Women Not the Only Ones With Ticking Biological Clocks

By Jeanette McCarthy, MPH, PhD

For years, women have single-handedly carried the burden of the ticking biological clock — the desire to have children while they are physically capable, but also to ensure that the children they have are healthy. Pregnancies in older women are characterized by increased risk of adverse outcomes, including having children with chromosomal abnormalities such as Down syndrome. Down syndrome results from a fetus inheriting an extra copy of chromosome 21, usually from the mother as a result of failure of her chromosomes to separate during egg development. The incidence of Down syndrome has declined in modern times due to prenatal screening, but the risk of carrying a Down fetus still weighs on prospective older mothers.

So why do older fathers remain unscathed? It turns out they don’t. Genome sequencing has led to the discovery that older males contribute the bulk of new mutations in human populations. Mutations are naturally occurring, neutral phenomena that occur at random during DNA replication, whenever a cell divides. Those that occur in the germ cells, the sperm or egg, can be passed down to subsequent generations. By comparing the genomes of parents and children, we can identify new or “de novo” mutations as those found in children but absent in either parent.

A couple of years ago, researchers in Iceland discovered that de novo mutations are more commonly derived from males than females. The average child will be born with about 70 de novo mutations, with three to four times as many coming from the father compared to the mother. Moreover, the number of new mutations rises exponentially with increasing paternal age — approximately two additional mutations per year of father’s age at conception.

So why is this newsworthy today? A study published just this month in the journal Science describes the same scenario in our closest living relative, the chimpanzee. It turns out that in chimps, the male bias in mutation rate is even more prominent, lending credence to the observations in humans. Male chimps contribute seven to eight times as many mutations as females, and the paternal age effect results in three new mutations per year of father’s age.

What implications do these new findings have for health and reproductive choices? Will men finally begin to feel the ticking biological clock as well? The answers depend on how you view new mutations. On the one hand, any mutation has the chance of being a deleterious variant (a variant leading to a genetic disease). Could new mutations due to increasing paternal age over the years be responsible for the rise in autism or other disorders? No doubt research into questions like this will ensue as we delve into the biological basis of sex-biased diseases.

On the other hand, not all mutations are bad. Mutations are the basis of biological diversity. Without mutation, there is no evolution. Mutations that confer an advantage will be selected for over time, advancing the species. As the human life span has increased, so has the age of reproduction and, with it, the rate of mutation. Does this mean that the rate of evolution itself is increasing? How will we know a good mutation when we see it?

Whether one views these findings as older fathers adversely increasing the rate of genetic diseases or heroically propelling the species forward, you have to admit that this simple discovery is quite profound. Genome sequencing will continue to expand our understanding of genetic variation in human health and disease in ways we can’t even imagine.