Following my recent post on reversions, also known as back mutations, which shows that mutation rates are higher than expected due to back-mutations, I decided to update the information about the errors in "molecular clocks."
Behar DM, et al. A "Copernican" reassessment of the human mitochondrial DNA tree from its root, published in 2012 (Am J Hum Genet. 2012 Apr 6;90(4):675-84. doi: 10.1016/j.ajhg.2012.03.002. Erratum in: Am J Hum Genet. 2012 May 4;90(5):936. PMID: 22482806; PMCID: PMC3322232), included a section titled "Indications for Violation of the Molecular Clock", which compared the number of mutations from the base (called RSRS or Reconstructed Sapiens Reference Sequence) along haplogroup lineages. They noticed a wide variation, from 42 to 71 substitutions with a mean of just over 57. This is a wide spread of data, clearly the clock by which mutations ocurr is clicking at different rates for different haplogroups.
In line with my recent post (mutation rates are faster in Africa), Behar et al. noticed that there were 77 mutations in the L2b1a mtDNA variant (supposedly old, and ancient, and only found within Africa). But... M2b1b and M7b3a, found outside of Africa, and "daughters" of the African L clades, has 71 mutations. Below I quote this paper:
"The accepted notion of a molecular clock means that contemporary mtDNA haplotypes should show statistically insignificant differences in the number of accumulated mutations from the RSRS. Triggered by the suggested change in the reference sequence that facilitates substitution counts from the ancestral root, we further evaluated this hypothesis. The range of substitution counts separating contemporary mitogenomes belonging to major haplogroups from the RSRS is shown in Figure S2.
The mean distance is 57.1 substitutions, the median is 56 and the empirical standard deviation is 5.9. Widely different distances ranging from 41 substitutions in some L0d1a1 mitogenomes to 77 in some L2b1a mitogenomes are observed. Interestingly, the ranges of substitution counts within haplogroups M and N, which are hallmarks of the relatively recent out-of-Africa exodus of humans, are also very large. For example, within M there are two mitogenomes with 43 substitutions (in M30a and M44) and two mitogenomes with as many as 71 substitutions (in M2b1b and M7b3a). This is especially striking because the path from the RSRS to the root of M already contains 39 substitutions. Hence, the difference between the M root and its M44 descendant is only four substitutions (two in the coding region and two in the control region) as compared to 32 substitutions in the M2b1b and M7b3a mitogenomes.
These observations raise the possibility that the tree in general, and haplogroup M in particular, might not adhere uniformly to the assumed molecular clock, under which substitutions occur at a fixed rate on all branches of the tree over time. We evaluated this scenario by performing generalized likelihood ratio tests of the molecular clock by using PAML33 on subsets of samples from the entire tree, on haplogroup L2 (following past evidence of clock violations in this haplogroup40) and on the sister haplogroups M and N. Our results demonstrate violations of the molecular clock in M (0.00015 ≤ p value ≤ 0.0003 for χ2 GLR test in three different analyses) and give mixed results for the entire tree (p = 0.005 and p = 0.018 for two analyses, which might be sensitive to the parts of the tree randomly sampled) and L2 (GLR χ2 p value = 5 × 10−5 and p value = 0.033 for two analyses) and borderline results in N (GLR χ2 p value = 0.049 and p value = 0.054 in two analyses). We are currently unable to offer well-founded explanations for these findings, which remain the scope of future studies."
The researchers couldn't explain why!
Generation Times or Generation interval
One explanation for variability in mutation rates is a gradual decrease in the rate of germ-line mitoses per year in the human lineage caused by longer generation times. This is known as the "hominoid slowdown hypthesis", first proposed by Morris Goodman in the 1950s.
The "generation length" or interval, (time between birth and reproduction) vary from one species to another. The concept of the slowdown is that creatures with a short generation time, go through many more generations per unit time than animals with a long generation time (like humans). Humans have longer generations than chimps and other old and new world monkeys. The same can be noted for humans and mice.
The explanation is simple: take an animal, like a dog, which can produce a litter per year after the age of 1. If allowed to mate on a yearly basis, it will have produced 12 generations in 12 years (its lifespan). So if each for each generation there are n random mutations taking at take place in the germline (ova and sperm) dogs will have an accumulated mutation number of 10n mutations after ten years. Considering human generation times of 29 years, a human being will only have produced one generation, with only n mutations in 29 years (assuming both species undergo the same random number of mutations per generation), while dogs will have undergone 29n mutations.
Can we be certain that Neanderthals, Denisovans, Homo erectus, or even H. sapiens who lived 200,000 years ago, had generation times shorter, equal, or longer than ours? Were they 25, 29, or 30 years long?
One 2006 paper states that "Using 15 years as the generation time for chimpanzees and ancient humans and 20 years for that of modern humans, the estimated time of the evolution of long generation time in the modern humans is approximately one million years."
