Another paper mentioning different mutation rates in Africans and non-Africans!
The paper by Mallick, S., Li, H., Lipson, M. et al. The Simons Genome Diversity Project: 300 genomes from 142 diverse populations. Nature 538, 201–206 (2016). https://doi.org/10.1038/nature18964, reported that "Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence."
The branch-length issue
This reminded me of a recent post I wrote about Short branch lengths in Africans for Y-chromosomes. Branch lengths are linked to accumulated mutations (the lenght of a branch is the number of mutations in it) so if we start from the fork where Africans and non-Africans split, the branch of Africans is shoreter because it has accumulated fewer mutations, while the non-African one is longer, as it has more accumulated mutations. In that post I asked "...but we are all the same age and equally distant from our common ancestor. So why do the Africans have fewer mutations? Do Eurasians accumulate more mutations?"
I also went back to reread a recent post Mutation rate is faster in Africa where I mentioned different studies suggesting that a higher diversity in Africans (measured by their heterozygosity) promoted a higher mutation rate or μ. But Mallick, Li and Lipson et al. in their 2016 paper suggest otherwise. I quote them below and highlight their findings, which seem to baffle them:
"More mutation accumulation in non-Africans than in Africans
The SGDP data provide an opportunity to compare the rates at which mutations have accumulated across populations. We restricted our analyses to samples for which our genotypes are likely to be most reliable ... We pooled samples by region to increase power, and for all pairs of regions, computed the expected number of positions where, if we picked a random chromosome from both, region A would mismatch chimpanzee and region B would be identical to chimpanzee (or vice versa). If the rate of accumulation of mutation has been the same since the two populations diverged, these numbers are expected to be equal. However, when we compute the ratio of mutations on one lineage or the other since separation, we find a subtle (average of 0.5%) but significant excess of mutations in nonAfricans relative to sub-Saharan Africans. Because any difference must reflect events since non-African / African population divergence which is a less than a tenth of average genetic divergence, this implies a greater difference in mutation accumulation rates since population divergence (~5%). We were concerned that these results might be biased by the fact that the human genome reference sequence is more closely related to non-Africans than to Africans, or by higher levels of heterozygosity in Africans, as both these issues could make detection of divergent sites in Africans more difficult. However, we replicated the findings after remapping to chimpanzee, which is equally distant to all present populations, and after restricting analyses to the X chromosome in males (males only have a single X chromosome, and so this procedure avoids bias due to different error rates in detecting heterozygous genotypes in populations with different rates of heterozygosity). These observations are most likely to be explained by acceleration in the rate of mutation accumulation in non-Africans, since the same signal appears in comparisons to sub-Saharan Africans related in different ways to non-Africans. It is known that the rate of CCT>CTT mutations differs across human populations. However, this particular mutation class was found to be enriched relative to Africans in Europeans but not in East Asians, and thus cannot explain our signal. One of several possible explanations for these findings is a decrease in the generation interval in non-Africans compared to Africans since separation..."
What is going on?
Mallick, S., Li, H., Lipson, M. et al. affirm that mutations accumulate at a higher rate in non-Africans than within Africa, this does not mean that mutation rates (μ) are different, it means that the mutations are fixed differently. It is also higher among Europeans than East Asians. To explain it they propse that non-Africans have a shorter "generation time": they are mating at a younger age than Africans so they accumulate more generations in a given span of time, and therefore more mutations than Africans in the same period.
Generation Time
I am surprised because other research has shown that longer generation times lead to more mutations because "each additional year of paternal age results in an average of 3.9 × 10−10 more mutations per base per generation (Source) and hunter-gatherer people nowadays have longer generation ages (32.3 years for fathers) than sedentary groups and because older fathers accumulate more mutations, if Africans are mating at an older age, there will be more mutations. There is something that isn't adding up here!
A similar viewpoint was reported by Wang and Obbard, 2023: "Our analysis also shows that mutation rates increase significantly with increasing generation time... The relationship we observe between generation time and per-generation mutation rate could therefore be a consequence of either a greater number of cell divisions or of accumulating damage over time." Which makes sense.
