Study Links Autism Risk to Paternally Passed Down Genes
A new study probing so-called noncoding DNA has found that alterations in regions that regulate gene activity may also contribute to autism. And surprisingly, these variations tended to be inherited from fathers who aren’t autistic.
While de novo protein-altering variants contribute to about a quarter of autism spectrum disorder (ASD) cases, researchers from University of California, San Diego, suspected that variants affecting regulatory elements could also contribute to risk of the condition.
UCSD’s Jonathan Sebat and his colleagues searched for structural variants in cis-regulatory elements (CRE-SVs) within the whole genomes of more than 9,000 people from 2,600 families affected by ASD. The researchers found that paternal-origin CRE-SVs were more likely to be inherited by their children with ASD rather than by their unaffected children.
The newly discovered risk factors differ from known genetic causes of autism in two important ways. First, these variants do not alter the genes directly but instead disrupt the neighboring DNA control elements that turn genes on and off, called cis-regulatory elements or CREs. Second, these variants do not occur as new mutations in children with autism, but instead are inherited from their parents.
“For ten years we’ve known that the genetic causes of autism consist partly of de novo mutations in the protein sequences of genes”
said Jonathan Sebat, a professor of psychiatry, cellular and molecular medicine and pediatrics at UC San Diego School of Medicine and chief of the Beyster Center for Genomics of Psychiatric Genomics. “However, gene sequences represent only 2 percent of the genome.”The study is the largest yet to explore how mutations outside of genes contribute to autism: It is based on an analysis of 9,274 whole genomes. And it focuses on ‘structural variants’—deletions or duplications in DNA—in these noncoding regions. Once dismissed as ‘junk DNA,’ some of these regions are now known to control the expression of genes.
Sebat and his colleagues sequenced the genomes of 311 families that have at least one child with autism. They also analyzed the genomes of 518 individuals with autism and their unaffected parents and siblings. Sebat’s team detected structural variants of 100 or more DNA letters. They found an average of about 3,700 such inherited variants in any one person.
The researchers further analyzed structural variants, deleted or duplicated segments of DNA that disrupt regulatory elements of genes, dubbed CRE-SVs. From the complete genomes of families, the researchers found that CRE-SVs that are inherited from parents also contributed to ASD.
“We also found that CRE-SVs were inherited predominantly from fathers, which was a surprise,” said co-first author William M. Brandler, PhD, a postdoctoral scholar in Sebat’s lab at UC San Diego and bioinformatics scientist at HLI.
“Previous studies have found evidence that some protein-coding variants are inherited predominantly from mothers, a phenomenon known as a maternal origin effect. The paternal origin effect we see for non-coding variants suggests that the inherited genetic contribution from mothers and fathers may be qualitatively different.”
Sebat said current research does not explain with certainty what mechanism determines these parent-of-origin effects, but he has proposed a plausible model.
“There is a wide spectrum of genetic variation in the human population, with coding variants having strong effects and noncoding variants having weaker effects“, he said. “If men and women differ in their capacity to tolerate such variants, this could give rise to the parent-of-origin effects that we see.”
