A new study confirms potential maternal contribution to autism based on analysis of unaddressed areas of the genome

August 10, 2016

Findings emerging from ongoing work by Autism Research Group Co-Lead Dr. Stephen Scherer, colleague Dr. Ryan Yuen, and collaborators indicate that clusters of de novo, or new mutations in the genome of mothers likely to contribute to autism.

“Genome-wide characteristics of de novo mutations in autism,” published August 3 in npj |Genomic Medicine is the largest-yet whole genome study of autism, involving data from 200 children and their unaffected parents.

Drawing from 600 whole genomes, and using novel statistical methods supported by Google, Sick Kids researchers replicated earlier findings in paternal germline (sperm) cells that link with pathways involved with early brain development. Newly discovered are maternal germline (egg) mutations, concentrated in clusters in DNA outside of the gene-coding regions of the genome.

Previously disregarded, despite comprising 98 percent of genetic material, non-coding regions are receiving fresh consideration for their regulatory influence on epigenetics (gene expression). Typical brain development is highly dependent on genes expressing at the right interval.

“If you think about the heritability of autism,” says Dr. Yuen, “before, when we were looking only at the coding region, we were just looking at part of the story.” The clustering observed in de novo mutations from the mother may indicate that different gene-change and gene-repair mechanisms are at work in men and women, he adds. Clustered mutations tended to occur near sequences of deleted or repeated DNA, known as copy number variations, or CNVs, a type of mutation previously identified and linked to autism by Dr. Scherer and colleagues.

The new study also indicated that gene-environment interactions likely play a role in autism: ASD-related mutations were found in the children in the study, that weren’t passed on by their parents. Environmental exposures that may influence gene expression are thought to include pollution, dietary deficiencies and inflammation during pregnancy.

“These findings represent a step toward better understanding the interplay between the genetic and non-genetic factors that contribute to autism risk,” Dr. Scherer adds. “But we need to analyze many more whole genomes to fully understand these intriguing findings.” Autism Speaks’ MSSNG project, on its way to sequencing 10,000 genomes, will provide the necessary scope and scale, according to Scherer.

Future directions are already being explored, says Yuen. “We’re coming up with a lot of novel ideas and findings, and are trying to drive the field forward. Eventually, these insights will help with diagnosis and treatment. We haven’t solved the whole picture, and it doesn’t change diagnostic practice at the moment, but we hope that the findings will push clinical diagnosis to consider non-coding regions, and to do a better job of evaluating those regions.”

Genome-wide characteristics of de novo mutations in autism was funded by Autism Speaks, Autism Speaks Canada, the Canadian Institutes for Advanced Research, the University of Toronto McLaughlin Centre, Genome Canada/Ontario Genomics Institute, the Government of Ontario, the Canadian Institutes of Health Research (CIHR), NeuroDevNet and The Hospital for Sick Children Foundation. BGI-Shenzhen and The Centre for Applied Genomics provided important analytical and technical support.

Story compiled incorporating material from Autism Speaks’ “MSSNG Study Expands Understanding of Autism’s Complex Genetics”
Photo Credit: SickKids