Mapping Copy Number Variation by Population-scale Genome Sequencing

Overview

Journal Nature

Specialty Science

Date 2011 Feb 5

PMID 21293372

Citations 632

Authors

Ryan E Mills

Klaudia Walter

Chip Stewart

Robert E Handsaker

Ken Chen

Can Alkan

Alexej Abyzov

Seungtai Chris Yoon

Kai Ye

R Keira Cheetham

Asif Chinwalla

Donald F Conrad

Yutao Fu

Fabian Grubert

Iman Hajirasouliha

Fereydoun Hormozdiari

Lilia M Iakoucheva

Zamin Iqbal

Shuli Kang

Jeffrey M Kidd

Miriam K Konkel

Joshua Korn

Ekta Khurana

Deniz Kural

Hugo Y K Lam

Jing Leng

Ruiqiang Li

Yingrui Li

Chang-Yun Lin

Ruibang Luo

Xinmeng Jasmine Mu

James Nemesh

Heather E Peckham

Tobias Rausch

Aylwyn Scally

Xinghua Shi

Michael P Stromberg

Adrian M Stutz

Alexander Eckehart Urban

Jerilyn A Walker

Jiantao Wu

Yujun Zhang

Zhengdong D Zhang

Mark A Batzer

Li Ding

Gabor T Marth

Gil McVean

Jonathan Sebat

Michael Snyder

Jun Wang

Kenny Ye

Evan E Eichler

Mark B Gerstein

Matthew E Hurles

Charles Lee

Steven A McCarroll

Jan O Korbel

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Long-read sequencing of 945 Han individuals identifies structural variants associated with phenotypic diversity and disease susceptibility.

Gong J, Sun H, Wang K, Zhao Y, Huang Y, Chen Q Nat Commun. 2025; 16(1):1494.

PMID: 39929826 PMC: 11811171. DOI: 10.1038/s41467-025-56661-9.

Advancing long-read nanopore genome assembly and accurate variant calling for rare disease detection.

Negi S, Stenton S, Berger S, Canigiula P, McNulty B, Violich I Am J Hum Genet. 2025; 112(2):428-449.

PMID: 39862869 PMC: 11866955. DOI: 10.1016/j.ajhg.2025.01.002.

Diversity and consequences of structural variation in the human genome.

Collins R, Talkowski M Nat Rev Genet. 2025; .

PMID: 39838028 DOI: 10.1038/s41576-024-00808-9.

Replication stress increases de novo CNVs across the malaria parasite genome.

Brown N, Luniewski A, Yu X, Warthan M, Liu S, Zulawinska J bioRxiv. 2025; .

PMID: 39803504 PMC: 11722320. DOI: 10.1101/2024.12.19.629492.

Structural polymorphism and diversity of human segmental duplications.

Jeong H, Dishuck P, Yoo D, Harvey W, Munson K, Lewis A Nat Genet. 2025; 57(2):390-401.

PMID: 39779957 PMC: 11821543. DOI: 10.1038/s41588-024-02051-8.

References

Harrow J, Denoeud F, Frankish A, Reymond A, Chen C, Chrast J . GENCODE: producing a reference annotation for ENCODE. Genome Biol. 2006; 7 Suppl 1:S4.1-9. PMC: 1810553. DOI: 10.1186/gb-2006-7-s1-s4. View

Handsaker R, Korn J, Nemesh J, McCarroll S . Discovery and genotyping of genome structural polymorphism by sequencing on a population scale. Nat Genet. 2011; 43(3):269-76. PMC: 5094049. DOI: 10.1038/ng.768. View

Yoon S, Xuan Z, Makarov V, Ye K, Sebat J . Sensitive and accurate detection of copy number variants using read depth of coverage. Genome Res. 2009; 19(9):1586-92. PMC: 2752127. DOI: 10.1101/gr.092981.109. View

Levy S, Sutton G, Ng P, Feuk L, Halpern A, Walenz B . The diploid genome sequence of an individual human. PLoS Biol. 2007; 5(10):e254. PMC: 1964779. DOI: 10.1371/journal.pbio.0050254. View

