Phenologs An example of using bioinformatics to find new genes for genetic traits

Publish in

Documents

6 views

Please download to get full document.

View again

of 25
All materials on our website are shared by users. If you have any questions about copyright issues, please report us to resolve them. We are always happy to assist you.
Share
Description
Phenologs An example of using bioinformatics to find new genes for genetic traits. BIO337 Systems Biology / Bioinformatics – Spring 2014 . Edward Marcotte, Univ of Texas at Austin. Edward Marcotte/Univ. of Texas/BIO337/Spring 2014.
Transcript
PhenologsAn example of using bioinformatics to find new genes for genetic traitsBIO337 Systems Biology / Bioinformatics – Spring 2014 Edward Marcotte, Univ of Texas at AustinEdward Marcotte/Univ. of Texas/BIO337/Spring 2014Virtually all genetic traits and diseases affect molecular structures that are evolutionarily conserved. Consequently, human traits and diseases often have equivalents in other species, even distant ones. Edward Marcotte/Univ. of Texas/BIO337/Spring 2014We know far more about genes & traits in lower organisms than in us.How do deeply conserved gene networks relate to traits, structures, and diseases in different organisms?Can these tellus about these?…McGary, Park et al. PNAS (2010)Edward Marcotte/Univ. of Texas/BIO337/Spring 2014Phenologs = significantly overlapping sets oforthologous genes, such that each gene in a given setgives rise to the same phenotype in that organism(e.g., human)(e.g., worm)(e.g., breast cancer)(e.g., specific worm phenotype)McGary, Park et al. PNAS 107:6544-9 (2010)Edward Marcotte/Univ. of Texas/BIO337/Spring 2014An example phenolog: a high incidence of male C. elegans maps to human breast/ovarian cancersincludesBRCA1McGary, Park et al. PNAS 107:6544-9 (2010)Edward Marcotte/Univ. of Texas/BIO337/Spring 2014Building & searching a collection of phenotypesMining available databases + manual collection from the primary literatureSpanning ~300 human diseases,>7,000 model organism mutational phenotypesComputational scan phenotypes for novel models of a disease of interest,identify significant phenologs using permutation testsMcGary, Park et al. PNAS (2010)Edward Marcotte/Univ. of Texas/BIO337/Spring 2014Discovering phenologsMcGary, Park et al. PNAS (2010)Edward Marcotte/Univ. of Texas/BIO337/Spring 2014There are 1,000’s of phenologs between human diseases and mouse, yeast, worm, and even plant traitsSome cases we knew about already, serving as positive controls…For example, genes for mouse cataracts suggest genes for human cataracts...But many cases were surprising!A defect in...suggests genes for ...yeast lovastatin sensitivity angiogenesis defectsworm abnormal body wall muscle cell polarization gastrointestinal hemorrhageyeast hydroxyurea sensitivity hemolytic anemia plant cotyledon development defects mental retardationE. coli chemical sensitivies chemically-induced seizures McGary, Park et al. PNAS 107:6544-9 (2010)Woods, Blomet al. BMC Bioinformatics, 14:203 (2013)Edward Marcotte/Univ. of Texas/BIO337/Spring 2014Example #2: plant negative gravitropismdefects predictWaardenburg syndrome, a congenital disease withcharacteristic craniofacial, hearing, and pigmentation alterationsMichael Murphy, M.D. ~~Fukaki et al., The Plant Journal14, 425–430 (1998)Assorted websitesWaardenburg syndrome(accounts for ~2-5% of cases of deafness)Plants failing to grow upwardsEdward Marcotte/Univ. of Texas/BIO337/Spring 2014www.petplanet.co.ukWaardenburg syndrome is a defect of neural crest cellsSome WS correlates in other animals:Deafness in Dalmatian dogs (22% unilaterally deaf)Variations in the Blenheim spot ofCavalier King Charles SpanielsAssociation between white blue-eyed cats and deafness(noted by Darwin in 1859)White forelock and deafness/bowel bowel blockage in foals& many more...Neural crest cells migrateduring embryonic developmentwww.silvarcea.co.ukHeike & Hing, Gene Reviews (2009)Edward Marcotte/Univ. of Texas/BIO337/Spring 2014Inactivating SEC23IP—predicted from Arabidopsis—in a tadpole disrupts neural crest cells, consistent with Waardenburg syndromeSEC23IP localizes to theneural crest cells & inducesneural crest defects upon knockdownMcGary, Park et al. PNAS 107:6544-9 (2010)Edward Marcotte/Univ. of Texas/BIO337/Spring 2014Phenologs identify evolutionarily conserved systems of proteins relevant to particular