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The landscape of to...
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Gao, HongIllumina Inc, Illumina Artificial Intelligence Lab, Foster City, CA 94404 USA.
(författare)
The landscape of tolerated genetic variation in humans and primates
- Artikel/kapitelEngelska2023
Förlag, utgivningsår, omfång ...
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American Association for the Advancement of Science (AAAS),2023
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printrdacarrier
Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:uu-508588
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-508588URI
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https://doi.org/10.1126/science.abn8197DOI
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Språk:engelska
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Sammanfattning på:engelska &engelska
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Ämneskategori:ref swepub-contenttype
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Ämneskategori:art swepub-publicationtype
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Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.
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INTRODUCTION: Millions of people have received genome and exome sequencing to date, a collective effort that has illuminated for the first time the vast catalog of small genetic differences that distinguish us as individuals within our species. However, the effects of most of these genetic variants remain unknown, limiting their clinical utility and actionability. New approaches that can accurately discern disease-causing from benign mutations and interpret genetic variants on a genome-wide scale would constitute a meaningful initial step towards realizing the potential of personalized genomic medicine.RATIONALE: As a result of the short evolutionary distance between humans and nonhuman primates, our proteins share near-perfect amino acid sequence identity. Hence, the effects of a protein-altering mutation found in one species are likely to be concordant in the other species. By systematically cataloging common variants of nonhuman primates, we aimed to annotate these variants as being unlikely to cause human disease as they are tolerated by natural selection in a closely related species. Once collected, the resulting resource may be applied to infer the effects of unobserved variants across the genome using machine learning.RESULTS: Following the strategy outlined above we obtained whole-genome sequencing data for 809 individuals from 233 primate species and cataloged 4.3 million common missense variants. We confirmed that human missense variants seen in at least one nonhuman primate species were annotated as benign in the ClinVar clinical variant database in 99% of cases. By contrast, common variants from mammals and vertebrates outside the primate lineage were substantially less likely to be benign in the ClinVar database (71 to 87% benign), restricting this strategy to nonhuman primates. Overall, we reclassified more than 4 million human missense variants of previously unknown consequence as likely benign, resulting in a greater than 50-fold increase in the number of annotated missense variants compared to existing clinical databases.To infer the pathogenicity of the remaining missense variants in the human genome, we constructed PrimateAI-3D, a semisupervised 3D-convolutional neural network that operates on voxelized protein structures. We trained PrimateAI-3D to separate common primate variants from matched control variants in 3D space as a semisupervised learning task. We evaluated the trained PrimateAI-3D model alongside 15 other published machine learning methods on their ability to distinguish between benign and pathogenic variants in six different clinical benchmarks and demonstrated that PrimateAI-3D outperformed all other classifiers in each of the tasks.CONCLUSION: Our study addresses one of the key challenges in the variant interpretation field, namely, the lack of sufficient labeled data to effectively train large machine learning models. By generating the most comprehensive primate sequencing dataset to date and pairing this resource with a deep learning architecture that leverages 3D protein structures, we were able to achieve meaningful improvements in variant effect prediction across multiple clinical benchmarks.
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Biuppslag (personer, institutioner, konferenser, titlar ...)
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Hamp, TobiasIllumina Inc, Illumina Artificial Intelligence Lab, Foster City, CA 94404 USA.
(författare)
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Ede, JeffreyIllumina Inc, Illumina Artificial Intelligence Lab, Foster City, CA 94404 USA.
(författare)
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Schraiber, Joshua G.Illumina Inc, Illumina Artificial Intelligence Lab, Foster City, CA 94404 USA.
(författare)
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McRae, JeremyIllumina Inc, Illumina Artificial Intelligence Lab, Foster City, CA 94404 USA.
(författare)
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Singer-Berk, MorielBroad Inst MIT & Harvard, Program Med & Populat Genet, Boston, MA 02142 USA.