Willer C, Speliotes E, Loos R, Li S, Lindgren C, Heid I . Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet. 2008; 41(1):25-34. PMC: 2695662. DOI: 10.1038/ng.287. View

Lee J, Carvalho C, Lupski J . A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell. 2007; 131(7):1235-47. DOI: 10.1016/j.cell.2007.11.037. View

Iafrate A, Feuk L, Rivera M, Listewnik M, Donahoe P, Qi Y . Detection of large-scale variation in the human genome. Nat Genet. 2004; 36(9):949-51. DOI: 10.1038/ng1416. View

Korbel J, Urban A, Affourtit J, Godwin B, Grubert F, Simons J . Paired-end mapping reveals extensive structural variation in the human genome. Science. 2007; 318(5849):420-6. PMC: 2674581. DOI: 10.1126/science.1149504. View

Stefansson H, Rujescu D, Cichon S, Pietilainen O, Ingason A, Steinberg S . Large recurrent microdeletions associated with schizophrenia. Nature. 2008; 455(7210):232-6. PMC: 2687075. DOI: 10.1038/nature07229. View

10.

Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T . Strong association of de novo copy number mutations with autism. Science. 2007; 316(5823):445-9. PMC: 2993504. DOI: 10.1126/science.1138659. View

11.

Craddock N, Hurles M, Cardin N, Pearson R, Plagnol V, Robson S . Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature. 2010; 464(7289):713-20. PMC: 2892339. DOI: 10.1038/nature08979. View

12.

Stankiewicz P, Lupski J . Structural variation in the human genome and its role in disease. Annu Rev Med. 2010; 61:437-55. DOI: 10.1146/annurev-med-100708-204735. View

13.

Stewart C, Kural D, Stromberg M, Walker J, Konkel M, Stutz A . A comprehensive map of mobile element insertion polymorphisms in humans. PLoS Genet. 2011; 7(8):e1002236. PMC: 3158055. DOI: 10.1371/journal.pgen.1002236. View

14.

McKernan K, Peckham H, Costa G, McLaughlin S, Fu Y, Tsung E . Sequence and structural variation in a human genome uncovered by short-read, massively parallel ligation sequencing using two-base encoding. Genome Res. 2009; 19(9):1527-41. PMC: 2752135. DOI: 10.1101/gr.091868.109. View

15.

McCarroll S, Kuruvilla F, Korn J, Cawley S, Nemesh J, Wysoker A . Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet. 2008; 40(10):1166-74. DOI: 10.1038/ng.238. View

16.

Chen K, Wallis J, McLellan M, Larson D, Kalicki J, Pohl C . BreakDancer: an algorithm for high-resolution mapping of genomic structural variation. Nat Methods. 2009; 6(9):677-81. PMC: 3661775. DOI: 10.1038/nmeth.1363. View

17.

Campbell P, Stephens P, Pleasance E, OMeara S, Li H, Santarius T . Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nat Genet. 2008; 40(6):722-9. PMC: 2705838. DOI: 10.1038/ng.128. View

18.

Conrad D, Bird C, Blackburne B, Lindsay S, Mamanova L, Lee C . Mutation spectrum revealed by breakpoint sequencing of human germline CNVs. Nat Genet. 2010; 42(5):385-91. PMC: 3428939. DOI: 10.1038/ng.564. View

19.

Chiang D, Getz G, Jaffe D, OKelly M, Zhao X, Carter S . High-resolution mapping of copy-number alterations with massively parallel sequencing. Nat Methods. 2008; 6(1):99-103. PMC: 2630795. DOI: 10.1038/nmeth.1276. View

20.

Conrad D, Pinto D, Redon R, Feuk L, Gokcumen O, Zhang Y . Origins and functional impact of copy number variation in the human genome. Nature. 2009; 464(7289):704-12. PMC: 3330748. DOI: 10.1038/nature08516. View