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Autism Data Shows Evidence of Human-Specific Regulatory Sequences Affecting Brain-Related Functions

NEW YORK (GenomeWeb) – A new study suggests parts of the human genome that are conserved in other animals but relatively divergent in humans appear to contribute to normal human brain development, social behavior, and/or some cognitive processes.

As they reported online today in Cell, the researchers used new sequence data alongside existing population sequence and gene regulatory information to assess human accelerated regions and their potential contributions to autism spectrum disorder. Their results suggest that de novo copy number changes that are over-represented in some individuals with ASD tend to coincide with parts of the genome that regulate brain-related genes and have undergone rapid sequence changes in humans.

"This work brings together the study of evolution and the study of neurological disease," senior author Christopher Walsh, a genetics and genomics researcher affiliated with Boston Children's Hospital, the Broad Institute, and Harvard Medical School, said in a statement. "Studying the kinds of mutations in [human accelerated regions] that cause neurodevelopmental disorders like ASD may tell us about the sorts of changes that led to us having a different brain than other animals."

Sequences that have diverged dramatically in humans relative to other animals have long been of interest for those trying to tease apart traits that are specific to our species, he and his colleagues noted.

The researchers set out to assess potential functions of human accelerated regions by attempting to differentiate the functional changes that accompany mutations in these sequences. Because a significant proportion of sequences with pronounced differences in humans seem to fall in regulatory regions, the team started by scrutinizing Epigenomics Roadmap regulatory profiles alongside sequence human-specific variants in thousands of human accelerated regions identified in prior studies.

The analyses uncovered overlap between human accelerated regions and regulatory sites influencing the expression patterns in developing and adult human brains, including some transcription factor binding sites associated with genes such as SOX2 or MEF2A that are involved in human brain development.

When they focused in on disease-related genes targeted by promoters in human accelerated regions, the researchers saw more than two-dozen genes implicated in ASD and/or intellectual disability. Likewise, genes associated with mammalian brain features, schizophrenia, or nervous system function tended to fall near sequences that have diverged quickly in humans.

The team then examined copy number variant data from 2,100 families from the Simons Simplex Collection, comprised of children with ASD, their unaffected siblings, and parents. There, the researchers found that de novo copy number changes, particularly those found in children with ASD, were more common in human accelerated regions.

Similar patterns turned up when the researchers sequenced 218 ASD-affected, consanguineous families from the Middle East. From genome sequencing data for 30 affected and five unaffected individuals and targeted human accelerated region sequencing data on the remaining family members, they uncovered 43 percent more recessive variants in human accelerated regions in the individuals with ASD than in those without.

In a series of follow-up experiments, the team got a better look at some of the variants that were specific to individuals with ASD or intellectual disability, along with their functional consequences. 

"We provide the first direct evidence that rare de novo CNVs involving [human accelerated regions] can contribute to simplex ASD and that rare biallelic mutations in neutrally active [human accelerated regions] can confer risk to ASD in as many as [5 percent] of individuals from a consanguineous population," the authors wrote.