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Autism origins in junk DNA

Speed read
  • New genome analysis reveals influence of rare inherited variants in non-coding DNA
  • Genetic contribution from both mothers and fathers may play unique roles in autism risk
  • Comet supercomputer meets the needs of underserved domains like autism research

One percent of the world’s population lives with autism spectrum disorder (ASD), and the prevalence is increasing by around ten percent each year. Though there is no obvious straight line between autism and any single gene, genetics and inherited traits play an important role in development of the condition.

In recent years, researchers have firmly established that gene mutations appearing for the first time, called de novo mutations, contribute to approximately one-third of cases of autism spectrum disorder (ASD).

<strong>Early symptoms.</strong> Children with ASD may avoid eye contact, have delayed speech, and fail to demonstrate interest. Courtesy Unsplash.In a new study, an international team led by scientists at University of California San Diego (UCSD) School of Medicine have identified a culprit that may explain some of the remaining risk: rare inherited variants in regions of non-coding DNA.

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 UCSD School of Medicine and chief of the Beyster Center for Genomics of Psychiatric Genomics. “However, gene sequences represent only 2 percent of the genome.”

Autism facts

  • Autism affects 1 in 68 children
  • Boys are four times more likely than girls to have autism
  • Symptoms usually appear before age 3
  • Autism varies greatly; no two people with autism are alike
  • There is currently no cure for autism
  • Early intervention is key to successful treatment

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 genomes were sequenced in San Diego at Human Longevity Inc. (HLI) and at Illumina Inc.

DNA sequences were analyzed with the Comet supercomputer at the San Diego Supercomputer Center (SDSC). These data were then combined with other large studies from the Simons Simplex Collection and the Autism Speaks MSSNG Whole Genome Sequencing Project.

“Whole genome sequence data processing and analysis are both computationally and resource intensive,” said Madhusudan Gujral, an analyst with SDSC and co-author of the paper.

Using SDSC’s Comet, processing and identifying specific structural variants from a single genome took about 2½-days 

Since Comet has 1,984 compute nodes and several petabytes of scratch space for analysis, tens of genomes can be processed at the same time,” added SDSC scientist Wayne Pfeiffer. “Instead of months, with Comet we were able to complete the data processing in weeks.”

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.

HPC for the 99 percent. The Comet supercomputer at SDSC meets the needs of underserved researchers in domains that have not traditionally relied on supercomputers to help solve problems. Courtesy San Diego Supercomputer Center.

“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 UCSD 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.”

Read more: 

Read the original article on SDSC's website here.

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