(författare)
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Yang, YanshenIllumina Inc, Illumina Artificial Intelligence Lab, Foster City, CA 94404 USA.
(författare)
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Dietrich, Anastasia S. D.Illumina Inc, Illumina Artificial Intelligence Lab, Foster City, CA 94404 USA.
(författare)
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Fiziev, Petko P.Illumina Inc, Illumina Artificial Intelligence Lab, Foster City, CA 94404 USA.
(författare)
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Kuderna, Lukas F. K.Illumina Inc, Illumina Artificial Intelligence Lab, Foster City, CA 94404 USA.;CSIC, Inst Evolutionary Biol UPF, PRBB, Dr Aiguader 88, Barcelona 08003, Spain.
(författare)
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Sundaram, LaksshmanIllumina Inc, Illumina Artificial Intelligence Lab, Foster City, CA 94404 USA.
(författare)
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Wu, YibingIllumina Inc, Illumina Artificial Intelligence Lab, Foster City, CA 94404 USA.
(författare)
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Adhikari, AashishIllumina Inc, Illumina Artificial Intelligence Lab, Foster City, CA 94404 USA.
(författare)
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Field, YairIllumina Inc, Illumina Artificial Intelligence Lab, Foster City, CA 94404 USA.
(författare)
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Chen, ChenIllumina Inc, Illumina Artificial Intelligence Lab, Foster City, CA 94404 USA.
(författare)
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Batzoglou, SerafimIllumina Inc, Illumina Artificial Intelligence Lab, Foster City, CA 94404 USA.;Seer Inc, Redwood City, CA 94065 USA.
(författare)
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Aguet, FrancoisIllumina Inc, Illumina Artificial Intelligence Lab, Foster City, CA 94404 USA.
(författare)
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Lemire, GabrielleBroad Inst MIT & Harvard, Program Med & Populat Genet, Boston, MA 02142 USA.;Harvard Med Sch, Boston Childrens Hosp, Dept Pediat, Div Genet & Genom, Boston, MA 02115 USA.
(författare)
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Reimers, RebeccaHarvard Med Sch, Boston Childrens Hosp, Dept Pediat, Div Genet & Genom, Boston, MA 02115 USA.;Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA.
(författare)
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Balick, DanielHarvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA.;Harvard Med Sch, Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA.
(författare)
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Janiak, Mareike C.Univ Salford, Sch Sci Engn & Environm, Salford M5 4WT, Lancs, England.
(författare)
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Kuhlwilm, MartinCSIC, Inst Evolutionary Biol UPF, PRBB, Dr Aiguader 88, Barcelona 08003, Spain.;Univ Vienna, Dept Evolutionary Anthropol, Djerassipl 1, A-1030 Vienna, Austria.;Univ Vienna, Human Evolut & Archaeol Sci HEAS, A-1030 Vienna, Austria.
(författare)
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Orkin, Joseph D.CSIC, Inst Evolutionary Biol UPF, PRBB, Dr Aiguader 88, Barcelona 08003, Spain.;Univ Montreal, Dept Anthropol, 3150 Jean Brillant, Montreal, PQ H3T 1N8, Canada.
(författare)
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Manu, ShivakumaraAcad Sci & Innovat Res AcSIR, Ghaziabad 201002, India.;CSIR Ctr Cellular & Mol Biol, Lab Conservat Endangered Species, Hyderabad 500007, India.
(författare)
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Valenzuela, AlejandroCSIC, Inst Evolutionary Biol UPF, PRBB, Dr Aiguader 88, Barcelona 08003, Spain.
(författare)
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Bergman, JurajAarhus Univ, Bioinformat Res Ctr, DK-8000 Aarhus, Denmark.;Aarhus Univ, Dept Biol, Sect Ecoinformat & Biodivers, DK-8000 Aarhus, Denmark.
(författare)
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Rousselle, MarjolaineAarhus Univ, Bioinformat Res Ctr, DK-8000 Aarhus, Denmark.
