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Autism Spectrum Disorder Risk Variant Effects Influenced by 3D Genome Organization

NEW YORK – New research suggests the consequences of some autism spectrum disorder (ASD)-related de novo variants (DNVs) depend on the 3D location of these variants in the genome.

"Our results may contribute to risk prediction for ASD patients, especially for so-called exome-negative cases without pathogenic mutations in the protein-coding regions," senior and co-corresponding author Atsushi Takata, a researcher affiliated with the RIKEN Center for Brain Science and the Juntendo University Graduate School of Medicine, said in an email, adding that "the analytical approach of this study would be useful to better understand the role of noncoding mutations in human complex traits and diseases other than ASD."

In a paper published in Cell Genomics on Friday, Takata and his colleagues performed a meta-analysis that encompassed the whole-genome sequences for 5,044 individuals with ASD from the Simons Simplex Collection (SSC) and Simons Foundation Powering Autism Research for Knowledge (SPARK) collection, along with their parents and 4,095 unaffected siblings.

In particular, they focused on ASD-related DNVs falling within regulatory element-rich topologically associating domains (TADs), which they defined using available high-throughput chromosome conformation capture profiles on a region of the adult prefrontal cortex, including 15,376 gene promoter DNVs. The work made it possible to consider the gene regulatory consequences of ASD gene promoter DNVs, while revealing ASD-related TADs and the promoter DNV interactions within these regions.

"Although it has been known that [TADs regulate] neurodevelopment and that disruption of specific TAD boundaries can cause neurodevelopmental disorder syndromes, to my knowledge, this is the first study to statistically demonstrate a direct association between ASD and TAD-related gene regulatory mechanisms based on an analysis of large-scale WGS data," Takata added.

Along with an overrepresentation of ASD-associated DNVs falling in the promoter region of ASD genes in TADs in individuals with autism, the team also flagged TADs with higher-than-usual rates of promoter DNV changes in affected individuals. In a TADome-wide association study spanning more than 1,800 promoter DNV-containing TADs, for example, the researchers highlighted ties between ASD-associated promoter DNVs and TADs on chromosome 1 and chromosome 13.

Through a series of follow-up cell line and RNA sequencing experiments in induced pluripotent stem cell-derived neurons containing deleterious ASD-related DNVs on chromosome 7 or chromosome 22 that were introduced by CRISPR-Cas9 gene editing, meanwhile, the investigators saw signs that multiple genes encompassed in a shared TAD can be altered in the presence of specific DNVs.

"[O]ur findings show that TADs and their gene contents define the impact of promoter DNVs on ASD risk based on statistical evidence from an analysis of large WGS datasets," the authors reported, noting that the work "suggests that the integration of information on TADs with appropriate gene sets contributes to a better understanding of the role of rare noncoding variants in the genetic architectures of other diseases and traits."