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Decode-led Team Uncovers Elevated De Novo Mutation Rate in Children of Older Fathers

NEW YORK (GenomeWeb News) – Children born to older fathers tend to have more de novo mutations in their genomes than those with younger dads, according to a study by researchers at Decode Genetics, the University of Iceland, and Illumina Cambridge.

"When we started to look at variation in mutation rates in the population, about 97 percent of it is accounted for by the age of the father," senior author Kari Stefansson, Decode's founder and CEO and a researcher with the University of Iceland, told GenomeWeb Daily News.

As they reported online today in Nature, Stefansson and his colleagues sequenced the genomes of 78 Icelandic children and their family members, comparing sequences within the trios to one another and to sequences for another 1,859 unrelated individuals from Iceland. The patterns they saw were consistent with a model in which children had two more de novo mutations for every year older their fathers were at conception, on average.

As such, the researchers said, the results may explain epidemiological evidence from the new study and previous research that points to a jump in the incidence of conditions that can stem from de novo mutations — such as autism and schizophrenia — in children with older dads.

"One of our suggestions … is that part of the increase in the diagnosis of autism that has happened over the past 25 years may be due to the increase in the age of fathers," Stefansson said.

As part of its larger effort to understand genetic diversity using samples from Iceland, the Decode-led team used Illumina GAIIx and HiSeq 2000 instruments to sequence the genomes of 219 Icelandic individuals from 78 parent-child trios to 30-fold coverage depth, on average.

For some of the trios, the team also sequenced siblings and/or family members from other generations. The age of fathers in these trios ranged from 18 to 40.5 years old and averaged 29.7 years old.

Of the 78 children in these trios, 41 had been diagnosed with autism spectrum disorder and 21 were schizophrenic.

"What we were interested in doing was to have, among the trios we sequenced, trios that had individuals with diseases that have been shown to be sometimes caused by de novo mutations," Stefansson explained.

The team's analyses of the genomes, as well as sequences from 1,839 other individuals from the Icelandic population who had been sequenced to a depth of at least 10 times, uncovered just over 63 de novo mutations on autosomal chromosomes per trio, on average.

Although children with older fathers also tended to have older mothers, the team found that it was the father's age at conception that was mostly highly associated with the number of new mutations in a child's genome. That pattern was further confirmed when the researchers tracked maternal and paternal chromosome transmission across the generations in five families for which multi-generational information was available.

Although the location of de novo mutations in the genome varied from one family to the next, the researchers saw examples of siblings who shared the new mutations, hinting that sperm from the same man may be prone to genetic glitches at non-random sites.

Based on the latest research, combined with previous studies, Stefansson and his co-authors concluded that older mothers tend to pass along chromosomes with more extensive recombination, while older fathers pass on more new mutations.

The reason seems to stem from the ongoing proliferation of sperm precursor cells throughout a man's lifetime, Stefansson explained. "There is a continuing proliferation of cells leading to the sperms, giving rise to these mutations.

"They are increased by two mutations per year and the number of mutations is doubled every 16.5 years," he added. "We have some hints in our data that the increase is even greater per year in the top range of age."

To explore that possibility, the researchers continuing to look at de novo mutation patterns in around 200 more trios, including some with older fathers.

The team is also interested in teasing apart the relative contributions of de novo and inherited mutations in schizophrenia and autism, which are more common in children with older fathers.

"It's very important to know this, so we can begin to assess the total implications of these increasing de novo mutation rates when it comes to the risk of autism and schizophrenia," Stefansson said.

Among the de novo mutations detected in the current study, for instance, researchers found a glitch in the schizophrenia-associated gene NRXN1 in an individual with the condition. Similarly, de novo mutations in children with non-familial forms of autism showed up in CUL3 and EPHB2, genes identified in previous studies of ASD and nervous system development, respectively.

More generally, Stefansson explained, studies of de novo mutation provide a peek at the new mutations, which are the genetic fodder for the all of the genetic diversity found in the human genome.

"Although the de novo mutations may turn out to be dangerous for the members of the next generation, for the children, the de novo mutations are extraordinarily important contributors to diversity," he noted, "from which nature can select to help us to adjust to a changing world."

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