NEW YORK (GenomeWeb) – New research by investigators at Decode Genetics/Amgen, the University of Iceland, and Reykjavik University suggests children born to older parents are particularly prone to de novo mutations, though the nature of these changes differs depending on whether aging moms or dads are considered.
A study published by researchers at Decode and elsewhere in 2012 suggested that increasing paternal age coincided with an uptick in new mutations in their children, based on patterns for a few dozen Icelandic families, including trios with children affected by autism spectrum disorder or schizophrenia. That work did not see significant effects related to maternal age, though other teams have described some increases in de novo mutations in children of older mothers.
For their latest Nature study, Decode and University of Iceland researchers Kari Stefansson and Daniel Gudbjartsson led a team that analyzed genome sequence data for members of more than 1,500 Icelandic trios, generating sequence data on parents and children for 225 of the Icelandic individuals. With the help of haplotype-sharing patterns in the latter three-generation families, along with read-pair tracing, they retraced parent-of-origin for 42,961 of the nearly 109,000 de novo SNPs or small insertions or deletions detected in the families.
The team's results suggest that de novo mutations do creep up in children born to aging moms. But the number of new single base or indel changes for each additional year of maternal age — estimated at 0.37 — was far lower than the 1.51 de novo mutations added, on average, for every year that dads aged.
On the other hand, new mutations associated with advancing maternal age appeared more apt to cluster and often cropped up in parts of the genome suspected of harboring frequent double-strand DNA breaks leading to cytosine-to-guanine changes.
Indeed, as moms got older, the team saw shifts in the types of mutations that were most common in their children: a sequence spanning some 20 million bases of chromosome 8 tended to accumulate cytosine-to-guanine changes, for example — changes that the investigators attributed to maternal non-crossover gene conversions.
"[T]he regional excess of [cytosine-to-guanine] variation in humans is largely shared by chimpanzees, less by gorillas, and is almost absent from orangutans," Stefansson, Gudbjartsson and their colleagues wrote. "This demonstrates that sequence diversity in humans results from evolving interactions between age, sex, mutation type, and genomic location."
The researchers tapped into a collection of whole-genome sequences for 14,688 Icelandic individuals for the current study, focusing on members of 1,548 parent-child trios containing 101,377 de novo single nucleotide changes and thousands more indels that appeared de novo in offspring.
They estimated that more than 80 percent of the 15,746 de novo mutations detected in children from 225 families with representatives from three generations stemmed from fathers, for example. Across all of the families, they phased 42,961 de novo mutations in children before looking at the types of mutations, mutation distribution, and other features associated with paternal age and maternal age.
Every additional year of paternal age was associated with more new mutations overall. But from comparisons with cytosine-to-guanine mutation-rich parts of other primate genomes, the investigators got clues that delving into parts of the genome prone to mutation in children of older mothers will likely provide insights into the genes and regulatory sequences evolving especially quickly in populations with enhanced maternal age.
"De novo or new mutations provide an important part of the substrate for evolution, launching a constant flow of new versions of the human genome into the environment," Stefansson, who is Decode's CEO, said in a statement.
"However, they are also believed to be responsible for the majority of cases of rare diseases of childhood," Stefansson added. "Providing a comprehensive catalogue of such mutations from across an entire population is therefore not just scientifically interesting, but also an important contribution to improving rare disease diagnostics."