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Origins and functional impact of copy number variation in the human genome

Abstract

Structural variations of DNA greater than 1 kilobase in size account for most bases that vary among human genomes, but are still relatively under-ascertained. Here we use tiling oligonucleotide microarrays, comprising 42 million probes, to generate a comprehensive map of 11,700 copy number variations (CNVs) greater than 443 base pairs, of which most (8,599) have been validated independently. For 4,978 of these CNVs, we generated reference genotypes from 450 individuals of European, African or East Asian ancestry. The predominant mutational mechanisms differ among CNV size classes. Retrotransposition has duplicated and inserted some coding and non-coding DNA segments randomly around the genome. Furthermore, by correlation with known trait-associated single nucleotide polymorphisms (SNPs), we identified 30 loci with CNVs that are candidates for influencing disease susceptibility. Despite this, having assessed the completeness of our map and the patterns of linkage disequilibrium between CNVs and SNPs, we conclude that, for complex traits, the heritability void left by genome-wide association studies will not be accounted for by common CNVs.

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Figure 1: Overview of experimental strategy for CNV discovery and genotyping.
Figure 2: Functional impact of CNVs by type, frequency and population.
Figure 3: DNA sequence context enrichments around CNV breakpoints.
Figure 4: Circular map showing the genomic distribution of different classes of CNVs and their population differentiation.
Figure 5: Population properties of CNV show functional impact.

Accession codes

Primary accessions

ArrayExpress

Data deposits

The CNV discovery and CNV genotyping data are available at ArrayExpress (http://www.ebi.ac.uk/microarray-as/ae/) under accession numbers E-MTAB-40 and E-MTAB-142, respectively. Normalized CNV discovery data are available at http://www.sanger.ac.uk/humgen/cnv/42mio. CNVs are displayed at the Database of Genomic Variants (http://projects.tcag.ca/variation). CNV locations and genotypes are reported in Supplementary Tables 1 and 2.

References

  1. International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature 431, 931–945 (2004)

  2. Levy, S. & Strausberg, R. L. Human genetics: Individual genomes diversify. Nature 456, 49–51 (2008)

    CAS  ADS  Article  Google Scholar 

  3. Frazer, K. A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007)

    CAS  ADS  Article  Google Scholar 

  4. Marchini, J. et al. A new multipoint method for genome-wide association studies by imputation of genotypes. Nature Genet. 39, 906–913 (2007)

    CAS  Article  Google Scholar 

  5. Levy, S. et al. The diploid genome sequence of an individual human. PLoS Biol. 5, e254 (2007)

    Article  Google Scholar 

  6. Wheeler, D. A. et al. The complete genome of an individual by massively parallel DNA sequencing. Nature 452, 872–876 (2008)

    CAS  ADS  Article  Google Scholar 

  7. Conrad, D. F. et al. A high-resolution survey of deletion polymorphism in the human genome. Nature Genet. 38, 75–81 (2006)

    CAS  Article  Google Scholar 

  8. McCarroll, S. A. et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nature Genet. 40, 1166–1174 (2008)

    CAS  Article  Google Scholar 

  9. Redon, R. et al. Global variation in copy number in the human genome. Nature 444, 444–454 (2006)

    CAS  ADS  Article  Google Scholar 

  10. Hurles, M. E., Dermitzakis, E. T. & Tyler-Smith, C. The functional impact of structural variation in humans. Trends Genet. 24, 238–245 (2008)

    CAS  Article  Google Scholar 

  11. Stranger, B. E. et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315, 848–853 (2007)

    CAS  ADS  Article  Google Scholar 

  12. Buchanan, J. A. & Scherer, S. W. Contemplating effects of genomic structural variation. Genet. Med. 10, 639–647 (2008)

    Article  Google Scholar 

  13. McCarroll, S. A. et al. Deletion polymorphism upstream of IRiGM associated with altered IRGM expression and Crohn’s disease. Nature Genet. 40, 1107–1112 (2008)

    CAS  Article  Google Scholar 

  14. Willer, C. J. et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nature Genet. 41, 25–34 (2009)

    CAS  Article  Google Scholar 

  15. de Cid, R. et al. Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nature Genet. 41, 211–215 (2009)

    CAS  Article  Google Scholar 

  16. Yang, T. L. et al. Genome-wide copy-number-variation study identified a susceptibility gene, UGT2B17, for osteoporosis. Am. J. Hum. Genet. 83, 663–674 (2008)

    CAS  Article  Google Scholar 

  17. Lee, C., Iafrate, A. J. & Brothman, A. R. Copy number variations and clinical cytogenetic diagnosis of constitutional disorders. Nature Genet. 39 (suppl). S48–S54 (2007)

    CAS  Article  Google Scholar 

  18. Kidd, J. M. et al. Mapping and sequencing of structural variation from eight human genomes. Nature 453, 56–64 (2008)

    CAS  ADS  Article  Google Scholar 

  19. Korbel, J. O. et al. Paired-end mapping reveals extensive structural variation in the human genome. Science 318, 420–426 (2007)

