Cis-regulatory structural variants, inherited from the father, are associated with autism

Within just this last week, these GEITP pages included several email chats about “the increasing incidence/frequency of autism spectrum disorder (ASD)” among young children, not only in the U.S. but also in countries such as South Korea. Genome-wide association studies (GWAS) and whole-exome sequencing (WES) studies over the past decade have demonstrated that protein-altering (i.e. nonsynonymous) single-nucleotide variants (SNVs) contribute to ~25% of cases of ASD. Much of the allelic spectrum (remember: “allele” is the copy of a gene from one parent; each gene comprises two alleles in the chromosome pair, one from each parent) of ASD genetics has been unexplored –– particularly variants that lie outside the protein-coding sequence of each gene.

Recent studies have made great progress in identifying regulatory elements throughout the genome; another challenge is to identify ASD risk variants affecting genetic regulatory elements. However, deleterious cis-regulatory variants (remember: “cis” means “nearby,” within a few hundred thousand DNA base-pairs, whereas “trans” denotes “further away” –– on another chromosome or perhaps the same chromosome) are not easily distinguishable from the vast background of neutral variation throughout the genome. Thus, to date, initial applications of whole-genome sequencing (WGS) in ASD have been statistically underpowered to detect associations of rare cis-regulatory SNVs with ASD.

Structural variants (SVs) –– such as insertions, deletions, duplications, and inversions –– are more likely than SNVs to affect gene regulation, because of their potential to disrupt or rearrange functional (regulatory) elements in the genome. Recent WGS efforts led by the 1000 Genomes Consortium and other groups have revealed thousands of rare SVs in each genome that had been previously undetectable by GWAS or WES technologies. Authors [see attached study] therefore hypothesized that rare inherited structural variants in cis-regulatory elements (CRE-SVs) of these genes might also contribute to ASD risk.

Authors assessed evidence for NATURAL SELECTION (i.e. Darwin’s original theory, whereby organisms that are “better adapted to their environment” tend to survive and produce more offspring –– and this is now believed to be the main process that brings about evolution) versus TRANSMISSION DISTORTION (i.e. distorted transmission of genes, or chromosomes, to the offspring –– resulting in a significant difference from the usual Mendelian prediction of the chance for a given gene or chromosome to be transmitted from each parent to a child = 1:1, or 50%) of CRE-SVs in whole genomes of 9,274 ASD individuals from 2,600 families. In a discovery cohort of 829 families, structural variants were depleted within promoters and untranslated regions (regulatory modules near genes), and paternally inherited CRE-SVs were preferentially transmitted to ASD offspring and not to their unaffected siblings. This association of paternal CRE-SVs with ASD risk was replicated in an independent sample of 1,771 families. This intriguing study suggests that rare inherited noncoding variants predispose children to ASD –– with differing contributions from each parent..!!

P.S. I like very much the authors’ distinction of SNVs from SVs. The vast majority of genomic studies have used “single-nucleotide polymorphisms” (SNPs) to signify “all DNA variants”: single-nucleotide alterations PLUS insertions, deletions, duplications, and inversions. There are important differences –– especially when comparing protein-coding regions with cis- (or trans-) regulatory regions (as this study has done).

Science 20 Apr 2o18; 360: 327–331

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