De novo rates and selection of large copy number variation
Andy Itsara1, Hao Wu2, Joshua D. Smith1, Deborah A. Nickerson1, Isabelle Romieu3,5, Stephanie J. London2 and Evan E. Eichler1,4,6
+Author Affiliations
1 Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;
2 National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA;
3 National Institute of Public Health, Cuernavaca, Morelos 62100, Mexico;
4 Howard Hughes Medical Institute, Seattle, Washington 98195, USA
↵5 Present address: International Agency for Research on Cancer, 69372 Lyon CEDEX 08, France.
Abstract
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.
Footnotes
↵6 Corresponding author.
E-mail eee@gs.washington.edu.
[Supplemental material is available online at http://www.genome.org. The microarray data from this study have been submitted to the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession no. GSE23645.]
Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.107680.110.
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