    CAS  ADS  Article  Google Scholar 

  20. Gu, W., Zhang, F. & Lupski, J. R. Mechanisms for human genomic rearrangements. Pathogenetics 1, 4 (2008)

    Article  Google Scholar 

  21. Barnes, C. et al. A robust statistical method for case-control association testing with copy number variation. Nature Genet. 40, 1245–1252 (2008)

    CAS  Article  Google Scholar 

  22. Lohmueller, K. E. et al. Proportionally more deleterious genetic variation in European than in African populations. Nature 451, 994–997 (2008)

    CAS  ADS  Article  Google Scholar 

  23. Ng, P. C. et al. Genetic variation in an individual human exome. PLoS Genet. 4, e1000160 (2008)

    Article  Google Scholar 

  24. Kim, P. M., Korbel, J. O. & Gerstein, M. B. Positive selection at the protein network periphery: evaluation in terms of structural constraints and cellular context. Proc. Natl Acad. Sci. USA 104, 20274–20279 (2007)

    CAS  ADS  Article  Google Scholar 

  25. Tuzun, E. et al. Fine-scale structural variation of the human genome. Nature Genet. 37, 727–732 (2005)

    CAS  Article  Google Scholar 

  26. Jeffreys, A. J. et al. Human minisatellites, repeat DNA instability and meiotic recombination. Electrophoresis 20, 1665–1675 (1999)

    CAS  Article  Google Scholar 

  27. Bacolla, A. & Wells, R. D. Non-B DNA conformations, genomic rearrangements, and human disease. J. Biol. Chem. 279, 47411–47414 (2004)

    CAS  Article  Google Scholar 

  28. Myers, S. et al. A common sequence motif associated with recombination hot spots and genome instability in humans. Nature Genet. 40, 1124–1129 (2008)

    CAS  Article  Google Scholar 

  29. Jeffreys, A. J. et al. Meiotic recombination hot spots and human DNA diversity. Phil. Trans. R. Soc. Lond. B 359, 141–152 (2004)

    CAS  Article  Google Scholar 

  30. Huppert, J. L. & Balasubramanian, S. G-quadruplexes in promoters throughout the human genome. Nucleic Acids Res. 35, 406–413 (2007)

    CAS  Article  Google Scholar 

  31. Down, T. A. & Hubbard, T. J. NestedMICA: sensitive inference of over-represented motifs in nucleic acid sequence. Nucleic Acids Res. 33, 1445–1453 (2005)

    CAS  Article  Google Scholar 

  32. Sen, S. K. et al. Human genomic deletions mediated by recombination between Alu elements. Am. J. Hum. Genet. 79, 41–53 (2006)

    CAS  Article  Google Scholar 

  33. Tian, D. et al. Single-nucleotide mutation rate increases close to insertions/deletions in eukaryotes. Nature 455, 105–108 (2008)

    CAS  ADS  Article  Google Scholar 

  34. Campbell, P. J. et al. Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nature Genet. 40, 722–729 (2008)

    CAS  Article  Google Scholar 

  35. Pickeral, O. K., Makalowski, W., Boguski, M. S. & Boeke, J. D. Frequent human genomic DNA transduction driven by LINE-1 retrotransposition. Genome Res. 10, 411–415 (2000)

    CAS  Article  Google Scholar 

  36. Gondo, Y. et al. High-frequency genetic reversion mediated by a DNA duplication: the mouse pink-eyed unstable mutation. Proc. Natl Acad. Sci. USA 90, 297–301 (1993)

    CAS  ADS  Article  Google Scholar 

  37. Boyko, A. R. et al. Assessing the evolutionary impact of amino acid mutations in the human genome. PLoS Genet. 4, e1000083 (2008)

    Article  Google Scholar 

  38. Emerson, J. J., Cardoso-Moreira, M., Borevitz, J. O. & Long, M. Natural selection shapes genome-wide patterns of copy-number polymorphism in Drosophila melanogaster . Science 320, 1629–1631 (2008)

    CAS  ADS  Article  Google Scholar 

  39. Wang, L. L. et al. Intron-size constraint as a mutational mechanism in Rothmund-Thomson syndrome. Am. J. Hum. Genet. 71, 165–167 (2002)

    CAS  Article  Google Scholar 

  40. Sabeti, P. C. et al. Genome-wide detection and characterization of positive selection in human populations. Nature 449, 913–918 (2007)

    CAS  ADS  Article  Google Scholar 

  41. Voight, B. F., Kudaravalli, S., Wen, X. & Pritchard, J. K. A map of recent positive selection in the human genome. PLoS Biol. 4, e72 (2006)

    Article  Google Scholar 

  42. Smith, E. E. & Malik, H. S. The apolipoprotein L family of programmed cell death and immunity genes rapidly evolved in primates at discrete sites of host-pathogen interactions. Genome Res. 19, 850–858 (2009)

    CAS  Article  Google Scholar 

  43. Pickrell, J. K. et al. Signals of recent positive selection in a worldwide sample of human populations. Genome Res. 19, 826–837 (2009)