traits/diseases. Last commonancestorSet of genes in LCAPlantHumanarabidopsis.infoGenes nowused to directpolarized growthin gravitropismGenes nowused to directneural crestcell migrationOrthologousgenesMcGary, Park et al. PNAS (2010)Edward Marcotte/Univ. of Texas/BIO337/Spring 2014Summary of a plant model of Waardenburg syndromeVALIDATECANDIDATE GENEin frog, CONFIRMPLANT MODEL…suggest new WS genes, confirmed in frogs, validating the plant model.BEGIN WITH KNOWN GENESfor Waardenburg syndromeFIND PLANT ORTHOLOGS thatshare mutant phenotypes (gravitropism)PREDICT novel Waardenburg genesWaardenburg syndromegenes……suggest a relevant plantsystem. Plant genes…??PREDICT AND VALIDATEnew gravitropismgenesSEARCH FORMUTATIONSin humansMcGary, Park et al. PNAS (2010)Edward Marcotte/Univ. of Texas/BIO337/Spring 2014Example #3: Yeast genes linked to statin drug sensitivity predict mammalian blood vessel defectsThe human versions of these yeast genes are candidate angiogenesis genesCan these really tell us about these?www.chemistryland.comMcGary, Park et al. PNAS (2010)Dorling Kindersley Edward Marcotte/Univ. of Texas/BIO337/Spring 2014Disrupting the SOX13 gene causes strong blood vessel defectshemorrhaging in later stage embryos& angiogenesis defects in culturedhuman umbilical vein cellsMcGary, Park et al. PNAS (2010)Edward Marcotte/Univ. of Texas/BIO337/Spring 2014Last commonancestorSet of genes in LCAYeast HumanGenes nowused tomaintain cellwallsGenes nowused toform bloodvesselsOrthologousgenesEdward Marcotte/Univ. of Texas/BIO337/Spring 2014The yeast/angiogenesis gene moduleEdward Marcotte/Univ. of Texas/BIO337/Spring 2014Chemicals that interact genetically with this module are candidate angiogenesis inhibitors1144 assays fromHillenmeyer et al.,Science (2008)www.chemistryland.comCha et al., PLoS Biology (2012)Edward Marcotte/Univ. of Texas/BIO337/Spring 2014Screening for drugs that interact genetically with this yeast module led us to identify a new angiogenesis inhibitorTBZ = thiabendazoleAn FDA-approved antifungal drug with 40 years of safety data
  • Approved by the U.S. Food and Drug Administration in 1967
  • fungicide and parasiticide
  • No mutagenic or carcinogenic effects
  • 2 year safety trials in animals
  • - Off-patent, now marketed as a generic drug
  • Edward Marcotte/Univ. of Texas/BIO337/Spring 2014Imaging the blood vessels of a living, transgenic tadpole in a dish of water200 mmkdr:GFP transgenic XenopuslaevisImage: HyeJiChaEdward Marcotte/Univ. of Texas/BIO337/Spring 2014Thiabendazole disrupts vascular integrity,causing retraction and rounding of vascular endothelial cellsControl (DMSO carrier)+ TBZCha et al., PLoS Biology (2012)Edward Marcotte/Univ. of Texas/BIO337/Spring 2014reversibly…Edward Marcotte/Univ. of Texas/BIO337/Spring 2014TBZ slows the growth of human fibrosarcoma tumors transplanted into immune-compromised miceVasculature in tumor sectionsCha et al., PLoS Biology (2012)Edward Marcotte/Univ. of Texas/BIO337/Spring 2014Summarizing the “road map” to a newvascular disrupting agentMouse genes linked toangiogenesis……suggest a relevant yeastsystem. Yeast genes……suggest new angiogenesis genes, confirmed in frogs, validating the method.…mouse tumor trials,and human cell assays.…confirmed in frogs…Drug screens in yeastsuggest candidateangiogenesis drugs…Cha et al., PLoS Biology (2012)Edward Marcotte/Univ. of Texas/BIO337/Spring 2014Summary of the major themes
  • Genetic traits and diseases often arise from perturbing any one (or more) of a set or module of genes, e.g. components of the same pathway or protein complex
  • Pathways and complexes can be deeply evolutionarily conserved, often more deeply than the diseases or traits they are linked to
  • Knowing the underlying module of genes thus predicts new candidate genes for any of the linked traits across organisms, e.g. as for yeast lovastatin sensitivity predicting vertebrate angiogenesis genes
  • Edward Marcotte/Univ. of Texas/BIO337/Spring 2014
    Related Search

    Previous Document

    Darwin

    Next Document

    Journal #10

    Related Documents
    View more...
    We Need Your Support
    Thank you for visiting our website and your interest in our free products and services. We are nonprofit website to share and download documents. To the running of this website, we need your help to support us.

    Thanks to everyone for your continued support.

    No, Thanks