Abstract
De novo mutation is highly implicated in autism spectrum disorder (ASD). However, the contribution of post-zygotic mutation to ASD is poorly characterized. We performed both exome sequencing of paired samples and analysis of de novo variants from whole-exome sequencing of 2,388 families. While we find little evidence for tissue-specific mosaic mutation, multi-tissue post-zygotic mutation (i.e. mosaicism) is frequent, with detectable mosaic variation comprising 5.4% of all de novo mutations. We identify three mosaic missense and likely-gene disrupting mutations in genes previously implicated in ASD (KMT2C, NCKAP1, and MYH10) in probands but none in siblings. We find a strong ascertainment bias for mosaic mutations in probands relative to their unaffected siblings (p = 0.003). We build a model of de novo variation incorporating mosaic variants and errors in classification of mosaic status and from this model we estimate that 33% of mosaic mutations in probands contribute to 5.1% of simplex ASD diagnoses (95% credible interval 1.3% to 8.9%). Our results indicate a contributory role for multi-tissue mosaic mutation in some individuals with an ASD diagnosis.
Highlights
DNA is constantly exposed to natural and artificial mutagenic processes and continually develops lesions and undergoes subsequent error-prone repair
Recent sequencing experiments have shown that genetic mutations present in children but not their parents contribute to autism diagnoses in a large fraction of affected families
Using a dataset of 2,388 families, we find that while these mutations are primarily inherited from parental germ cells, 5.4% of these mutations appear to arise after conception
Summary
DNA is constantly exposed to natural and artificial mutagenic processes and continually develops lesions and undergoes subsequent error-prone repair. In contrast to obligatory somatic mutation, de novo mutation is thought to primarily occur in the parental germline, typically resulting in genetic variation that is heterozygous in every cell of an organism Such mutation is de novo in the sense that it is below the limit of detection in a parental sample (usually DNA derived from blood). An early report using comparative genomic hybridization indicated that large de novo copy-number variants are enriched in ASD probands [2] From these results it was hypothesized, and subsequent microarray and wholeexome sequencing experiments have shown, that a substantial fraction of genetic liability arises de novo in every generation [3,4,5,6,7,8,9,10,11,12,13,14,15]
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