Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies.
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We would like to acknowledge C. Hardy, R. Smith, A. De Witte and S. Giles for their assistance with validation. M.A.B.’s group was supported by a grant from the National Institutes of Health (RO1 GM59290) and G.T.M.’s group by grants R01 HG004719 and RC2 HG005552, also from the NIH. J.O.K.’s group was supported by an Emmy Noether Fellowship of the German Research Foundation (Deutsche Forschungsgemeinschaft). J.W.’s group was supported by the National Basic Research Program of China (973 program no. 2011CB809200), the National Natural Science Foundation of China (30725008; 30890032; 30811130531; 30221004), the Chinese 863 program (2006AA02Z177; 2006AA02Z334; 2006AA02A302; 2009AA022707), the Shenzhen Municipal Government of China (grants JC200903190767A; JC200903190772A; ZYC200903240076A; CXB200903110066A; ZYC200903240077A; ZYC200903240076A and ZYC200903240080A) and the Ole Rømer grant from the Danish Natural Science Research Council. E.E.E.’s group was supported by grants P01 HG004120 and U01 HG005209 from the National Institutes of Health. C.L.’s group was supported by grants from the National Institutes of Health: P41 HG004221, RO1 GM081533 and UO1 HG005209 and X.S. was supported by a T32 fellowship award from the NIH. We thank the Genome Structural Variation Consortium (http://www.sanger.ac.uk/humgen/cnv/42mio/) and the International HapMap Consortium for making available microarray data. The authors acknowledge the individuals participating in the 1000 Genomes Project by providing samples, including the Yoruba people of Ibadan, Nigeria, the community at Beijing Normal University, the people of Tokyo, Japan, and the people of the Utah CEPH community. Furthermore, we thank R. Durbin and L. Steinmetz for comments on the manuscript.