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.
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.
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