Age is, unfortunately, more than just a number.
Prospective parents know this. Age is linked to declining fertility in both men and women, as well as an increased risk for certain rare genetic diseases in their children. Older parents tend to pass along new DNA variations to their children, which can drive certain disorders, including intellectual disabilities, autism, and schizophrenia. Fathers accumulate and pass on these variations through their sperm, while mothers pass them on through the DNA they contribute in their eggs. Now, a team of researchers studying more than 1,500 parent-child pairs in Iceland have teased apart patterns in these inheritable mutations based on their type, frequency, and location.
The goal, according to Kári Stefánsson, CEO of deCODE genetics and a co-author of the new study, is “to look in detail at the difference between the maternal and paternal contribution.”
The results, published September 28 in the journal Nature, provide evidence of the fathers’ greater contribution of new mutations to their children — a contribution that increases with age four times faster than the mothers’. In other words, older fathers pass along more variation in DNA from their sperm compared to their younger counterparts or mothers of the same age.
The pattern is expected, and likely due to a fundamental difference between male and female sex cells, researchers say. Potential fathers are constantly producing millions of sperm, which requires repeated replication of genetic material. This leads to a gradual accumulation of errors — or mutations — which can be inherited. By contrast, women pass on fewer mutations because they do not produce new eggs during their lifetime.
Changes that occur in the genetic material of sex cells include accidental substitutions of one DNA base pair for another, as well as insertions, and deletion of some information. Most of these follow the 4:1 ratio. But two types of mutations didn’t fit the general trend. In one section of chromosome 8, for example, the researchers found that variations in maternal DNA were just as common as paternal ones. In addition, changes of DNA sequences called CpG sites to another, TpG sites, were inherited from fathers more frequently than from mothers.
The second result is unexpected, says Aylwyn Scally, an evolutionary geneticist at the University of Cambridge who was not involved in the study. Limited evidence suggested that mutations at CpG sites were mostly spontaneous, rather than replicative errors, because previous studies had observed mutations at the same rate across different species. But the rate of paternal inheritance for these CpG mutations was actually more common than average and six times the rate of maternal inheritance.
“It’s clear that the size of their data allows them to see new patterns in the mutations that were previously undiscovered,” says Joris Veltman, who studies genetics and intellectual disabilities at Newcastle University, and was not involved in the study.
But mutations are not always a bad thing. There are some 3 billion base pairs in the human genome. While an average father might pass along dozens of novel mutations found only in his sperm, “the vast majority of them have no effect whatsoever, as far as we can tell,” Scally says. “A rare few may be beneficial.”
“[The study] is aimed squarely at understanding the basic process of human genetic inheritance,” Scally says. But it could eventually provide a knowledge base for “improving understanding of genetic diseases and improving genetic counseling.”