Decode Genetics has a new report out in Nature that shows how mutations increase with age, by sequencing family trios. They found that women contribute about 15 de novo mutations, independent of age.
Men contribute more (55 on average) , and the number increases rapidly with age. They found that the average 20-year old father passed on 25 mutations, while the average 40-year old passed on 65, an increase of about two mutations per year of paternal age.
The researchers talked about the problems caused by these de novo mutations – things like schizophrenia and autism. We already knew that such risks increased with paternal age, but this work quantifies the mutations responsible.
Stefánsson opines that the higher mutation rate with older fathers is not that worrisome, since the absolute risk for schizophrenia and/or autism is still small (~2%) and since mutations are our friends: “You could argue what is bad for the next generation is good for the future of our species. “
Well, not for the first time, Kari Stefánsson is wrong. If mutations with large effects are more common with increased paternal age, mutations with small effects must also be more common. Those small-effect mutations are removed slowly by natural selection, and so they accumulate with time. This eventually results in a population in which everyone has a higher genetic load, not just a few unfortunate kids out of each generation.
What this means is that modest differences in social structure, differences that cause changes in the average paternal age, are likely to have major effects on the mutation rate. If those differences are maintained over time, say for a few thousand years, you would expect to see significantly different levels of mutational load in different populations. Genetic estimates of split times and such would also be wrong, but that’s a nit.
What do I mean by a modest difference? Assume that population A has an average paternal age of 25: then the average number of new mutations per generation is 50. Assume that population B has an average paternal age of 30: then the average number of new mutations per generation is 60, a 20% increase. As Kondrashov put it in his commentary, “It seems that multifactorial disorders that result from impaired brain function, such as autism, schizophrenia, dyslexia and reduced intelligence, are
particularly susceptible to the paternal-age effect. This is consistent with the fact that more genes are expressed in the brain than in any other organ, meaning that the fraction of new
mutations that will affect its functions is the highest. “
So, what is the likely consequence of a higher paternal age? Population B will eventually be significantly dumber and crazier than population A.
I would guess that paternal age was not too high for most hunter-gatherers. It should have been pretty low in Neanderthals, since they don’t seem to have lived to be very old, probably as a consequence of their high-risk hunting strategy. I would also guess that it can sometimes be considerably higher in post-Neolithic societies with greater inequality of wealth, which often leads to unequal reproduction. I would guess that the average paternal age is generally higher in strongly polygamous societies. But at this point I don’t have the numbers. I think we can get some of them fairly soon.
Generally, analysts have treated the human mutation rate as if it were a fundamental, unchanging physical quantity, something like the gravitational constant. It appears that this can only be the case if average paternal age never varies much. Since there may well be other factors that can affect the human mutation rater, even that might not be enough.