Enrichment of de novo mutations in non-SNP sites in autism spectrum disorders and an empirical test of the neutral DNA model

Abstract The genetic basis of autism spectrum disorders (ASD) remains better understood and might concern only a small fraction of the genome if the neutral theory were true. We here analyzed published de novo mutations (DNMs) in ASD and controls. We found that DNMs in normal subjects occurred at positions bearing SNPs at least 3.45 fold more frequent than expected from the neutral theory, whereas DNMs in ASD were less frequent relative to those in controls, especially so for common SNPs with minor allele frequency >0.01. Among sites bearing both SNPs and DNMs, DNMs in controls occurred significantly more frequent than DNMs in ASD at reference allele sites bearing C or G nucleotides, indicating depletion of ASD associated DNMs in known regions of hypermutability or less functional constraints such as CpG sites. We also analyzed the nucleotide compositions of DNMs and the parity (1:1 ratio) of pyrimidines and purines. We found that DNMs in ASD showed overall lower AT content than that in controls. Parity violations and AT bias in DNMs occurred at expected frequency based on chance in both ASD and controls. These results show enrichment of DNMs at positions bearing SNP sites and C or G sites in normal subjects and less so in ASD, which is not expected from the neutral model, and indicate that DNMs are on average more deleterious in ASD than in controls.