TY  - JOUR
A1  - Itsara, Andy
A1  - Wu, Hao
A1  - Smith, Joshua D.
A1  - Nickerson, Deborah A.
A1  - Romieu, Isabelle
A1  - London, Stephanie J.
A1  - Eichler, Evan E.
T1  - De novo rates and selection of large copy number variation
Y1  - 2010/11/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 1469 
EP  - 1481 
DO  - 10.1101/gr.107680.110 
VL  - 20 
IS  - 11 
UR  - http://genome.cshlp.org/content/20/11/1469.abstract 
N2  - 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. 
ER  -