(författare)
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Silva, Felipe EnnesMamiraua Inst Sustainable Dev, Res Grp Primate Biol & Conservat, Estr Bexiga 2584, BR-69553225 Tefe, Amazonas, Brazil.;Univ Libre Bruxelles ULB, Dept Biol Organismes, Evolutionary Biol & Ecol EBE, Av Franklin D Roosevelt 50,CP 160-12, B-1050 Brussels, Belgium.
(författare)
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Agueda, LidiaBarcelona Inst Sci & Technol BIST, Ctr Genom Regulat CRG, CNAG CRG, Baldiri & Reixac 4, Barcelona 08028, Spain.
(författare)
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Blanc, JulieBarcelona Inst Sci & Technol BIST, Ctr Genom Regulat CRG, CNAG CRG, Baldiri & Reixac 4, Barcelona 08028, Spain.
(författare)
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Gut, MartaBarcelona Inst Sci & Technol BIST, Ctr Genom Regulat CRG, CNAG CRG, Baldiri & Reixac 4, Barcelona 08028, Spain.
(författare)
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de Vries, DorienUniv Salford, Sch Sci Engn & Environm, Salford M5 4WT, Lancs, England.
(författare)
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Goodhead, IanUniv Salford, Sch Sci Engn & Environm, Salford M5 4WT, Lancs, England.
(författare)
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Harris, R. AlanBaylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA.;Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA.
(författare)
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Raveendran, MuthuswamyBaylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA.;Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA.
(författare)
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Jensen, AxelUppsala universitet,Zooekologi(Swepub:uu)axeje389
(författare)
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Chuma, Idriss S.Tanzania Natl Pk, Arusha, Tanzania.
(författare)
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Horvath, Julie E.North Carolina Museum Nat Sci, Raleigh, NC 27601 USA.;North Carolina Cent Univ, Dept Biol & Biomed Sci, Durham, NC 27707 USA.;North Carolina State Univ, Dept Biol Sci, Raleigh, NC 27695 USA.;Duke Univ, Dept Evolutionary Anthropol, Durham, NC 27708 USA.;Univ North Carolina Chapel Hill, Renaissance Comp Inst, Chapel Hill, NC 27599 USA.
(författare)
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Hvilsom, ChristinaCopenhagen Zoo, DK-2000 Frederiksberg, Denmark.
(författare)
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Juan, DavidCSIC, Inst Evolutionary Biol UPF, PRBB, Dr Aiguader 88, Barcelona 08003, Spain.
(författare)
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Frandsen, PeterCopenhagen Zoo, DK-2000 Frederiksberg, Denmark.
(författare)
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de Melo, Fabiano R.Univ Fed Vicosa, BR-36570900 Vicosa, MG, Brazil.
(författare)
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Bertuol, FabricioUniv Fed Amazonas, Dept Genet, Lab Evolucao & Genet Anim LEGAL, BR-69080900 Manaus, Amazonas, Brazil.
(författare)
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Byrne, HazelUniv Utah, Dept Anthropol, Salt Lake City, UT 84102 USA.
(författare)
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Sampaio, IracildaUniv Fed Para, BR-66075110 Belem, Para, Brazil.
(författare)
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Farias, IzeniUniv Fed Amazonas, Dept Genet, Lab Evolucao & Genet Anim LEGAL, BR-69080900 Manaus, Amazonas, Brazil.
(författare)
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do Amaral, Joao ValsecchiMamiraua Inst Sustainable Dev, Res Grp Terr Vertebrate Ecol, BR-69553225 Tefe, Amazonas, Brazil.;Rede Pesquisa Estudos Div Conservacao & Uso Fauna, BR-69080900 Manaus, Amazonas, Brazil.;Comunidad Manejo Fauna Silvestre Amazonia Latinoa, Loreto 16001, Peru.
