"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."
‘While the genetic causes of autism consist partly of de novo mutations, variants in regions of non-coding DNA also increase risk for inherited autism.’
To investigate the other 98 percent of the genome in ASD, Sebat and his colleagues analyzed the complete genomes of 9,274 subjects from 2,600 families. One thousand were sequenced in San Diego at Human Longevity Inc. (HLI) and at Illumina Inc., and DNA sequences were analyzed at the San Diego Supercomputer Center at UC San Diego. These data were then combined with other large studies from the Simons Simplex Collection and the Autism Speaks MSSNG Whole Genome Sequencing Project.
The researchers then 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."
Source: Eurekalert
