August 2, 2021


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Tags: Autism, contribute, genome, mutations, noncoding, Spectrum


Categories: autism

Mutations within the noncoding genome contribute to autism | Spectrum

Non-Coding Contributors: New evidence links autism to three spontaneous mutations in a part of the genome that regulates the EBF3 gene.

Spontaneous mutations in “non-coding” regions of the genome have been linked to autism, according to a new study. The work strongly supports the idea that the genetic roots of autism lie not only in protein-coding genes, but also in non-gene DNA.

“This is substantial evidence that these non-coding mutations can have a strong phenotypic influence,” says Alex Nord, associate professor of psychiatry at the University of California, Davis, who was not involved in the new work.

Researchers have long focused on autism-related mutations in genes that code for proteins and make up only 2 percent of the genome. The other 98 percent of the genome is “non-coding”: it does not contain instructions for proteins, but rather influences when, where and how much genes are expressed.

Statistics-based studies have found that the non-coding region of the genome contains genetic variants that contribute to autism, but the new work could be the first to identify three such mutations, says Tychele Turner, assistant professor of genetics at Washington University in St. Louis directed the new work.

“I just thought it was cool that we could start digging into the non-coding variation space,” says Turner. “Maybe in three or four years we will have a pretty cool list [of additional noncoding variants]. “

Unexplored area:

Turner and her team searched a database of 544 non-coding sections of the genome that are active in the brain of mouse embryos. These so-called enhancer segments increase gene transcription.

They then searched entire genome sequences of 2,671 families with an autistic child in the Simons Simplex Collection database to see which of these enhancers contained de novo variants. (The Simons Simplex Collection is funded by the Simons Foundation, Spectrum’s parent organization.)

In particular, one enhancer known as hs737 showed significantly more de novo mutations in both a discovery cohort of 516 families and a replication cohort of 2,155 families. Notably, these de novo mutations in hs737 occurred in three people with autism, unaware of any other autism-related variants.

In experiments with neuronal cell lines, the three de novo mutations caused the enhancer to lower and not increase gene expression, the researchers found. Existing maps of genome interactions in mouse and human brain cells indicated that h737 regulates a gene called EBF3. The team announced preliminary results at the American Society of Human Genetics 2020 conference and published them in Human Genomics on July 13.

To the surprise of researchers, EBF3 is a well-studied gene. Mutations in EBF3 cause a condition called hypotension, ataxia, and delayed developmental syndrome (HADDS), which is characterized by poor muscle tone and motor problems. Autistic people with mutations in hs737 also had motor problems or low muscle tone, the team found. That may be because hs737 is only active in the brain during the development of an embryo, although EBF3 is widespread in the body, Turner says. Mutations in the enhancer could lead to similar but less serious traits than mutations in the gene itself.

“That’s really interesting,” says Turner. “It’s starting to wonder … why some people might have these major syndromes, but if you only influence one tissue-specific regulator of this gene, [the effect] maybe not that serious, but it will still be important. “

Just the beginning:

The statistical significance of the association of hs737 with autism is marginal, but follow-up work by Turner and her colleagues to establish the association “is very compelling to me,” said Dan Arking, professor of genetic medicine at the Johns Hopkins University School of Medicine who was not involved in the work.

The work offers “a nice model” of how to link a non-coding mutation to a phenotype, he says. “They captured a lot of the pieces, put the puzzle together, and did it really well.”

Although only one enhancer reached the level of nominal significance in this study, more enhancers could be associated with autism over time, say the researchers as well as other scientists.

It’s like “first looking for fish in a pond and then moving to a huge lake,” says Nord. This means that more samples are needed to determine significance, but “this is the first, not the only”.

Turner’s lab is working on developing a strain of mice lacking the hs737 enhancer to better understand how mutations in this section of non-coding DNA affect behavior.

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