(författare)
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Messias, MariluceUniv Fed Rondonia, BR-78900000 Porto Velho, Rondonia, Brazil.;Univ Fed Rondonia, PPGREN Programa Posgrad Conservacao & Uso Recurso, BR-78900000 Porto Velho, Rondonia, Brazil.;Univ Fed Rondonia, BIONORTE Programa Posgrad Biodiversidade & Biotec, BR-78900000 Porto Velho, Rondonia, Brazil.
(författare)
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da Silva, Maria N. F.Inst Nacl de Pesquisas da Amazonia, Petropolis, BR-69067375 Manaus, Amazonas, Brazil.
(författare)
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Trivedi, MihirCSIR Ctr Cellular & Mol Biol, Lab Conservat Endangered Species, Hyderabad 500007, India.
(författare)
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Rossi, RogerioUniv Fed Mato Grosso, BR-78060900 Cuiaba, MT, Brazil.
(författare)
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Hrbek, TomasUniv Fed Amazonas, Dept Genet, Lab Evolucao & Genet Anim LEGAL, BR-69080900 Manaus, Amazonas, Brazil.;Trinity Univ, Dept Biol, San Antonio, TX 78212 USA.
(författare)
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Andriaholinirina, NicoleUniv Mahajanga, Life Sci & Environm Technol & Environm Mahajang, Mahajanga 401, Madagascar.
(författare)
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Rabarivola, Clement J.Univ Mahajanga, Life Sci & Environm Technol & Environm Mahajang, Mahajanga 401, Madagascar.
(författare)
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Zaramody, AlphonseUniv Mahajanga, Life Sci & Environm Technol & Environm Mahajang, Mahajanga 401, Madagascar.
(författare)
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Jolly, Clifford J.NYU, 550 1St Ave, New York, NY 10012 USA.
(författare)
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Phillips-Conroy, JaneWashington Univ St Louis, St Louis, MO 63130 USA.
(författare)
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Wilkerson, GregoryUniv Texas MD Anderson Canc Ctr, Keeling Ctr Comparat Med & Res, Houston, TX 77030 USA.;North Carolina State Univ, Coll Vet Med, Dept Clin Sci, Raleigh, NC 27606 USA.
(författare)
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Abee, ChristianUniv Texas MD Anderson Canc Ctr, Keeling Ctr Comparat Med & Res, Houston, TX 77030 USA.
(författare)
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Simmons, Joe H.Univ Texas MD Anderson Canc Ctr, Keeling Ctr Comparat Med & Res, Houston, TX 77030 USA.
(författare)
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Fernandez-Duque, EduardoYale Univ, New Haven, CT 06520 USA.;Univ Nacl Formosa, Argentina Fdn ECO, Formosa, Argentina.
(författare)
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Kanthaswamy, SreeArizona State Univ, Tempe, AZ 85281 USA.
(författare)
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Shiferaw, FekaduCarter Ctr Ethiopia, Guinea Worm Eradicat Program, PoB 16316, Addis Ababa 1000, Ethiopia.
(författare)
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Wu, DongdongChinese Acad Sci, Kunming Inst Zool, State Key Lab Genet Resources & Evolut, Kunming 650223, Yunnan, Peoples R China.
(författare)
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Zhou, LongZhejiang Univ, Sch Med, Ctr Evolutionary & Organismal Biol, Hangzhou 310058, Peoples R China.
(författare)
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Shao, YongChinese Acad Sci, Kunming Inst Zool, State Key Lab Genet Resources & Evolut, Kunming 650223, Yunnan, Peoples R China.
(författare)
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Zhang, GuojieZhejiang Univ, Sch Med, Ctr Evolutionary & Organismal Biol, Hangzhou 310058, Peoples R China.;Univ Copenhagen, Dept Biol, Villum Ctr Biodivers Genom, Sect Ecol & Evolut, DK-2100 Copenhagen, Denmark.;Chinese Acad Sci, Kunming Inst Zool, State Key Lab Genet Resources & Evolut, Kunming 650223, Yunnan, Peoples R China.;Zhejiang Univ, Med Ctr, Liangzhu Lab, 1369 West Wenyi Rd, Hangzhou 311121, Peoples R China.;Zhejiang Univ, Womens Hosp, Sch Med, 1 Xueshi Rd, Hangzhou 310006, Peoples R China.
