De novo rates and selection of large copy number variation

被引：219

作者：

Itsara, Andy ^{[1
]}

Wu, Hao ^{[2
]}

Smith, Joshua D. ^{[1
]}

Nickerson, Deborah A. ^{[1
]}

Romieu, Isabelle ^{[3
]}

London, Stephanie J. ^{[2
]}

Eichler, Evan E. ^{[1
,4
]}

机构：

[1] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA

[2] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA

[3] Natl Publ Hlth Inst, Cuernavaca 62100, Morelos, Mexico

[4] Howard Hughes Med Inst, Seattle, WA 98195 USA

来源：

GENOME RESEARCH | 2010年 / 20卷 / 11期

基金：

美国国家卫生研究院;

关键词：

22Q11.2; DELETION; STRUCTURAL VARIATION; RECURRENT REARRANGEMENTS; ANGELMAN-SYNDROMES; GENOMIC DISORDERS; PRADER-WILLI; MICRODELETION; AUTISM; POLYMORPHISM; PHENOTYPE;

D O I：

10.1101/gr.107680.110

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 similar to 30 kb, nine de novo CNVs were observed from 772 transmissions, corresponding to a mutation rate of mu = 1.2 X 10(-2) CNVs per genome per transmission (mu = 6.5 X 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 X 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. [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.]

引用

页码：1469 / 1481

页数：13

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