A new study from Autism Speaks' MSSNG program expands understanding of autism's complex causes and may hold clues for the future development of targeted treatments. The report, appearing in npj Genomic Medicine is the largest-ever whole genome study of autism, involving 200 children with the condition and both their unaffected parents.
The new research focuses on newly arising, or de novo, gene changes in the germline cells that produce a parent's eggs or sperm. Previous studies have shown that these mutations can be major contributors to autism through their effects on early brain development.
The 600 fully sequenced genomes came from MSSNG (pronounced "missing"), the world's largest collection of autism genomes and a collaborative effort of Autism Speaks and The Hospital for Sick Children (SickKids), in Toronto. More than halfway to its goal of sequencing more than 10,000 autism genomes, MSSNG has made this unprecedented resource freely available for worldwide research into the causes and personalized treatments for autism.
Geneticists Stephen Scherer and Ryan Yuen, of SickKids, led the study team, which also included scientists with the University of Toronto, Google, BGI-Shenzhen (China) and Autism Speaks.
The researchers found:
"This represents the most comprehensive assessment to date on the contribution of non-coding variants to autism," Dr. Yuen says. "As such, it provides an important road map on how whole genome sequencing can advance autism research in the future."
However, the researchers also found that clustered, or concentrated, stretches of de novo mutations tend to come from the mother. "This new finding may be evidence that different types of gene-change and gene-repair mechanisms are at work in men versus women," Dr. Yuen says. Indeed, the clustered mutations from the mother tended to occur near stretches of deleted or repeated DNA called copy number variations (CNVs) -- a type of mutation that the research team had previously linked to autism.
In addition to genetic changes in egg and sperm, the analysis turned up autism-associated mutations that likely occurred in the embryo soon after fertilization. "These genetic changes can arise due to environmental insults [such as exposure to toxic chemicals]," Dr. Yuen says.
"These findings advance our efforts to improve diagnostics and precision healthcare for autism," says geneticist Mathew Pletcher, Autism Speaks interim chief science officer and a co-author on the report. "There's so much about the causes of autism that we would miss if we focused only on the gene-coding regions of the genome. This demonstrates again why whole genome sequencing is so important."
"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 -- such as the number being sequenced through MSSNG -- to fully understand these intriguing findings." Dr. Scherer is project director for the Autism Speaks MSSNG program and directs the Centre for Applied Genomics at Toronto's Sick Children's Hospital. Dr. Yuen's research was supported by an Autism Speaks Meixner Postdoctoral Fellowship in Translational Research.
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