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Population Analysis of Large Copy Number Variants and Hotspots of Human Genetic Disease
Open accessAbstract
Copy number variants (CNVs) contribute to human genetic and phenotypic diversity. However, the distribution of larger CNVs in the general population remains largely unexplored. We identify large variants in approximately 2500 individuals by using Illumina SNP data, with an emphasis on "hotspots" prone to recurrent mutations. We find variants larger than 500 kb in 5%-10% of individuals and variants greater than 1 Mb in 1%-2%. In contrast to previous studies, we find limited evidence for stratification of CNVs in geographically distinct human populations. Importantly, our sample size permits a robust distinction between truly rare and polymorphic but low-frequency copy number variation. We find that a significant fraction of individual CNVs larger than 100 kb are rare and that both gene density and size are strongly anticorrelated with allele frequency. Thus, although large CNVs commonly exist in normal individuals, which suggests that size alone can not be used as a predictor of pathogenicity, such variation is generally deleterious. Considering these observations, we combine our data with published CNVs from more than 12,000 individuals contrasting control and neurological disease collections. This analysis identifies known disease loci and highlights additional CNVs (e.g., 3q29, 16p12, and 15q25.2) for further investigation. This study provides one of the first analyses of large, rare (0.1%-1%) CNVs in the general population, with insights relevant to future analyses of genetic disease.
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“a review of reported data from control cohorts (n = 66,462 subjects) summarized to date show that about 0.25% of controls are found with the 15q11.2 BP1–BP2 microdeletion [18,27,28,29,30,31].”
From The 15q11.2 BP1–BP2 Microdeletion Syndrome: A Review (2015) · cites this paper as [30]
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Metadata
- Authors
- Itsara, A., Cooper, G. M., Baker, C., Girirajan, S., Li, J., Absher, D., Krauss, R. M., Myers, R. M., Ridker, P. M., Chasman, D. I., Mefford, H., Ying, P., Nickerson, D. A., & Eichler, E. E.
- Affiliations
- University of Washington (US)
- University of Michigan (US)
- HudsonAlpha Institute for Biotechnology (US)
- Brigham and Women's Hospital (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Eichler, Evan E.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2009-02
- Volume
- 84
- Issue
- 2
- Pages
- 148-161
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC2668011
- OpenAlex
- W2148095347
- Cited by
- 591
- References
- 59
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 23 · 2023: 15 · 2022: 27 · 2021: 24 · 2020: 25 · 2019: 19 · 2018: 19 · 2017: 26 · 2016: 25 · 2015: 43 · 2014: 40 · 2013: 57 · 2012: 74
- FWCI
- 42.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Department of Health and Human Services
- Donald W. Reynolds Foundation
- National Institutes of Health
- National Institute on Aging (Z01AG000932)
- National Heart, Lung, and Blood Institute (HL01069757)
- National Human Genome Research Institute (P01HG004120, HG004120, T32HG000035)
- National Institute of General Medical Sciences (T32GM007266)
- National Institute of Neurological Disorders and Stroke
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD043569, R01HD043569)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- copy number variation, population genetics, recurrent mutations, allele frequency, gene density, neurological disorders, disease loci, rare variants
- MeSH terms
- Genetics, Population, Genotype, Geography, Humans, Polymorphism, Genetic, Genetic Variation, Genome, Human, Sequence Deletion, Gene Dosage, Oligonucleotide Array Sequence Analysis, Gene Duplication, Polymorphism, Single Nucleotide, Genetic Diseases, Inborn
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