title: De novo rates and selection of large copy number variation.
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.
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors.forename: Andy
authors.initials: A
authors.lastname: Itsara
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Smith
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Isabelle
authors.initials: I
authors.lastname: Romieu
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: London
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D000293:Adolescent; D001249:Asthma / Q000235:genetics; D001321:Autistic Disorder / Q000235:genetics; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic