Major progress has been made in understanding the genetic basis of autism spectrum disorders. Rare or de novo mutations throughout the genome are now known to be important factors. These include copy number variations (CNVs) and point mutations that disrupt the protein-coding sequences of genes.

Despite this progress, however, only a fraction of the overall heritability of autism has been accounted for. Jonathan Sebat and his team at the University of California, San Diego plan to investigate the hypothesis that rare genetic variants and de novo mutations of noncoding DNA contribute to the genetic risk for autism.

Noncoding DNA represents 99 percent of the genome. Although these DNA sequences do not encode protein, they are responsible for other important biological functions. Regulatory elements, such as promoters and enhancers, control the expression of genes. Noncoding RNAs regulate multiple biological processes, including the translation of RNA into protein. Genetic variation within these regulatory elements could have significant effects on brain development. However, the contribution of noncoding genetic variation to developmental disorders is poorly understood.

Sebat’s team plans to carry out targeted high-throughput sequencing of noncoding regions using DNA samples from the Simons Simplex Collection. One focus of the study will be the cis-regulatory elements of genes that have strong prior evidence for association with autism.

A second target of their study will be a set of evolutionarily conserved mutation hotspots, a phenomenon Sebat’s group discovered in 2012¹. Many of the hotspots are in noncoding sequences, which may be regions of the genome that are prone to high rates of deleterious mutation.

The identification of noncoding regions that are associated with autism would represent a significant advance in understanding the genetics of autism and other complex diseases. Functional characterization of these regions may provide insight into the genetic mechanisms that regulate brain development.