(författare)
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Keyyu, Julius D.Tanzania Wildlife Res Inst TAWIRI, Head Off, POB 661, Arusha, Tanzania.
(författare)
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Knauf, SaschaFed Res Inst Anim Hlth, Friedrich Loeffler Inst, Inst Int Anim Hlth Hlth 1, D-17493 Greifswald, Germany.
(författare)
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Le, Minh D.Vietnam Natl Univ, Univ Sci, Fac Environm Sci, Dept Environm Ecol, Hanoi 100000, Vietnam.;Vietnam Natl Univ, Cent Inst Nat Resources & Environm Studies, Hanoi 100000, Vietnam.
(författare)
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Lizano, EstherCSIC, Inst Evolutionary Biol UPF, PRBB, Dr Aiguader 88, Barcelona 08003, Spain.;Catalan Inst Res & Adv Studies ICREA, Passeig de Lluis Companys 23, Barcelona 08010, Spain.
(författare)
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Merker, StefanState Museum Nat Hist Stuttgart, Dept Zool, D-70191 Stuttgart, Germany.
(författare)
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Navarro, ArcadiCSIC, Inst Evolutionary Biol UPF, PRBB, Dr Aiguader 88, Barcelona 08003, Spain.;Univ Autonoma Barcelona, Inst Catala Paleontol Miquel Crusafont, Edifici ICTA ICP,C Columnes S-N, E-08193 Barcelona, Spain.;Barcelona Inst Sci & Technol, Ctr Genom Regulat CRG, Av Doctor Aiguader N88, Barcelona 08003, Spain.;Pasqual Maragall Fdn, BarcelonaBeta Brain Res Ctr, C Wellington 30, Barcelona 08005, Spain.
(författare)
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Bataillon, ThomasAarhus Univ, Bioinformat Res Ctr, DK-8000 Aarhus, Denmark.
(författare)
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Nadler, TiloCuc Phuong Commune, Nho Quan Dist 430000, Ninh Binh Provi, Vietnam.
(författare)
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Khor, Chiea ChuenASTAR, Genome Inst Singapore GIS, 60 Biopolis St, Singapore 138672, Singapore.
(författare)
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Lee, JessicaMandai Nat, 80 Mandai Lake Rd, Singapore 729826, Singapore.
(författare)
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Tan, PatrickASTAR, Genome Inst Singapore GIS, 60 Biopolis St, Singapore 138672, Singapore.;SingHlth Duke NUS Inst Precis Med PRISM, Singapore 168582, Singapore.;Duke NUS Med Sch, Canc & Stem Cell Biol Program, Singapore 168582, Singapore.
(författare)
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Lim, Weng KhongSingHlth Duke NUS Inst Precis Med PRISM, Singapore 168582, Singapore.;Duke NUS Med Sch, Canc & Stem Cell Biol Program, Singapore 168582, Singapore.;SingHlth Duke NUS Genom Med Ctr, Singapore 168582, Singapore.
(författare)
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Kitchener, Andrew C.Natl Museums Scotland, Dept Nat Sci, Chambers St, Edinburgh EH1 1JF, Midlothian, Scotland.;Univ Edinburgh, Sch Geosci, Drummond St, Edinburgh EH8 9XP, Midlothian, Scotland.
(författare)
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Zinner, DietmarLeibniz Inst Primate Res, Germany Primate Ctr, Cognit Ethol Lab, D-37077 Gottingen, Germany.;Georg August Univ Gottingen, Dept Primate Cognit, D-37077 Gottingen, Germany.;Leibniz Sci Campus Primate Cognit, D-37077 Gottingen, Germany.
