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8/13/2019 MOG Seattle

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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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