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Mapping copy number variation by population-scale genome sequencing


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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Figure 1: SV discovery and genotyping in population scale sequence data.
Figure 2: Comparative assessment of deletion discovery methods.
Figure 3: Analysis of deletion presence and absence in three populations.
Figure 4: Contribution of SV formation mechanisms to the SV size spectrum.
Figure 5: Mapping hotspots of SV formation in the genome.


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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 ( 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.

Author information

Authors and Affiliations




The authors contributed this study at different levels, as described in the following. SV discovery: K.W., C.S., R.E.H., K.C., C.A., A.A., S.C.Y., R.K.C., A.C., Y.F., I.H., F.H., Z.I., D.K., R.Li., Y.L., C.L., R.Lu., X.J.M., H.E.P., L.D., G.T.M., J.S., Ju.W., Ka.Y., Ke.Y., E.E.E., M.B.G., M.E.H., S.A.M. and J.O.K. SV validation: R.E.M., K.W., K.C., A.A., S.C.Y., F.G., M.K.K., J.K., J.N., A.E.U., X.S., A.M.S., J.A.W., Y.Z., Z.D.Z., M.A.B., J.S., M.S., M.E.H., C.L. and J.O.K. SV genotyping: K.W., R.E.H., J.K., J.N., M.E.H. and S.A.M. Data analysis: R.E.M., C.S., C.A., A.A., R.E.H., K.C., S.C.Y., R.K.C., A.C., D.F.C., Y.F., F.H., L.M.I., Z.I., J.M.K., M.K.K., S.K., J.K., E.K., D.K., H.Y.K.L., J.L., R.Li, Y.L., C.L., R.Luo, X.J.M., J.N., H.E.P., T.R., A.S., X.S., M.P.S., J.A.W., Ji.W., Y.Z., Z.D.Z., M.A.B., L.D., G.T.M., G.M., J.S., M.S., Ju.W., Ka.Y., Ke.Y., E.E.E., M.B.G., M.E.H., C.L, S.A.M. and J.O.K. Preparation of manuscript display items: R.E.M., K.W., C.S., C.A., A.A., R.E.H., S.C.Y., L.M.I., S.K., E.K., M.K.K., X.J.M., X.S., J.A.W., M.B.G., S.A.M. and J.O.K. Co-chairs of the Structural Variation Analysis group: E.E.E., M.E.H. and C.L. The following equally contributed to directing the described analyses and participating in the design of the study and should be considered joint senior authors: E.E.E., M.B.G., M.E.H., C.L., S.A.M. and J.O.K. The manuscript was written by the following authors: R.E.M. and J.O.K.

Corresponding author

Correspondence to Jan O. Korbel.

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Competing interests

H.E.P. and Y.F. are employees of Life Technologies, the manufacturers of the SOLiD sequencing platform. R.K.C. is an employee of Illumina Cambridge Ltd., the manufacturer of the Illumina sequencing platform.

Additional information

Data sets described here can be obtained from the1000 Genomes Project website at (July 2010 Data Release). Individual SV discovery methods can be obtained from sources mentioned in Supplementary Table 2, or upon request from the authors.

Lists of participants and affiliations are shown in Supplementary Information.

Supplementary information

Supplementary Information

This file contains Supplementary Notes, Supplementary Figures 1- 15 with legends, Supplementary Tables 2, 6-8, 12-17, 19 and legends for Supplementary Tables 1-20 (see separate files for Supplementary Tables 1, 3- 5, 9-11, 18 and 20) and Supplementary References. (PDF 3547 kb)

Supplementary Methods

This file contains Supplementary Methods and References. (PDF 281 kb)

Supplementary Table 1

This file contains the sequencing statistics for SV discovery. (XLS 47 kb)

Supplementary Table 3

This file contains a complete list of low coverage calls by institution and set. (ZIP 14400 kb)

Supplementary Table 4

This file contains a complete list of trio calls by institution and set. (ZIP 12314 kb)

Supplementary Table 5

This file contains the Gold standard SV sets for NA12878 and NA12156 from 4 external and orthogonal data sets. (XLS 209 kb)

Supplementary Table 9

This file contains the functional analysis of deletions, which overlap transcripts. (XLS 8530 kb)

Supplementary Table 10

This file contains the Gene Ontology (GO) enrichment analysis for deletions overlapping protein coding regions. (XLS 32 kb)

Supplementary Table 11

This file contains the formation mechanisms and ancestral states of SVs inferred with the BreakSeq pipeline. (XLS 3738 kb)

Supplementary Table 18

This file contains a summary of assembled breakpoints for deletion release set. (XLS 2117 kb)

Supplementary Table 20

This file contains the overlap of partial or whole genotyped, coding region deletions with OMIM Morbid Map. (XLS 26 kb)

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Mills, R., Walter, K., Stewart, C. et al. Mapping copy number variation by population-scale genome sequencing. Nature 470, 59–65 (2011).

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