(författare)
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Gut, IvoBarcelona Inst Sci & Technol BIST, Ctr Genom Regulat CRG, CNAG CRG, Baldiri & Reixac 4, Barcelona 08028, Spain.;Univ Pompeu Fabra, Pg Luis Companys 23, Barcelona 08010, Spain.
(författare)
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Melin, AmandaUniv Calgary, Dept Anthropol & Archaeol, 2500 Univ Dr NW, Calgary, AB T2N 1N4, Canada.;Dept Med Genet, 3330 Hosp Dr NW,HMRB 202, Calgary, AB T2N 4N1, Canada.;Univ Calgary, Alberta Childrens Hosp, Res Inst, 2500 Univ Dr NW, Calgary, AB T2N 1N4, Canada.
(författare)
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Guschanski, Katerina,Dr.1978-Uppsala universitet,Zooekologi,Univ Edinburgh, Sch Biol Sci, Inst Ecol & Evolut, Edinburgh EH8 9XP, Midlothian, Scotland.(Swepub:uu)katgu490
(författare)
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Schierup, Mikkel HeideAarhus Univ, Bioinformat Res Ctr, DK-8000 Aarhus, Denmark.
(författare)
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Beck, Robin M. D.Univ Salford, Sch Sci Engn & Environm, Salford M5 4WT, Lancs, England.
(författare)
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Umapathy, GovindhaswamyAcad Sci & Innovat Res AcSIR, Ghaziabad 201002, India.;CSIR Ctr Cellular & Mol Biol, Lab Conservat Endangered Species, Hyderabad 500007, India.
(författare)
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Roos, ChristianLeibniz Inst Primate Res, German Primate Ctr, Gene Bank Primates & Primate Genet Lab, D-37077 Gottingen, Germany.
(författare)
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Boubli, Jean P.Univ Salford, Sch Sci Engn & Environm, Salford M5 4WT, Lancs, England.
(författare)
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Lek, MonkolYale Sch Med, Dept Genet, New Haven, CT 06520 USA.
(författare)
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Sunyaev, ShamilHarvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA.;Harvard Med Sch, Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA.
(författare)
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O'Donnell-Luria, AnneBroad Inst MIT & Harvard, Program Med & Populat Genet, Boston, MA 02142 USA.;Harvard Med Sch, Boston Childrens Hosp, Dept Pediat, Div Genet & Genom, Boston, MA 02115 USA.;Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA 02115 USA.
(författare)
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Rehm, Heidi L.Broad Inst MIT & Harvard, Program Med & Populat Genet, Boston, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA 02115 USA.;Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA.
(författare)
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Xu, JinboIllumina Inc, Illumina Artificial Intelligence Lab, Foster City, CA 94404 USA.;Toyota Technol Inst, Chicago, IL 60637 USA.
(författare)
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Rogers, JeffreyBaylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA.;Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA.;Wisconsin Natl Primate Res Ctr, Madison, WI 53715 USA.
(författare)
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Marques-Bonet, TomasCSIC, Inst Evolutionary Biol UPF, PRBB, Dr Aiguader 88, Barcelona 08003, Spain.;Barcelona Inst Sci & Technol BIST, Ctr Genom Regulat CRG, CNAG CRG, Baldiri & Reixac 4, Barcelona 08028, Spain.;Catalan Inst Res & Adv Studies ICREA, Passeig de Lluis Companys 23, Barcelona 08010, Spain.;Univ Autonoma Barcelona, Inst Catala Paleontol Miquel Crusafont, Edifici ICTA ICP,C Columnes S-N, E-08193 Barcelona, Spain.
(författare)
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Farh, Kyle Kai-HowIllumina Inc, Illumina Artificial Intelligence Lab, Foster City, CA 94404 USA.
(författare)
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Illumina Inc, Illumina Artificial Intelligence Lab, Foster City, CA 94404 USA.Broad Inst MIT & Harvard, Program Med & Populat Genet, Boston, MA 02142 USA.
(creator_code:org_t)
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