Mutation rate, the speed at which mutations occur in the human genome plays an important role in generating diversity, and is also used as a way to calculate the dates on which different lineages split from a basal one. It also has its problems because mutations are random, and don't take place at a constant rate, which makes the molecular clock based on them, erratical and unreliable.
While researching about the diversity in African human populations, I came across research by William Amos published in 2020, with a very intriguing title: "Signals interpreted as archaic introgression appear to be driven primarily by faster evolution in Africa", it questioned the validity of the admixture events with Neanderthals and Denisovans (I posted about this a few days ago, here), and considered it an artifact caused by the rapid rate of evoultion found in Africa:
"A model where Africans are unusually different from Neanderthals through accelerated divergence rather than non-Africans being unusually similar to Neanderthals though carrying introgressed fragments requires both a large number of back-mutations and variation mutation rate between human populations. Specifically, the mutation rate in Africa would have to have been higher than the mutation rate outside Africa since the out of Africa event, causing significantly more back-mutations in Africans. By counting triallelic sites, I show that very large numbers of back-mutations are indeed present, estimated at more than half a million...
In conclusion, I present a simple analysis that reveals an unexpected pattern in which non-zero human D statistics are unambiguously dominated by heterozygous African genotypes. These sites invariably cause the African to be less closely related to archaics and so appear to carry signatures of increased divergence from our common ancestor. More work is needed to reconcile these results with those of previous studies that conclude most non-African humans carry 1–2% archaic sequences.
Putting these elements together suggests a model where large D is driven by a higher mutation rate in Africans causing relatively greater divergence from Neanderthals. Individuals not carrying heterozygous African sites, or who carry fewer than the individual against whom they are being compared, therefore appear closer to the ancestral state and, hence, closer to related taxa such as Neanderthals."
Modern Africans have evolved since the Out of Africa event and done so at a faster rate than other Eurasian and American humans, this shows even greater "diversity" difference, and cline between Africa and the rest of the world.
Heterozygosity modulates Mutation Rates
Another paper by W. Amos (2013) suggests that heterozygosity increases mutation rates, the chart below shows how Africans with high heterozygosity in comparison to other populations, has a higher mutation rate:
Amos suggests that "The “heterozygote instability” (HI) hypothesis suggests that gene conversion events focused on heterozygous sites during meiosis locally increase the mutation rate... As humans left Africa they lost variability, which, if HI operates, should have reduced the mutation rate in non-Africans... For humans, HI implies a reduction in mutation rate as we left Africa with the counter-intuitive result that non-Africans will appear more closely related than Africans to other hominid lineages such as Neanderthals, a trend that has been observed and used as evidence of introgression."
Furthermore, Amos posits that HI promotes genetic diversity by favoring recombination and mutation hotspots: "Phenomena like mutation hotspots might also be seen in a different light, as should variation in recombination rate, since both are likely to some extent to be exaggerated or even caused by HI: the gene conversion-like events attracted by heterozygous sites likely in some cases to be resolved by recombination." Recombination has been shown to be linked with higher heterozygosity, and genetic diversity (Source). So, is this a self-reinforcing feedback loop with heterozygosity pushing up mutation rate which will create higher heterozygosity?
The matter had been brought up in the past by J. H. Relethford (1997), who pointed out that "Global studies of within-group genetic variation have revealed a tendency for some traits, but not all, to show higher heterozygosity in sub-Saharan African populations. Although excess African diversity has been interpreted as reflecting a greater "age" of sub-Saharan African populations, more recent research has shown that this excess is more likely a consequence of a larger African long-term effective population size... Here, I examine another possible factor: that excess African heterozygosity is in part a function of mutation rate...The results indicate that there is little excess African heterozygosity for traits with low mutation rates and greater excess heterozygosity for traits with moderate to high aggregate mutation rates."
Let's look into Relethford's suggestion:
The larger effective population or Ne is a clear driver of diversity because being large, there is risk of loss of heterozygous variants (more of them initially, and more chances of at least some carriers of them, having offspring). They also accumulate new allelles that arise due to chance mutations in the population, and there is less inbreeding.
Regarding mutation rate (μ) is seems reasonable that a population with a higher mutation rate will produce new variants. A reason for this seems to be that heterozygous loci cause Heterozygote instability during meiosis (the process during which the chromosomes split and sparate, halving their number in the gametes -sperm in men and ovum in women), this instability reduces the effectiveness of DNA repair mechanisms. Also, if mutations are related to adaptative benefits, selection will promote them.
In a population that is in equilibrium there is a formula that calculates the average expected heterozygosity "H". It involves the following terms: the neutral mutation rate or μ, and the effective population size or Ne (Source).
H = 4Ne μ / (4Ne μ +1)
I calculated values of heterozygosity (y-axis) for different Ne sizes (x-axis) for two mutation rates, 10-5 and twice that value (2*10-5), the graph below shows the outcomes:
As Ne increases, so does heterozygosity. But, with a same effective population size and a higher mutation rate, H increases too! Africans with a higher mutation rate (μ) would have increased their heterozygosity due to that effect alone, compared to slower mutating Eurasians.
Finally, a very interesting paper by Amos, Flint, and Xu (2008). states that "our analysis suggests that a feedback loop can operate causing heterozygosity to increase over time, each increase also increasing the mutation rate which in turn raises heterozygosity." Could this have happened, and still ocurr in Africa?
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