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)
Mutations increase with age of parents. Yet, doesn’t meiosis create extra mutations? Thus, if you have 15yr vs. 30yr generations, in one case the parents contribute fewer mutations but over 1000 years the population would have more meiosis events, while the other more mutations but fewer meiosis events. Seems there might be a sweet spot in the middle.
Shouldn’t the expectation be balancing selection on mutation rate based on liefstyle niche? For example, whales have a lot of cells and live a long time, so the cellular controls on mutation are ratcheted up. Leaving their rate of cancer is roughly same as any other mammal. Peto’s paradox
https://en.wikipedia.org/wiki/Peto%27s_paradox
Of course this leaves the puzzle open, or perhaps makes it harder. That is to say, if standing variation at the population level for controlling on mutation rate is large, then it can quickly shift under selection pressure, and so we should be even doubly cautious about assuming a constant rate. As homo genus has been rapidly shifting it’s niche under gene-culture evolution (and a lot of migration) almost from the very start.
Not sure if this is a dumb comment on what’s going on or not. But if it makes sense, maybe you can ask Matt Hahn about it as part of your questioning on your podcast.
Like telomere shortening, mutation rates may be a regulated process. In which case, the issue is what is the regulatory mechanism and how do we adjust it.
For a long term evolutionary perspective: What about environmental factors which increase mutation rates like changing levels of radiation? I once heard the hypothesis that polar shifts might have increased the mutation rates and evolutionary processes significantly. Beside different species and their mutation levels, if talking about thousands or even millions of years, can we assume a constant environment which has no influence on mutation rates? I don’t think so.
Would be interesting to check for different places in the world. Is there actually a study done on the wider region of Chernobyl for example as an extreme example?
Haven’t they overlooked large deletion and chromosome rearrangements? Also, heterogeneity in mutation rates, stemming from the natural variation in the repair pathways genes, could affect the trio studies?
The link between advanced paternal age and certain diseases with a strong genetic component to their causation is well established and has been replicated many times across a variety of conditions. If it isn’t mutation, there is still something going on, and the Owl Monkey example certain suggests that it is mutation.
It could be that the mutation risk is not generalized and is particular to the process by which germ line cells integrate into a fertilized egg, rather than in the production of germ line cells, or something like that.
I also recall papers from not so long ago that indicated that mutation rates are different in different parts of the genome. It could be that some select areas of the genome are much more prone to suffering from advanced paternal age mutations than others (and that the functions of those areas drives the kinds of conditions associated with advanced paternal age), while a low baseline of mutation in less sensitive areas of the genome is masking the spike in the mutation rates of the parts of the genome that matter for these purposes.