Large-scale comparative sequencing promises to reconstruct the evolutionary history of the human genome and to highlight the functional genetic differences between human and other mammalian species. Regions enriched for segmental duplication are not adequately resolved within preliminary working draft genome assemblies;however, these regions contribute significantly to disease, the emergence of novel genes and significant genetic differences between and within species. The object of this four-year proposal is to a) assess the pattern of genome-wide segmental duplication of 10 mammalian species, b) to provide high quality sequence continuity across these genetically complex regions, and c) assess the extent of polymorphism within the great ape species by generating deeper sequencing datasets from diverse subspecies. The results of these analyses will address three questions: 1) Was the burst of recent duplications in the human and great ape ancestral lineage idiosyncratic to hominids? 2) How has the interspersed versus tandem configuration changed during the course of mammalian evolution? and 3) Is the diversity of these segments consistent with other forms of genetic variation among humans and great apes? The data will significantly enhance the quality and annotation of forthcoming mammalian genome assemblies, improve our understanding of the frequency of de novo duplications events, provide insight into the mechanisms underlying segmental duplication, and improve annotation of lineage-specific gene families that lack clear orthologs within outgroup species. Such targeted studies are essential to complete our understanding of the evolution of the human genome and the role of segmental duplication in human diversity and disease.

Public Health Relevance

Recently duplicated sequences contribute both directly and indirectly to human disease by contributing to copy-number polymorphism and sporadic rearrangements. This project will generate a comprehensive view of the evolution and diversity of duplicated sequences and provide insight into the mechanisms of disease- causing rearrangements and the origin of this susceptibility to disease in the human species.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Research Project (R01)
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Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Brooks, Lisa
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University of Washington
Schools of Medicine
United States
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Hehir-Kwa, Jayne Y; Marschall, Tobias; Kloosterman, Wigard P et al. (2016) A high-quality human reference panel reveals the complexity and distribution of genomic structural variants. Nat Commun 7:12989
Nuttle, Xander; Giannuzzi, Giuliana; Duyzend, Michael H et al. (2016) Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility. Nature 536:205-9
Gordon, David; Huddleston, John; Chaisson, Mark J P et al. (2016) Long-read sequence assembly of the gorilla genome. Science 352:aae0344
Shi, Lingling; Guo, Yunfei; Dong, Chengliang et al. (2016) Long-read sequencing and de novo assembly of a Chinese genome. Nat Commun 7:12065
Huddleston, John; Eichler, Evan E (2016) An Incomplete Understanding of Human Genetic Variation. Genetics 202:1251-4
Mohajeri, Kiana; Cantsilieris, Stuart; Huddleston, John et al. (2016) Interchromosomal core duplicons drive both evolutionary instability and disease susceptibility of the Chromosome 8p23.1 region. Genome Res 26:1453-1467
Dennis, Megan Y; Eichler, Evan E (2016) Human adaptation and evolution by segmental duplication. Curr Opin Genet Dev 41:44-52
Watson, C T; Steinberg, K M; Graves, T A et al. (2015) Sequencing of the human IG light chain loci from a hydatidiform mole BAC library reveals locus-specific signatures of genetic diversity. Genes Immun 16:24-34
1000 Genomes Project Consortium; Auton, Adam; Brooks, Lisa D et al. (2015) A global reference for human genetic variation. Nature 526:68-74
Xue, Yali; Prado-Martinez, Javier; Sudmant, Peter H et al. (2015) Mountain gorilla genomes reveal the impact of long-term population decline and inbreeding. Science 348:242-5

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