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 m = 1.2 3 10 -2 CNVs per genome per transmission (m = 6.5 3 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 3 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.

Copy number variations in 375 patients with oesophageal atresia and/or tracheoesophageal fistula

“…The total number of patients with rare de novo CNVs is 6 out of 375 (1.6%). The de novo rate of 1.6% is slightly elevated compared with the de novo rate per genome/generation described by Itsara et al 33,34 They estimate a de novo rate of large CNVs to be 1.2%. However, these include more prevalent CNVs and not a selected subset.…”

Analysis of Arabidopsis genome-wide variations before and after meiosis and meiotic recombination by resequencing Landsberg erecta and all four products of a single meiosis

“…The rates of de novo CNV in human have been estimated; for example, one study found that the rate for total genome-wide new large CNVs (>100 Kb) is about 1.2 3 10 À2 per genome per transmission (Itsara et al 2010), and another study reported that most of over 4000 CNVs analyzed had individual rates of ;10 À5 per generation (Fu et al 2010). Our limited analysis revealed that meiosis can rapidly generate CNVs among siblings, producing 21 and 32 CNVs in the two sets of four meiotic products, respectively (Supplemental Table 14).…”

A genetic model for neurodevelopmental disease

“…Consistent with this observation, the odds of a CNV being de novo is linearly proportional to its size with CNVs larger than 1 Mbp being more likely to arise sporadically than inherited from a parent ( Figure 1A). There is compelling evidence, then, that CNVs are under strong purifying selection in the general population [24,26,28]. Remarkably, as much as 8-10% of the general population carries such extremely rare or private CNVs suggesting that they must play an important role in human health.…”