However, not all agree, research conducted by Lewin and Eyre-Walker, 2025 confirms that mutation rate (μ) and generation time are inversely correlated (longer generation time = lower mutation rate; and shorter generation time = higher mutation rate).
Due to these conflicting findings, until consensus is reached, for the time being I will leave generation times out of the matter and look for other plausible causes for the higher number of mutations in non-Africans vs. Africans.
Other causes explaining higher accumulation of mutations
Effective population size or Ne. Wang and Obbard, 2023, also notice that "populations with larger Ne tend to have a lower mutation rate even after accounting for their shorter generation times." Africans are said to have a larger initial Ne due to the bottleneck effect that affected those leaving Africa, a small subset of the large original population. The authors suggest that if "... species with small Ne tend to have a longer generation time, and a longer generation time causes higher mutation rates then a higher μ in species with low Ne could be driven by a mechanistic generation-time effect." Since Eurasians seem to have both factors (small Ne and low generation times) is seems logical that their mutation rate is higher.
Besides the effective population size and generation time, there are more possible explanations for the shorter branch in Africans and the longer one in Eurasians are: natural selection, that removes noxious mutations, so looking back from the present, the mutations never seem to have taked place because they were not fixed. Reduced DNA repair mechanisms, one group has a less efficient repair mechanism for mutations and these tend to accumulate in comparison to another group with a more efficient repair system.
The increased TCC→TTC mutation rate in Europeans
This factor is mentioned in Mallick, S., Li, H., Lipson, M. et al. as a possible explanation. But, what does it really mean? I will quote from Harris and Pritchard, 2017, who studied the matter.
Our DNA is made up of two backbones, the intertwined helixes linked by "steps" like a ladder, made from bases called Guanine (G), Cytosine (C), Thymine (T) and Adenine (A). Guanine always links to Adenine G—A, and Thymine with Cytosine (C—T) bonds. Looking at the steps of one side of the helix you will see a sequence like "ATCGATTGAGCTCTAG", and opposing it, on the other strand the complementary bases: "GCTAGCCAGATCTCGA".
Research has shown that "European people experience more mutations within certain DNA motifs (specifically, the DNA sequences ‘TCC’, ‘TCT’, ‘CCC’ and ‘ACC’) than Africans or East Asians do." Why?
Harris and Pritchard propose that "the rate of TCC→TTC mutations increased dramatically ∼15,000 years ago and decreased again ∼2000 years ago... [and] hypothesize that this mutation pulse may have been caused by a mutator allele that drifted up in frequency starting 15,000 years ago, but that is now rare or absent from present day populations." They go on to explain the cause: " At this time, we cannot exclude a role for nongenetic factors such as changes in life history or mutagen exposure in driving these signals. However, given the sheer diversity of the effects reported here, it seems parsimonious to us to propose that most of this variation is driven by the appearance and drift of genetic modifiers of mutation rate."
So it seems that it is due to a chance appearance of genes that regulate mutation rates.
A curious yet interesting fact is that the same effect of TCC→TTC mutation increase is observed in East Asian cattle! It appeared in two separate mammal groups, indicine cattle, derived from the Bos taurus indicus and humans but outside of Africa (Talenti, et al., 20216)
A challenge to the "stable" molecular clock
Harris, 2015 also looks into the TCC→TTC subject and says that explaining the cause is beyond the scope of the paper. However, Harris concludes that "Even if the overall European mutation rate increase was small, it adds to a growing body of evidence that molecular clock assumptions break down on a faster timescale than generally assumed during population genetic analysis. It was once assumed that the human lineage’s mutation rate had changed little since we shared a common ancestor with chimpanzees, but this assumption is losing credibility due to the conflict between direct mutation rate estimates and molecular-clock-based estimates. Although this conflict might have arisen from a gradual decrease in the rate of germline mitoses per year as our ancestors evolved longer generation times, the results of this paper indicate that another force may have come into play: change in the mutation rate per mitosis. If the mutagenic spectrum was able to change during the last 60,000 years of human history, it might have changed numerous times during great ape evolution and beforehand."
I agree, mutation rates are variable, and conclusions based on a constant rate will be wrong.
Notice how different papers find opposite effects (faster mutation rates in Africans, or in Europeans), and don't quite understand the reason!
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