother of GreenPhylogenomics
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
Phylogenomics of plastids
• One cyanobacterial ancestor ?• Many?• Lineages are not linear
One plastid origin
Multiple plastid origins
The process of endosymbiosis.
Horizontal Gene Transfer (arrows) from the plastid to the nucleus.
The nucleomorph is a remnant of the original endosymbiont nucleus.
Primitive eukaryote
Endosymbiont plastid
Secondary endosymbionts
Second eukaryote
Secondary nonphotosynthetic endosymbiont
Cyanobacteria
Nucleus
Nucleus
Nucleomorph
Plastid disappears
Secondary endosymbiont
Tertiary endosymbionts
Third eukaryote
Tertiary nonphotosynthetic endosymbiont
Plastid disappears
Tertiary endosymbiosis. Horizontal Gene Transfer
P. falciparum
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-services “Smart” web-services
The computational problem
•Phylogenetic trees NP-hardPoisoned by information conflict
•Phylogenies based on individual genesMaximum likelihood models exist Processes are parallelizableAccess to compute farms inadequateRAW number-crunching powerGreedy
• Similar genealogies may be mergedConvergence not possible for allMakes computational problem more daunting
Light-dependent ATP synthesis (photophosphorylation)
Hypothesis:Evolution of ATP synthase severely constrained
Candidate for ascertainment of deep phylogeny
1st: Individual subunit genealogy
2nd: Merge the data, reanalyze
ATP synthaseThe wheel that powers life
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!
Indiana Center for Insect GenomicsIndiana Center for Insect Genomics
MissionMissionCreate genomics tools for high impact arthropods lacking such toolsCreate genomics tools for high impact arthropods lacking such tools
Develop integrated bioinformatics programs for arthropod genomicsDevelop integrated bioinformatics programs for arthropod genomics
Develop specific projects with potential practical applicationDevelop specific projects with potential practical application
Foster high risk ideas with mini-grantsFoster high risk ideas with mini-grants
Jeanne Romero-Severson, DirectorFrank Collins, Co-PI at University of Notre DamePeter Cherbas, Co-PI at Indiana UniversityJeff Stuart, Co-PI at Purdue University
Jeanne Romero-Severson, DirectorFrank Collins, Co-PI at University of Notre DamePeter Cherbas, Co-PI at Indiana UniversityJeff Stuart, Co-PI at Purdue University