    CAS  Article  Google Scholar 

  44. Silva, A. M. et al. Ethnicity-related skeletal muscle differences across the lifespan. Am. J. Hum. Biol. 10.1002/ajhb.20956 (16 June 2009)

  45. MacArthur, D. G. et al. Loss of ACTN3 gene function alters mouse muscle metabolism and shows evidence of positive selection in humans. Nature Genet. 39, 1261–1265 (2007)

    CAS  Article  Google Scholar 

  46. Nielsen, R. et al. Darwinian and demographic forces affecting human protein coding genes. Genome Res. 19, 838–849 (2009)

    CAS  Article  Google Scholar 

  47. Hindorff, L. A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl Acad. Sci. USA 106, 9362–9367 (2009)

    CAS  ADS  Article  Google Scholar 

  48. Pique-Regi, R. et al. Sparse representation and Bayesian detection of genome copy number alterations from microarray data. Bioinformatics 24, 309–318 (2008)

    CAS  Article  Google Scholar 

  49. Browning, S. R. & Browning, B. L. Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. Am. J. Hum. Genet. 81, 1084–1097 (2007)

    CAS  Article  Google Scholar 

  50. Iafrate, A. J. et al. Detection of large-scale variation in the human genome. Nature Genet. 36, 949–951 (2004)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We would like to thank A. Boyko, J. J. Emerson, J. Pickrell, S. Kudaravalli, J. Pritchard, T. Down, S. McCarroll, J. Collins, C. Beazley, M. Dermitzakis, P. Eis, T. Richmond, M. Hogan, D. Bailey, S. Giles, G. Speight, N. Sparkes, D. Peiffer, C. Chen, K. Li, P. Oeth, D. Stetson and D. Church for advice, sharing data, sharing software and technical assistance. We are grateful for the efforts and support of our colleagues at NimbleGen, Agilent, Illumina, Applied Biosystems and Sequenom. We thank J. Barrett for comments on an earlier version of the manuscript. The Centre for Applied Genomics at the Hospital for Sick Children and Wellcome Trust Sanger Institute are acknowledged for database, technical assistance and bioinformatics support. This research was supported by the Wellcome Trust (grant no. 077006/Z/05/Z; to M.E.H., N.P.C., C.T.-S.), Canada Foundation of Innovation and Ontario Innovation Trust (to S.W.S.), Canadian Institutes of Health Research (CIHR) (to S.W.S.), Genome Canada/Ontario Genomics Institute (to S.W.S.), the McLaughlin Centre for Molecular Medicine (to S.W.S.), Ontario Ministry of Research and Innovation (to S.W.S.), the Hospital for Sick Children Foundation (to S.W.S.), the Department of Pathology at Brigham and Women’s Hospital (to C.L.) and the National Institutes of Health (NIH) (grants HG004221 and GM081533; to C.L.). K.K. is supported by the Academy of Finland. D.P. is supported by fellowships from the Royal Netherlands Academy of Arts and Sciences (TMF/DA/5801) and the Netherlands Organization for Scientific Research (Rubicon 825.06.031). S.W.S. holds the GlaxoSmithKline Pathfinder Chair in Genetics and Genomics at the University of Toronto and the Hospital for Sick Children.

Author Contributions C.T.-S., N.P.C., C.L., S.W.S. and M.E.H. are all joint senior authors, and planned and managed the project. D.F.C. and D.P. lead the data analysis. Data analyses were performed by D.F.C., D.P., R.R., L.F., O.G., Y.Z., J.A., T.D.A., C.B., P.C., T.F., M.H., C.H.I., K.K., D.G.M., J.R.M., I.O., A.W.C.P., S.R., K.S., A.V., K.W., J.W. and M.E.H. The WTCCC collaborated on array design. Validation experiments were performed by Y.Z. and M.H. D.F.C., D.P., S.W.S. and M.E.H. wrote the paper.

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Correspondence to Stephen W. Scherer or Matthew E. Hurles.

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Lists of participants and affiliations appear in Supplementary Information.

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Supplementary Notes

This file contains Supplementary Notes, including Figures 1.1-1.12, Tables 1.1-1.7 and an Appendix of WTCCC authors and their affiliations. (PDF 3783 kb)

Supplementary Methods

This file contains Supplementary Methods, including Figures 2.1-2.30 and Tables 2.1-2.9, References and Appendices. (PDF 7430 kb)

Supplementary Table

This file contains Supplementary Table 1: CNV map. Genomic locations for all 11,700 candidate CNVs, including the number of CEU and YRI individuals in which the CNV was detected during the discovery experiment. (XLS 1860 kb)

Supplementary Table

This file contains Supplementary Table 2: CNV genotypes. Absolute integer copy number estimates for 5,238 CNVs in 450 individuals from 4 HapMap populations. (XLS 15811 kb)

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Conrad, D., Pinto, D., Redon, R. et al. Origins and functional impact of copy number variation in the human genome. Nature 464, 704–712 (2010). https://doi.org/10.1038/nature08516

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