Every few years I check to see if the great mutation accumulation controversy has resolved itself. I don’t know if anyone calls it that, but that’s what I think of it as. There are two major issues that matter here: mutation rates are a critical parameter in evolutionary models, and, mutation accumulation over time matters for parental age effects when it comes to disease (speaking as an older father!).
In the latter case, I’m talking about the reasons that people freeze their eggs or sperm. In the former case, I’m talking about whether we can easily extrapolate mutation rates over evolutionary time as semi-fixed, so we can infer dates of last common ancestry and such. To give a concrete example of what I’m talking about, if mutation rates varied a lot over the evolutionary history of our hominin lineage, then we might need to rethink some of the inferred timings.
Today two preprints came out on mutation accumulation. First, Overlooked roles of DNA damage and maternal age in generating human germline mutations. Second, Reproductive longevity predicts mutation rates in primates. What a coincidence in synchronicity!
Additionally, the last author on the second preprint, Matt Hahn, is someone I’ll be doing a podcast with this week. So aside from talking about neutral theory, and his book Molecular Population Genetics, I’m going to have to bring up this mutation business.
The figure above from the first preprint shows that the proportion of mutations derived from the father don’t increase over time, as textbooks generally state. Why would we expect this? Sperm keeps replicating after puberty so you should be gaining more mutations. In contrast, the eggs are arrested in meiosis. There are various mechanistic reasons that the authors of the first preprint give for why the ratio does not change between paternal and maternal mutations (e.g., non-replicative mutations seem to be the primary one). The authors are using a very “pedigree” strategy, rather than an “evolutionary” one. They’re looking at sequenced trios, and noticing patterns. I think in the near future they’ll be far more sure of what’s going on because they’ll have bigger sample sizes. They admit the effects are subtle (also, some of the p-values are getting close to 0.05).
Instead of focusing on a human pedigree, the second preprint does some sequencing on owl monkeys (I had no idea there were “owl monkeys” before this paper). They find that the mutation rate is ~32% lower in owl monkeys than in humans. Why is this?
The plot to the left shows that mutations increase across age with species (though the number of data points is pretty small). The authors contend that:
The association between mutation rates and reproductive longevity implies that changes in life history traits rather than changes to the mutational machinery are responsible for the evolution of these rates. Species that have evolved greater reproductive longevity will have a higher mutation rate per generation without any underlying change to the replication, repair, or proofreading proteins.
If I read this right: owl monkeys reproduce fast and don’t have as much reproductive longevity. Ergo, lower mutation rates (less mutational build-up from paternal side).
After all these years I’m still not convinced about anything. I assume that eventually bigger data sets will come online and we’ll resolve this. Someone has to be right!
(not too many people on Twitter get what’s going on either)
