Evaluation ups estimate of spontaneous mutations’ position in autism | Spectrum
Family Matters: Spontaneous genetic mutations are much more likely to contribute to autism in children whose siblings are unaffected than in children whose siblings do.
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Spontaneous genetic mutations contribute to autism in 30 to 39 percent of people with the condition, an increase from previous estimates, according to a new study. The rate is even higher – 52 to 67 percent – in autistic children whose siblings do not also have the disease.
These spontaneous or “de novo” mutations are not found in any of the parents of an autistic person and are more common in autistic people than in non-autistic people. They can also mainly contribute to autism in so-called “simplex” families who have an autistic child, say the researchers who run the new study. In contrast, inherited mutations explain most cases in “multiplex” families who have more than one autistic child, they say.
“This study clearly confirms our observation that de novo is not very important in the multiplex,” says lead researcher Ivan Iossifov, associate professor of genetics at the Cold Spring Harbor Laboratory in New York. “It sounds like an obvious thing and we certainly took it for granted, but there was no clear observation.”
Some studies have identified de novo autism-related mutations in children from multiplex families, but the new work estimates that the mutations only play a role in about 10 percent of these children. The discrepancy from previous estimates could be related to sample differences that tarnish comparisons, say Iossifov and colleagues.
Some analyzes of multiplex families have relied on cell lines that can accumulate de novo mutations as they grow in culture dishes – a problem known as “genetic drift” – and thus skew the results. The new work screens samples for these stray mutations, making it possible to distinguish the de novo mutations that contribute to autism.
“They went through a lot of statistical tests and comparisons,” says Santhosh Girirajan, an adjunct professor of genomics at Pennsylvania State University who was not involved in the work. “I think it’s done well.”
Researchers analyzed the entire genome sequences of 1,869 autistic children and 1,874 of their non-autistic siblings from the Simons Simplex Collection (SSC), which collects data on simplex families, and 1,107 autistic children in multiplex families from the Autism Genetic Resource Exchange ( I AGREE). The Simons Simplex Collection is funded by the Simons Foundation, Spectrum’s parent organization.
The sequences in SSC are from blood samples, while some of those in the AGRE database are from lymphoblastoids, which continuously replicate from blood cells. Because these cell lines are prone to genetic drift, the researchers developed a technique to screen the samples and remove participants with an unusually high number of new mutations.
Next, they looked for three types of de novo mutations – single nucleotide swaps, short insertions and deletions of DNA called “indels”, and larger ones called copy number variations – and focused on those that did most likely to disrupt the function of a gene. About 9.8 percent of autistic children from simplex families have disruptive de novo mutations, the researchers found, compared with 2.2 percent of children in multiplex families.
The team then examined the part of the genome that does not code for proteins, but only in the simplex families. About 13 percent of children from simplex families had non-coding mutations likely to contribute to autism; 6 percent had mutations in sequences between the coding parts of genes known as introns, which often help regulate gene expression.
Combining these results with previous findings on the prevalence of other types of de novo mutations in simplex families, the researchers estimate that de novo mutations contribute to autism in 52 to 67 percent of autistic people in simplex families, 9 up to 11 percent of autistic people in multiplex families and a total of 30 to 39 percent of autistic people. Previous studies had shown de novo mutations to be responsible for autism in about 25 percent of people with the condition, but those studies didn’t include mutations from non-coding regions of the genome, says Iossifov.
The results were published in Communications Biology on September 1.
The technique of eliminating samples with high genetic drift is useful, according to other researchers, and helps clarify previous results on de novo mutations.
“I am pleased with the rigorous comparison of the de novo contribution between simplex and multiplex families,” wrote Joon-Yong An, Assistant Professor of Biosystems and Biomedical Sciences at Korea University in Seoul, South Korea, in an email Spectrum. “It was always a bit confusing with the numbers from so many different studies.” An was not involved in the work.
While the results support the argument for de novo mutations to be implicated in autism, they are likely not the be-all and end-all of the origins of autism, says Girirajan. Several factors are likely to influence the heredity of autism, including the combined effects of inherited variants from both parents and environmental factors on gene expression.
“It emerges from this work that we should look at more complex forms of inheritance and other factors,” says Girirajan.
The researchers say they next plan to dig deeper into variants in the non-coding genome by analyzing their effects on RNA expression levels.
Quote this article: https://doi.org/10.53053/HNUI6902