September 17, 2021


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Tags: Autism, detectable, linked, mens, mutations, Spectrum, sperm


Categories: autism

Mutations linked to autism could also be detectable in males’s sperm | Spectrum

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About 1 in 15 men carries genetically damaging mutations – some linked to autism or congenital heart disease – only in their semen, a small study suggests.

An advanced DNA sequencing technique detected the “mosaic” mutations in 25 men in the general population. Mosaic mutations arise after conception and therefore only occur in a fraction of the body’s cells.

“If you look at the sperm mosaic, you are right in the middle of what will happen in the next generation,” says lead researcher Joseph Gleeson, professor of neuroscience and pediatrics at the University of California, San Diego.

Men accumulate mutations in their sperm as they age. Some researchers say these mutations explain why a man’s chances of conceiving an autistic child double between the ages of 30 and 50, while others suggest that these mutations account for less than 10 percent of that increasing chance. But the prevalence of the mutations discovered in the new study remained constant over a period of 12 months, suggesting that these genetic changes occurred when the men were embryos. The advanced sequencing method used by the team can also calculate the likelihood of a child inheriting the mutations – odds that also remain stable over time.

“What they show is that mosaic makes a small but significant contribution to autism and congenital heart disease,” says Anne Goriely, Associate Professor of Human Genetics at Oxford University in the UK who was not involved in the study. “And this sperm analysis enables you to address that.”

Mutation secret:

Since many of the genetic mutations that contribute to a person’s autism cannot be detected in their parents ‘blood, it is believed that they arise spontaneously or “de novo” at conception or in the parents’ egg or sperm. In line with this idea, Gleeson and other researchers have already detected these de novo mutations in the sperm of fathers with autistic children.

When the team presented its results, “however, we always felt we had the same questions,” says study researcher Martin Breuss, assistant professor of pediatric clinical genetics and metabolism at the University of Colorado in Denver. Since men are constantly producing new sperm, would a mutation identified in a particular semen sample still be present in subsequent samples? And would these mutations become more common with age?

To answer these questions, the team took blood and semen samples from 25 men up to three times within a year. The men were between 18 and 70 years old. The researchers sequenced the entire genome of each sample at least 300 times – about ten times more than traditional methods. This deep sequencing enabled them to confidently differentiate mosaic mutations from sequencing errors.

“Without the advancement of sequencing technology, it is almost impossible to find mosaic mutations,” says study researcher Xiaoxu Yang, a postdoctoral fellow in Gleeson’s laboratory.

The men carried an average of 33 mutations in their sperm, two-thirds of which are undetectable in their blood, the team found. The results appeared in Cell in August.

Deep sequencing:

The proportion of sperm containing these mutations remained the same in each man over time, and the sperm-only mutations were no more common in older men than in younger ones. Taken together, this means the mutations likely occurred during embryogenesis, the researchers say.

“By measuring the percentage of cells with [a specific, potentially damaging] Mutation we can actually make a prediction about the likelihood of having a child with this disease, ”says Gleeson. For example, if 5 percent of a man’s sperm contains a mutation today, there is a 5 percent chance of passing that mutation on to his children today, tomorrow, and 10 years from now.

Of the mutations found only in sperm, an average of 1.6 per sample occur in the coding regions of genes, and 0.3 are likely to affect the function of a gene, the researchers found.

Such mutations with loss of function in one copy of a gene occur in the sperm of about 7 out of 100 men, the team estimates. These mutations could account for about 15 percent of cases of autism, congenital heart disease, and serious pediatric disease, they say.

It is noteworthy that the study only focused on “clonal” mutations and not on the more common but less detectable “non-clonal” mutations that only occur in a single sperm.

“To get a complete picture of the disease risk for a particular person’s offspring, you need to look at the non-clonal variants as well,” said Maria Chahrour, an assistant professor of genetics and neuroscience at the University of Texas Southwestern in Dallas, who was not enrolled .

Gleeson says he and his colleagues hope to study these variants with larger sample sizes in the future, he says. “There’s a whole different world that we haven’t even explored and that’s these non-clonal mutations.”

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