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De novo rates and selection of large copy number variation
Open accessAbstract
While copy number variation (CNV) is an active area of research, de novo mutation rates within human populations are not well characterized. By focusing on large (>100 kbp) events, we estimate the rate of de novo CNV formation in humans by analyzing 4394 transmissions from human pedigrees with and without neurocognitive disease. We show that a significant limitation in directly measuring genome-wide CNV mutation is accessing DNA derived from primary tissues as opposed to cell lines. We conservatively estimated the genome-wide CNV mutation rate using single nucleotide polymorphism (SNP) microarrays to analyze whole-blood derived DNA from asthmatic trios, a collection in which we observed no elevation in the prevalence of large CNVs. At a resolution of ∼30 kb, nine de novo CNVs were observed from 772 transmissions, corresponding to a mutation rate of μ = 1.2 × 10−2 CNVs per genome per transmission (μ = 6.5 × 10−3 for CNVs >500 kb). Combined with previous estimates of CNV prevalence and assuming a model of mutation-selection balance, we estimate significant purifying selection for large (>500 kb) events at the genome-wide level to be s = 0.16. Supporting this, we identify de novo CNVs in 717 multiplex autism pedigrees from the AGRE collection and observe a fourfold enrichment (P = 1.4 × 10−3) for de novo CNVs in cases of multiplex autism versus unaffected siblings, suggesting that many de novo CNV mutations contribute a subtle, but significant risk for autism. We observe no parental bias in the origin or transmission of CNVs among any of the cohorts studied.
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“The over-representation of large de novo CNVs in ASD has been replicated in studies ranging from 60 to 393 simplex trios (Itsara et al., 2010; Marshall et al., 2008; Pinto et al., 2010)”
From Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism (2011) · cites this paper as Itsara et al., 2010
In the citing paper
“Subsequent studies in larger samples have confirmed a high (5–10%) rate of de novo CNVs in ASD and further elucidated the extent of genetic heterogeneity in ASD (Itsara et al., 2010; Levy et al., 2011; Marshall et al., 2008; Pinto et al., 2010; Sanders et al., 2011).”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Itsara et al., 2010
In the citing paper
“CNVs >10 Kb in size occur at a rate of ~0.01–0.02 per generation.(Itsara et al., 2010; Levy et al., 2011; Marshall et al., 2008; Sanders et al., 2011; Sebat et al., 2007).”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Itsara et al., 2010
In the citing paper
“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 Itsara et al., 2010
In the citing paper
“Notably, the median size of SD and non-SD-mediated de novo CNVs was 722 kb and 67 kb respectively, consistent with previous studies that have found differences in CNV size related to the underlying mutational mechanism (Itsara et al., 2010 and Stefansson et al., 2008).”
From High frequencies of de novo CNVs in bipolar disorder and schizophrenia (2011) · cites this paper as Itsara et al., 2010
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Citations
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Additional file 1 of Genome plasticity in Paramecium bursaria revealed by population genomics
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“Although we did not evaluate de novo SVs, previous studies have estimated that around 1 in 80–100 individuals have a de novo SV > 30,000 bp [82], whilst 1 in 6–7 individuals has a de novo SVs > 20 bp, which (excluding chromosomal aneuploidies) were also mostly paternally-derived [83, 84].”
Metadata
- Authors
- Itsara, A., Wu, H., Smith, J. D., Nickerson, D. A., Romieu, I., London, S. J., & Eichler, E. E.
- Affiliations
- University of Washington (US)
- National Institutes of Health (US)
- Instituto Nacional de Salud Pública (MX)
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2010-09-14
- Volume
- 20
- Issue
- 11
- Pages
- 1469-1481
- ISSN
- 1088-9051 (ISSN-L)
- PMC
- PMC2963811
- OpenAlex
- W2158959870
- Cited by
- 328
- References
- 65
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 9 · 2023: 9 · 2022: 8 · 2021: 14 · 2020: 16 · 2019: 10 · 2018: 43 · 2017: 19 · 2016: 30 · 2015: 25 · 2014: 25 · 2013: 36 · 2012: 43
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Department of Health and Human Services
- Autism Speaks
- Simons Foundation
- Simons Foundation Autism Research Initiative (137578)
- Consejo Nacional de Ciencia y Tecnología (26206-M)
- National Institutes of Health (26206-M)
- National Institute of Mental Health (U24MH081810)
- National Institute of General Medical Sciences (T32GM007266)
- National Institute of Environmental Health Sciences (26206-M, ES049019, ES025045, ZIAES049019, ZIAES025045)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
- Keywords
- copy number variation, de novo mutations, mutation rate, purifying selection, mutation-selection balance, autism spectrum disorder, human pedigrees, SNP array, parental bias
- MeSH terms
- Adolescent, Asthma, Autistic Disorder, Base Sequence, Child, Child, Preschool, Female, Gene Frequency, Humans, Male, Pedigree, Selection, Genetic, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Genome-Wide Association Study, DNA Copy Number Variations
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