People have been desperate to learn more about the potential causes of autism, and researchers have been making some progress in recent years. Now, work reported in Science has shown that new genetic mutations that appear in the genome just before the start of genes, in regions called promoters, play a role in the development of autism.
For many years genetic research focused on the portions of the genome that code for protein, but there are many other critical parts, some of which help regulate how genes are expressed. This study focused on noncoding regions, which make up over 98 percent of the human genome."We wouldn't have that DNA if it didn't do something," said Stephan Sanders of the University of California, San Francisco, one of the study leaders.
This research utilized genetic data from 2,000 families, which generated a large enough amount of data to find a significant role for mutation in promoter regions. Those regions are upstream of the start of genes and are where the cellular machinery activates a gene. This work assessed 1,902 families called quartets - two parents and two children, one child with autism and one without, from the Simons Simplex Collection of genetic data. The investigators showed that children with autism have more de novo (spontaneous, uninherited) mutations in promoter regions compared to their siblings without autism.
"Being able to show that de novo mutations in noncoding regions contribute to autism is phenomenally exciting," said Sanders. "It's our first chance to really come to grips with rare mutations in the other 98 percent of the genome."
Some mutations occurred in promoters that were upstream of genes that interact with a common autism risk gene called CHD8, or genes involved in development or neurodifferentiation.
"All of that collectively fits," said Alan Packer, a senior scientist at the Simons Foundation Autism Research Initiative. "It's a reassuring sign that they're on the right track."
They identified mutations in conserved promoter regions, which are found in many species of animals, not just humans. "Although autism is a very human trait, the mechanisms involved are potentially ones that have been with us for millions of years," Sanders said. It suggests that animal models may indeed be a reliable way to study autism.
The work could also help reveal how problems in the many complicated changes in gene expression that occur throughout development may lead to autism. ”The eventual long-term payoff of the study may be in pointing to particular places and times in brain development that you want to focus on, from among the many possibilities," Packer said.
Another massive collection of genetic data is sure to advance this work even further. The SPARK cohort involves around 21,000 families, with more enrollment planned.
"SPARK is the largest study of autism in the United States," said lead investigator Wendy Chung of Columbia University. "With a goal of studying over 50,000 individuals with autism, we will be confident of the genetic factors we identify."
Stephan Sanders discusses the genetics of autism in the video.