, 2009). From sequencing adjacent linked polymorphisms in children and parents, we infer that on the order of 3/4 of new point mutations (50 of 67) derive from the father’s germline. Although we have less data, this conclusion holds as well for de novo small indels (6 of 7). These data confirm the paternal line is the main source for these types of new human variation. The data also indicate that the majority of the de novo calls in this study are not somatic in origin, but occur prior to conception. We infer this by assuming that after zygote formation, the mother’s and father’s genomes are equally vulnerable to subsequent somatic

mutation. selleck inhibitor By contrast, a previous study indicated that for de novo copy number variation both parents contribute almost

equally (Sanders et al., 2011). We observe very few cases where two siblings share the same de novo mutation, about one for every fifty occurrences, suggesting BMS-354825 concentration that the parent is rarely a broad mosaic. However, this conclusion could be an ascertainment bias, because our operational identification of “de novo” precludes observing the mutation in the parent at levels higher than expected from sequencing error. As presented, we do observe some evidence of parental mosaicism, and this is a subject of ongoing scrutiny using enhanced statistical modeling and validation. Finding the correct contribution from each genetic mechanism is critical for understanding the nature of the factors causing autistic spectrum disorders. Adding the 6% differential for large-scale

de novo copy number mutation previously observed (Levy et al., 2011 and Sanders et al., 2011) to the 10% differential for LGDs, we reach a total differential of 16% between affected children and siblings. This is far less than our predictions, based on modeling the AGRE population (Zhao et al., 2007), that causal de novo mutations would occur in about 50% of the SSC. This gap could be attributable to having modeled a more severely affected population. The SSC is skewed to higher functioning cases with a male to female ratio of 6:1 (Fischbach and Lord, 2010), so there may be more borderline cases in that collection than in the AGRE collection (male to female ratio of 3:1), from which we built our model (Zhao et al., 2007). But our Adenosine differential must underestimate the contribution from de novo events. First, we use extremely stringent criteria meant to eliminate false positives, and we fail to detect many true positives as a consequence. Second, even among the de novo events we do observe, we may be missing gene-disruptive events, for example, mutations outside the consensus that disrupt splicing and in-frame indels that disrupt the spacing of the peptide backbone. It would not be unlikely to miss even a 5% differential from de novo missense mutation in a study of this size, given the high background rate of neutral missense mutation. Third, our coverage of the genome is incomplete.