More mutations in children of older fathers, and how it relates to human origins

Most of the coverage of the new Kong et al. paper has focused on the rising risk for inheritable diseases such as autism and schizophrenia in the children of older fathers. And, indeed, that is is the larger story, and, perhaps, the more useful one for society.

But, for those of us interested in the origins of our species, there is another story:

We show that in our samples, with an average father’s age of 29.7, the average de novo mutation rate is 1.20 × 10−8 per nucleotide per generation.

This mutation rate is in line with other direct measured rates, and is about twice smaller than the widely used 2.5x10^-8 rate used in evolutionary studies. Application of the low rate has led to a much older Human-Chimp divergence than was previously thought. That, in turn, will make mitochondrial Eve much older, because the mtDNA clock is calibrated on the Human-Chimp divergence. Practically every study of the last 10 years that looked at human origins and used the 2.5x10^-8 rate needs to be dusted off and made up to date.

But there is yet another story. The beauty of the Langergraber et al. paper is that it inferred the Human-Chimp divergence on the basis of directly observed quantities: mutation rates and generation times. But, there was one quantity which they could not measure directly: the mutation rate in the apes. Thus, they used the mutation rate of humans for the apes as well; that is very reasonable, because presumably the same underlying chemical machinery affects the rate in humans and their simian friends. But, here's where things get complicated:

Mean human paternal ages are about ~7 years older than chimp ones, and ~10 years older than gorilla ones. What this means, is that on average, younger chimp dads and younger gorilla dads have babies. But, the new Kong et al. paper:

Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5 years.

A back-of-the envelope calculation suggests that the higher age of human fathers may contribute ~30-50% more mutation in humans than in chimps/gorillas. Conversely, the mutation rate used for chimps should not be the human one: it should be even lower.

What are the implications of this?

The divergence of Humans from Chimps has been estimated by summing up mutations on two branches to their most recent common ancestor (MRCA). Younger chimp fathers = lower mutation rate / generation = Chimp-to-MRCA branch just got older.

In other words, just as we learned than humans diverged from chimps ~7-13 million years ago, it may be that they did so even earlier.

Nature 488, 471–475 (23 August 2012) doi:10.1038/nature11396

Rate of de novo mutations and the importance of father’s age to disease risk

Augustine Kong et al.

Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. Here we conduct a study of genome-wide mutation rates by sequencing the entire genomes of 78 Icelandic parent–offspring trios at high coverage. We show that in our samples, with an average father’s age of 29.7, the average de novo mutation rate is 1.20???10?8 per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5?years. After accounting for random Poisson variation, father’s age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father’s age on the risk of diseases such as schizophrenia and autism.

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