To assess the relative impact of inherited and de novo variants on autism risk, we generated a comprehensive set of exonic single nucleotide variants (SNVs) and copy number variants (CNVs) from 2,377 autism families. We find that private, inherited truncating SNVs in conserved genes are enriched in probands (odds ratio=1.14, p=0.0002) compared to unaffected siblings, an effect with significant maternal transmission bias to sons. We also observe a bias for inherited CNVs, specifically for small (<100 kbp), maternally inherited events (p=0.01) that are enriched in CHD8 target genes (p=7.4×10−3). Using a logistic regression model, we show that private truncating SNVs and rare, inherited CNVs are statistically independent autism risk factors, with odds ratios of 1.11 (p=0.0002) and 1.23 (p=0.01), respectively. This analysis identifies a second class of candidate genes (e.g., RIMS1, CUL7, and LZTR1) where transmitted mutations may create a sensitized background but are unlikely to be completely penetrant.

Copy number variation (CNV) contributes to disease and has restructured the genomes of great apes. The diversity and rate of this process, however, have not been extensively explored among great ape lineages. We analyzed 97 deeply sequenced great ape and human genomes and estimate 16% (469 Mb) of the hominid genome has been affected by recent CNV. We identify a comprehensive set of fixed gene deletions (n = 340) and duplications (n = 405) as well as >13.5 Mb of sequence that has been specifically lost on the human lineage. We compared the diversity and rates of copy number and single nucleotide variation across the hominid phylogeny. We find that CNV diversity partially correlates with single nucleotide diversity (r 2 = 0.5) and recapitulates the phylogeny of apes with few exceptions. Duplications significantly outpace deletions (2.8-fold). The load of segregating duplications remains significantly higher in bonobos, Western chimpanzees, and Sumatran orangutans-populations that have experienced recent genetic bottlenecks (P = 0.0014, 0.02, and 0.0088, respectively). The rate of fixed deletion has been more clocklike with the exception of the chimpanzee lineage, where we observe a twofold increase in the chimpanzee-bonobo ancestor (P = 4.79 3 10 -9 ) and increased deletion load among Western chimpanzees (P = 0.002). The latter includes the first genomic disorder in a chimpanzee with features resembling Smith-Magenis syndrome mediated by a chimpanzee-specific increase in segmental duplication complexity. We hypothesize that demographic effects, such as bottlenecks, have contributed to larger and more gene-rich segments being deleted in the chimpanzee lineage and that this effect, more generally, may account for episodic bursts in CNV during hominid evolution.

No abstract