Origins and functional impact of copy number variation in the human genome
Open accessAbstract
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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At least some ASD CNVs (and the genes they affect) are under purifying selection.
“These findings, similar to those recently described in schizophrenia 26 , suggest that at least some of these ASD CNVs (and the genes that they affect) are under purifying selection 27 .”
From Functional impact of global rare copy number variation in autism spectrum disorders (2010) · cites this paper as [27]
The Population genetics of CNV section reports purifying selection on CNVs, strongest for exonic CNVs, followed by intronic CNVs. The paper does not establish that the particular ASD-associated CNVs or genes in the citing sentence are under purifying selection; its finding is about CNVs by functional category generally. No page number is available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredHuman genomes carry on average more than 1,000 CNVs, amounting to about 4 million base pairs of difference.
“On average, there are >1000 CNVs in the genome, accounting for ~4 million base pairs of genomic difference (Conrad et al., 2010; Mills et al., 2011).”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Conrad et al., 2010
Most variants present in an individual human genome are common alleles.
“In truth, structural variants come in many shapes, sizes and allele frequencies, and a majority of variants present in an individual genome are common alleles (Conrad et al., 2010; McCarroll et al., 2008; Mills et al., 2011; Sudmant et al., 2010).”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Conrad et al., 2010
The control de novo CNV rate of 0.9% is consistent with previous estimates ranging from 0.5% to 3%.
“This rate is consistent with estimates from previous studies ranging from 0.5% to 3% (Conrad et al., 2010, Itsara et al., 2010, Levy et al., 2011, Sebat et al., 2007 and Xu et al., 2008).”
From High frequencies of de novo CNVs in bipolar disorder and schizophrenia (2011) · cites this paper as Conrad et al., 2010
The fraction of the genome affected by structural variants is larger than that affected by single-nucleotide polymorphisms.
“The fraction of the genome affected by SVs is comparatively larger than that accounted for by single nucleotide polymorphisms1 (SNPs), implying significant consequences of SVs on phenotypic variation.”
From Mapping copy number variation by population-scale genome sequencing (2011) · cites this paper as [1]
The median structural-variant size was 729 bp (mean 8 kb), about four times smaller than in a recent tiling CGH study.
“The median SV size was 729 bp (mean=8 kb), approximately four times smaller than in a recent tiling CGH based study1”
From Mapping copy number variation by population-scale genome sequencing (2011) · cites this paper as [1]
Non-homologous and non-allelic homologous recombination mechanisms occurred across a wide size range, whereas variable-number tandem-repeat expansion or shrinkage produced relatively small structural variants.
“NH and NAHR based mechanisms occurred across a wide size-range, whereas VNTR expansion/shrinkage, consistent with earlier findings1, led to relatively small SV sizes”
From Mapping copy number variation by population-scale genome sequencing (2011) · cites this paper as [1]
The genotypes showed 99.1% concordance with CGH array-based genotypes for 1,970 deletions, suggesting high genotyping accuracy.
“The genotypes displayed 99.1% concordance with CGH array1 based genotypes (available for 1,970 of the deletions), suggesting high genotyping accuracy.”
From Mapping copy number variation by population-scale genome sequencing (2011) · cites this paper as [1]
Deletion discovery sensitivity was assessed against a gold standard assembled from four earlier surveys.
“We further assessed the sensitivity of deletion discovery methods by collating data from four earlier surveys1,13,22,28 into a gold standard”
From Mapping copy number variation by population-scale genome sequencing (2011) · cites this paper as [1]
None of the 42 known, confirmed or possible novel menarche loci were related to CNVs.
“we established that none of the 42 known, confirmed or possible novel menarche loci were related to CNVs.”
From Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies (2010) · cites this paper as [25]
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- Authors
- The Wellcome Trust Case Control Consortium, Conrad, D. F., Pinto, D., Redon, R., Feuk, L., Gokcumen, O., Zhang, Y., Aerts, J., Andrews, T. D., Barnes, C., Campbell, P., Fitzgerald, T., Hu, M., Ihm, C. H., Kristiansson, K., MacArthur, D. G., MacDonald, J. R., Onyiah, I., Pang, A. W. C., Robson, S., Stirrups, K., Valsesia, A., Walter, K., Wei, J., Tyler-Smith, C., Carter, N. P., Lee, C., Scherer, S. W., & Hurles, M. E.
- Affiliations
- Wellcome Sanger Institute (GB)
- Hospital for Sick Children (CA)
- Inserm (FR)
- Uppsala University (SE)
- Brigham and Women's Hospital (US)
- University of Toronto (CA)
- Corresponding author
- Scherer, Stephen W.
- Hurles, Matthew E.
- ORCID
- Conrad, Donald F.
- Pinto, Dalila
- Redon, Richard
- Feuk, Lars
- Aerts, Jan
- Andrews, T. Daniel
- Barnes, Chris
- Campbell, Peter
- Fitzgerald, Tomas
- Hu, Min
- Kristiansson, Kati
- MacArthur, Daniel G.
- MacDonald, Jeffrey R.
- Pang, Andy Wing Chun
- Valsesia, Armand
- Walter, Klaudia
- Wei, John
- Lee, Charles
- Scherer, Stephen W.
- Hurles, Matthew E.
- Venue
- Nature
- Published
- 2009-10-07
- Volume
- 464
- Issue
- 7289
- Pages
- 704-712
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3330748
- OpenAlex
- W2021714239
- Cited by
- 1,970
- References
- 52
- Citations by year
- 2026: 23 · 2025: 41 · 2024: 61 · 2023: 53 · 2022: 64 · 2021: 90 · 2020: 95 · 2019: 88 · 2018: 124 · 2017: 107 · 2016: 98 · 2015: 147 · 2014: 144 · 2013: 195 · 2012: 235
- FWCI
- 123.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Document Server@UHasselt (UHasselt) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Lirias (KU Leuven) (submittedVersion)
- ANU Open Research (Australian National University) (submittedVersion)
- Funders
- Wellcome Trust (077009, 077014, 088340, 077008, 077006/Z/05/Z)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (825.06.031)
- National Institutes of Health (5p41hg004221-03)
- Canadian Institutes of Health Research
- National Human Genome Research Institute (HG004221, P41-HG004221)
- National Institute of General Medical Sciences (GM081533, R01GM081533)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- copy number variation, structural variants, human genome, retrotransposition, mutational mechanisms, disease susceptibility loci, linkage disequilibrium, complex traits, heritability, genome-wide association study, HapMap, de novo mutations, Wellcome Trust Case Control Consortium, single nucleotide polymorphisms
- MeSH terms
- Genotype, Haplotypes, Humans, Reproducibility of Results, Genome, Human, Mutagenesis, Genetic Predisposition to Disease, Oligonucleotide Array Sequence Analysis, Gene Duplication, Polymorphism, Single Nucleotide, Racial Groups, Genome-Wide Association Study, DNA Copy Number Variations
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