Subset of autism circumstances linked to mutations in noncoding genome | Spectrum
Gene-free zone: Mutations in promoters, stretches of non-coding DNA that modulate the expression of genes, contribute to autism in some people.
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Mutations in non-coding parts of the genome contribute to autism in at least 3 percent of people with this condition. The mutations affect regions that help regulate known genes associated with autism.
The unpublished results were presented today by researchers at the American Society of Human Genetics 2021 conference, which is taking place virtually for the second year in a row.
Autism is largely genetic and has been linked to mutations in more than 100 genes within the exome, which makes up about 1 percent of the genome. But only about a quarter of autistic people have a known genetic explanation for their diagnosis.
To fill this gap, some researchers have started studying the other 99 percent of the genome that does not contain genes.
In the new work, the researchers examined promoters, sections of non-coding DNA that modulate the expression of genes. Because promoters are in close proximity to the genes that regulate them, researchers can more easily see the effects of mutations in them compared to other parts of the non-coding genome, says Ryan Doan, assistant professor of pediatrics at Boston Children’s Hospital in Massachusetts, who presented the work.
The ultimate goal is to “improve genetic testing for families,” Doan says. “With a promoter, it will be a lot easier to get us to a point where we can actually give a result back to a family.”
The researchers used several public databases to identify non-coding regions likely to regulate genes involved in brain development. They focused on what are known as biallelic mutations that occur in both the maternal and paternal copies of the regions.
They next looked for the mutations in 662 people, including 193 with autism, from the Homozygosity Mapping Collaborative for Autism cohort, which recruits families from the Middle East, Turkey, and Pakistan. The parents in the cohort have an above-average number of marriages within the family, which increases the likelihood of biallelic mutations in their children.
Such mutations are more common in the promoter sequences of autistic people than non-autistic people, Doan and his team found. The same result came when the team replicated the analysis on 21,247 people, including 5,456 autistic people participating in the Autism Sequencing Consortium.
Overall, these non-coding mutations contributed to autism in about 3 percent of autistic people, the researchers found; the mutations affect more than 20 genes that are strongly linked to autism.
Three people in the Autism Sequencing Consortium cohort carry non-coding mutations upstream of the FMR1 gene, mutations that cause Fragile X syndrome. One family carries a mutation near the TTI2 gene that has been linked to autism, intellectual disability, and microcephaly.
This mutation suppressed almost all TTI2 expression, Doan says, confirming that the non-coding mutations interfered with the function of the nearby gene.
“We can link these [mutations] directly to a particular gene, and we can assess its function on a gene much more easily, ”he says. “If we want to slowly expand from the exome, the promoter regions will be the next most important area for genetic contribution.”
Read more reports from the American Society of Human Genetics’ annual 2021 meeting.