Postzygotic single nucleotide mosaicisms and autism risk

The principle of “parsimony” has underlined our understanding of science since the middle of the 18th century by telling us to choose the simplest scientific explanation that fits (all) the observed evidence. In studying the genetics of multifactorial diseases (MFD), such as autism spectrum disorder (ASD), this has been reflected in our belief that identifying common gene mutations present among large populations exhibiting the disease phenotype is a key to understanding the ontology of the disease. However, the validity of this concept is being challenged by the increasing evidence of genetic diversity within individuals. The article in this issue by Dou et al. (Hum Mutat 38: 1002–1013, 2017) reveals evidence of postzygotic single nucleotide mosaicism (pSNMs) in ASD. Further, the mounting evidence that pSNMs also exist within normal tissues raises some even more fundamental questions with regard to the role of specific mutations in MFD phenotypes. The study by Dou et al. clearly expands on previous attempts to associate pSNMs with ASD by using ultradeep next-generation sequencing and a sophisticated approach to the bioinformatics analyses. The authors detected and validated both child pSNMs and transmitted parental pSNMs in the largest data set analysis to date of confident pSNMs of ASD cohorts. They found that pSNMs with varied mutant allele fraction (MAF) have different amounts of risk contributing to ASD. This was accomplished because of the much higher sensitivity in detecting pSNMs with relatively low MAFs. Their results highlighted that mosaicisms resulting from postzygotic mutations could explain at least a proportion of the unrecognized genetic etiology of ASD. These results are, however, more indicative of the potential of such an approach to give new insights into hypotheses explaining MFD ontology rather than identifying new genes as possible risk factors for ASD. One possible hypothesis is that occurrence of pSNMs, which are complex forms of genetic heterogeneity, suggests that selection of certain postzygotic gene mutations is the cause of disease progression and variable disease phenotypes. Further, the accumulating evidence of nongenomic, often environmental factors as risk factors for ASD, would lend support to such a hypothesis. Indeed, the complexity of postzygotic variation has added emphasis to the importance of environmental factors in determining ASD phenotypes.

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