Another paper using introgressed Neanderthal segments in Eurasians (the paper is very interesting!) calculated that East and West Eurasians had different generation times: "differences in the generation interval across Eurasia, by up 10–20%, over the past 40,000 years... we estimate that this difference corresponds to a 2.68 or 3.39 years shorter generation interval in West Eurasia if East Asian mean generation time was 28 or 32 years respectively."
Richard Wang et al., (2023) explored the subject in depth "Our analyses of whole-genome data reveal an average generation time of 26.9 years across the past 250,000 years, with fathers consistently older (30.7 years) than mothers (23.2 years). Shifts in sex-averaged generation times have been driven primarily by changes to the age of paternity, although we report a substantial increase in female generation times in the recent past. We also find a large difference in generation times among populations, reaching back to a time when all humans occupied Africa." The image below shows how generation time changes over time, and region. The image caption reads "Fig. 3. Change in generation interval across different human populations. Generation intervals were estimated in ancestors of four major continental human populations included in the 1000 Genomes Project; sex-averaged generation intervals are shown here as smoothed by loess (see fig. S6 for full results). Confidence intervals for each population were obtained by bootstrapping, as in Fig. 2. The inset shows results from including polymorphisms that date back to 78,000 generations ago; note that age estimates of mutations in the very distant past have decreased accuracy (15). AFR, Africa; EAS, East Asia; EUR, Europe; SAS, South Asia.
Note: In case you wonder why the graph shows South Asians and Eurasians 10000 generations ago (roughly 300,000 years ago) a time when modern humans were just originating inside of Africa, the paper points out that "While the continental labels for each population are used across the span of the analysis, note that beyond roughly 2000 generations ago, all non-African populations were likely located in Africa and show little differentiation among themselves; coalescence among all ancestral populations living in Africa does not occur until more than 10,000 generations ago."
The paper quantifies the time and its impact on mutation rates: "The dominating pattern across the past 10,000 generations is a significantly shorter sex-averaged generation interval for East Asian, European, and South Asian populations— 20.1 ± 3.9, 20.6 ± 3.8, and 21.0 ± 3.7 years—compared to the African population, 26.9 ± 3.5 years. The estimated generation times do not converge between populations until we expand our analysis to include periods older than 10,000 generations ago (Fig. 3, inset)... The large difference in generation times between populations suggests that different time scales are needed to estimate events outside of Africa (20 to 21 years per generation) versus those in Africa (27 years per generation). These results are consistent with the prediction of a shorter generation time in non-Africans, based on the observation of a slightly elevated per-year mutation rate in these populations."
Environmental Factors and Mutations
In a recent post I discussed a hypothesis that suggested a climatic influence on mtDNA mutations. Today I will mention the effects of the Ultraviolet Radiation (UV) in sunlight on mutation rates.
Research by Kelley Harris (2015) looked at European mutation rates, and found "Europeans experience higher rates of a specific mutation type that has known associations with UV light exposure." It isn't recent either, it is very old: "rate acceleration seems to have occurred between 25,000 and 60,000 y ago, not long after Europeans diverged from Asians."
This is not trivial, Harris goes on to explain its significance: "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 owing to the conflict between direct mutation rate estimates and molecular-clock-based estimates."
Harris then argues that "the results of this paper indicate that another force may have come into play: change in the mutation rate per mitosis." In the case of germline mutation rates, those passed on to the next generation because they take place in the germ cells, there are several drivers that can cause them:
Paternal Age: the older the father, more chances that mutations have accumulated in the spermatogonial stem cells due to repeated mitosis. Replication errors: mistakes in copying the DNA sequence (chunks are deleted, repeated, substituted). Methylation: DNA methylation (addition of a methyl —CH3) influences mutations, etc.
Harris attributes it to the light skin of Europeans and UV radiation. Yet wonders about the mechanism: "
The question remains how UV could affect germ-line cells that are generally shielded from solar radiation" (there is an answer provided, folate deficienty due to UV depletion that causes mutations).
Closing Comments
We have seen that mutation rates are affected by climate, sunlight, generation times, and also natural selection. This means that we should be cautious when interpreting data using molecular clocks.
Soojin Yi, Darrell L. Ellsworth, and Wen-Hsiung Li (2002) express this very clearly "Therefore, application of a molecular clock to estimate divergence dates should be exercised with great caution even in relatively closely related taxa. That is, a molecular clock calibrated for some lineages may not be applicable to other lineages because the assumption of rate constancy among lineages may not hold, as shown in the case of higher primates. Furthermore, the rate estimated from one genomic region may not be applicable to another region because the mutation rate varies among genomic regions."
Patagonian Monsters - Cryptozoology, Myths & legends in Patagonia Copyright 2009-2026 by Austin Whittall ©
No comments:
Post a Comment