Abstract
Mutation rates have long been measured as averages across many genomic positions. Recently, a method to measure the rates of individual mutations was applied to a narrow region in the human hemoglobin subunit beta (HBB ) gene containing the site of the hemoglobin S (HbS) mutation as well as to a paralogous hemoglobin subunit delta (HBD ) region, in sperm samples from sub-Saharan African and northern European donors [Melamed et al ., Genome Res.32 , 488–498 (2022)]. The HbS mutation, which protects against malaria while causing sickle-cell anemia in homozygotes, originated de novo significantly more frequently in the HBB gene in Africans compared to the other three test cases combined (the European HBB gene and the European and African HBD gene). Here, we apply this approach to the human apolipoprotein L1 (APOL1 ) gene containing the site of the G1 1024A→G mutation, which protects against African sleeping sickness caused by Trypanosoma brucei gambiense while causing a substantially increased risk of chronic kidney disease in homozygotes. We find that the 1024A→G mutation is the mutation of highest de novo origination rate and deviates most from the genome-wide average rate for its type (A→G) compared to all other observable mutations in the region and that it originates de novo significantly more frequently in Africans than in Europeans—i.e., in the population where it is of adaptive significance. The results are unexpected given the notion that the probability of a specific mutational event is independent of its value to the organism and underscore the importance of studying mutation rates at the individual-mutation resolution.
Fluff Article
My first thought is this lack of randomness could be due to many of these gene fusions events being fatal, and therefore never observed. They seems to be proposing a new mechanism though, which someone will need to explain to me.
It seems to me that the important question is whether the subjects are living in an area where malaria is endemic. If the difference is only related to ancestry then it suggests an evolved tendency for the mutation.
They claim to be measuring de novo mutations, which by definition can’t be affected by death or selection. (They are looking in sperm.) It could be that selection for something else is affecting the process; I haven’t read the paper in depth yet.
MONROE, J.G.; SRIKANT, T.; CARBONELL-BEJERANO, P. et al. (2022). Mutation bias reflects natural selection in Arabidopsis thaliana. Nature 602, 101–105.
Since the first half of the twentieth century, evolutionary theory has been dominated by the idea that mutations occur randomly with respect to their consequences1. Here we test this assumption with large surveys of de novo mutations in the plant Arabidopsis thaliana. In contrast to expectations, we find that mutations occur less often in functionally constrained regions of the genome—mutation frequency is reduced by half inside gene bodies and by two-thirds in essential genes. With independent genomic mutation datasets, including from the largest Arabidopsis mutation accumulation experiment conducted to date, we demonstrate that epigenomic and physical features explain over 90% of variance in the genome-wide pattern of mutation bias surrounding genes. Observed mutation frequencies around genes in turn accurately predict patterns of genetic polymorphisms in natural Arabidopsis accessions (r = 0.96). That mutation bias is the primary force behind patterns of sequence evolution around genes in natural accessions is supported by analyses of allele frequencies. Finally, we find that genes subject to stronger purifying selection have a lower mutation rate. We conclude that epigenome-associated mutation bias2 reduces the occurrence of deleterious mutations in Arabidopsis, challenging the prevailing paradigm that mutation is a directionless force in evolution.
Great citation, and it’s almost eerie how similar the text of the PNAS paper is to this much better Nature paper. I do think the PNAS paper differs in one main aspect: it looks at de novo mutations in sperm, which is more “immediate” than can be detected in the mutation accumulation experiments of Monroe et al.
But the failure of the PNAS authors to cite Monroe et al. is a major red flag. (There are other red flags in the paper, including some grotesque repeated self-citation.) I hope that the paper gets attention for this in the community, because it’s over the line in my view.
Right. But that’s one mutation. Since mutation rates differ both up and down across the genome, you can likely also find adaptive mutations in some human population with a significantly lower than genome-wide average frequency. It doesn’t make sense to me, to point out that this mutation has a higher than expected frequency, as if this is a surprising or significant result, if you don’t also look for adaptive low-frequency mutations and then compare the numbers of each. And even further, aren’t there also deleterious high-frequency mutations?
I’m not sure I really see the significance of this result in light of already established knowledge that mutation rates vary across the genome. Given this fact, isn’t it an inevitability that we’ll find adaptive ones with frequencies significantly above the genome-wide average?
Oh and just because an adaptive mutation has a higher than the genome-wide average frequency doesn’t mean it’s a non-random mutation. Why is the genome wide average frequency taken to be the one that is correctly random, and any deviation from this rate up or down makes it non-random? Clearly an absurd notion.
The point of the paper is that the rate of that particular mutations differs between the two populations. Which is more interesting. But it could be a result of selection - those more prone to acquiring an advantageous mutation have a fitness advantage by passing the mutation to their selection. Of course we’re only likely to see such an effect where the mutation does not become fixed - so sickle-cell is exactly the sort of case where we might see it.
My understanding of the paper is that they are looking at de novo mutations in sperm, and comparing populations – one population where malaria is a factor, one where it isn’t. If I’m right about both of those things, then the result is surprising and significant, and it probably doesn’t matter whether the mutations are beneficial or whatever. What would matter if this is true would be: de novo mutation rates vary at particular loci that are thought (accurately or not) to be relevant to the environment of a given population. If it’s true (and I’m not sure it is), the explanation need not be bizarre or even novel, but it’s a pretty crazy result if it’s true.
This is not quite right. The only way selection can be part of the explanation is something like this: selection has affected these populations in such a way as to make mutations more likely in particular genes. That might be true (I would say it HAS to be true), in other words it might be true that selection pushed the populations in two different directions re the occurrence of de novo mutations in specific genes. But the mechanism would have to be complex and it’s really hard for me to picture.
Presumably people who tan their testicles a lot (apparently this is a thing some men who obsess about their “t-levels” do) also have elevated mutation rates. Comparing the population of people who tan their testicles, to the population of people that don’t, you’ll probably also find a higher rate of de novo mutations that protect against UV radiation among the people who UV-bake their nutsack. It’s just, you also find higher rates of deleterious mutations. It might seem like a silly example, but the fact is environmental factors of all sorts can affect the mutation rate both up and down, and some parts of the genome are going to be more strongly affected than others.
There’s likely to be chemicals we eat that cause much more specific mutations to occur at higher rates for whatever mechanistic reason, than if we did not eat those chemicals. There’s probably going to be some of those mutations that protect against the unhealthy effects of those chemicals. And so on.
So it just seems to me completely inevitable that there are going to be some environmental factors that, simply by chance, affect the mechanisms that cause genomic mutations in a way where they do it in just such a way that they elevate the rate of those mutations that protect against their deleterious effects. But there’s probably also going to be the opposite.
It would be much more interesting to me if one could show that this phenomenon occurs at a rate higher than expected by chance. That is to say, environmental factors that are deleterious to the organism but also affect the mutation rate, are more likely to induce adaptive than deteleterious mutations. That would be interesting.
