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Mosaic Enhancer Mutations, CNVs Contribute to Risk of Developing Autism

This article has been updated with a comment from one of the researchers.

NEW YORK – In a pair of papers published in Nature Neuroscience on Monday, teams led by researchers at the Broad Institute and Harvard Medical School found that mosaic enhancer mutations may contribute to an individual's risk of developing autism spectrum disorder (ASD), and specifically that mosaic copy number variants (mCNVs) contribute a previously unexplained component of ASD risk.

In the first study, co-corresponding authors Peter Park and Christopher Walsh and their colleagues describe their characterization of the landscape of somatic mutations in the human brain using ultra-deep whole-genome sequencing to about 250x of the prefrontal cortex from 59 donors with ASD and 15 control donors. They observed a mean of 26 somatic single-nucleotide variants per brain in 4 percent or more of cells, with enrichment of mutations in coding and putative regulatory regions.

Their analysis revealed that the first cell division after fertilization produced about 3.4 mutations, followed by two to three mutations in subsequent generations, suggesting that a typical individual possesses about 80 somatic single-nucleotide variants (sSNVs) in 2 percent or more of cells. 

"This study reveals the contribution of mosaic mutations in ASD. Our analysis suggests that these mosaic mutations are accumulated in every individual but that those in ASD individuals are more likely to be found in enhancers," Park told GenomeWeb. "Our results illustrate the diversity of genetic mechanisms that lead to the ASD phenotype, and the importance of new technologies such as whole-genome sequencing in identifying genetic factors more comprehensively."

In the second paper, Park, Walsh, and co-senior author Po-Ru Loh described their assessment of the contribution of mCNVs to ASD. They ascertained the presence of mCNVs in genotype array intensity data from 12,077 probands with ASD and 5,500 unaffected siblings, observing 46 mCNVs in the probands and 19 mCNVs in the siblings. The probands carried a significant burden of large mCNVs, which were detected in 25 probands but only one sibling, the researchers said. They also experimentally validated two mCNVs in postmortem brain tissues from 59 additional probands.

In the first paper, the researchers noted that sSNVs have been shown to be enriched in exons at the single-neuron level, suggesting that transcriptional errors may contribute to somatic mutations. However, few studies have examined clonal somatic mutations genome-wide in bulk DNA samples to determine which regions of the genome harbor somatic mutations that arise in early development. In their analysis, they found that 35 sSNVs were exonic (2.2 percent), which is about twice as high as they expected. Among these, 12 were silent, two were protein-truncating, and 21 were missense. Approximately 43 percent of the samples had at least one detectable exonic sSNV, with one sample having three exonic mutations. These data suggested that coding regions are particularly vulnerable to somatic mutation during development.

One likely damaging missense mutation they observed, for example, was in CACNA1A, a gene previously documented to cause autism and intellectual disability in the heterozygous state. Importantly, the researchers added, while their study was not well powered enough to analyze germline ASD mutations, several individuals in the cohort exhibited rare germline variants in autism risk genes that are predicted to be damaging and likely to contribute to disease.

"Of note, predicting true deleteriousness is known to be very difficult, such that many mutations predicted as damaging would have functional impact only when homozygous and are likely to be well tolerated especially in a somatic state," the authors concluded. "Still other mutations may be incompatible with life when homozygous or even when germline heterozygous, meaning that their effects could only be observed in a somatic state. Therefore, although many predicted-damaging mosaic mutations may have subtle effects depending on their distributions, they nonetheless have potential to cause or contribute to a wide number of disease states in many individuals."

Overall, they added, the data showed that mosaic noncoding mutations represent an attractive candidate mechanism for study in ASD as well as other neuropsychiatric diseases.

In the second paper, the researchers noted that common variants, rare variants, and germline de novo variants contribute substantially to ASD risk, with germline de novo CNVs (dnCNVs) being observed in 5 percent to 10 percent of ASD probands. However, as a large portion of ASD susceptibility can't be explained by known risk variants, mCNVs have been proposed as a possible source of some of the unexplained susceptibility.

To determine the role these variants play, the investigators systematically analyzed mCNVs in 11,457 ASD-affected families using genotype array data from the Simons Simplex Collection and the Simons Powering Autism Research for Knowledge datasets. They found that the individuals with ASD had an excess of large mCNVs, with large defined as more than 4 megabases in size, and that such CNVs appeared to be extremely rare in unaffected individuals.

Data analyses also indicated that mCNVs comprised orthogonal genetic aberrations that independently contribute to ASD risk and did not seem to overlap with known ASD genes.

Interestingly, the researchers said, mCNVs in probands had characteristics different from germline dnCNVs previously reported in the probands from the Simons Simplex Collection cohort. For example, these mCNVs were significantly larger than dnCNVs and did not exhibit focal recurrence in any genomic location. The researchers hypothesized that such mosaic analogues of ASD-dnCNVs might be very rare or might confer little or no ASD risk.

To determine whether this might be true, they examined mosaic events previously detected in a population sample of 454,993 individuals of European ancestry in the UK Biobank. After an analysis of the data, the researchers noted that the burden of mCNVs in ASD probands was driven by large mCNVs that disrupted large swaths of the genome and that smaller mCNVs might generally have limited phenotypic consequences, even when disrupting ASD-associated regions.

"As efforts to directly assay the genome of the brain expand, we expect the risk contribution and molecular mechanisms of mCNVs to be further refined for both ASD and other neurodevelopmental disorders," the authors concluded.