Abstract
Autism arises in high and low-risk families. De novo mutation contributes to autism incidence in low-risk families as there is a higher incidence in the affected of the simplex families than in their unaffected siblings. But the extent of contribution in low-risk families cannot be determined solely from simplex families as they are a mixture of low and high-risk. The rate of de novo mutation in nearly pure populations of high-risk families, the multiplex families, has not previously been rigorously determined. Moreover, rates of de novo mutation have been underestimated from studies based on low resolution microarrays and whole exome sequencing. Here we report on findings from whole genome sequence (WGS) of both simplex families from the Simons Simplex Collection (SSC) and multiplex families from the Autism Genetic Resource Exchange (AGRE). After removing the multiplex samples with excessive cell-line genetic drift, we find that the contribution of de novo mutation in multiplex is significantly smaller than the contribution in simplex. We use WGS to provide high resolution CNV profiles and to analyze more than coding regions, and revise upward the rate in simplex autism due to an excess of de novo events targeting introns. Based on this study, we now estimate that de novo events contribute to 52–67% of cases of autism arising from low risk families, and 30–39% of cases of all autism.
Highlights
Autism arises in high and low-risk families
Some of the Autism Genetic Resource Exchange (AGRE) DNAs used for whole genome sequence (WGS) were extracted from cultured lymphoblastoid cell lines (LCL), and some from whole blood (WB)
These artifacts are made evident in the AGRE by examining the frequency and allele ratios of the substitutions observed in the children but not in either parent (Fig. 1)
Summary
De novo mutation contributes to autism incidence in low-risk families as there is a higher incidence in the affected of the simplex families than in their unaffected siblings. In this paper we used the newly generated whole genome sequencing (WGS) data from large multiplex (AGRE) and large simplex (SSC) family collections to compare the contributions of de novo variants in low and high-risk families and to evaluate the role of de novo intronic variants in SSC. We identify the AGRE multiplex samples with extensive somatic genomic drift by the presence of two hallmarks: (1) excess single nucleotide variations throughout the entire genome; and (2) a preponderance of variants with unexpected allele ratios Removing these samples, we measure rates of de novo events in the remainder. From our results we update estimates of the contribution of de novo events in high and low-risk families and in autism overall
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