Thursday, March 22, 2012

Human Mutation Rates May Be Lower than We Thought

The predicted mutation rate in humans is thought to be about 130 mutations per generation or 10-10 per nucleotide per generation [Mutation Rates]. About 120 (>90%)of these new mutations occur in males, mostly during spermatogenesis. Only about 10 mutations are contributed by females. These values are based on what we know about the biochemistry of DNA replication and repair.

The evidence from evolution was consistent with this calculation. Nachman and Crowell (2000), for example, calculated that the accumulation of mutations in 18 pseudogenes from humans and chimpanzees yielded a value of 175 mutations per generation.

Up until recently it wasn't possible to get a direct measurement of the mutation rate but I addressed some of the attempts in November 2010: Human Mutation Rates. In that posting I discussed two experimental results that yielded estimates of the mutation rates in humans.
Recently there have been two attempts to verify this calculation. In one, the Y chromosomes of two men separated by 13 generations in a paternal lineage from a common male ancestor were sequenced. The differences correspond to a mutation rate of 0.75 × 10-10 per generation, or almost the same as theory predicts. This is based on the fact that if most mutations are nearly neutral (they are) then the rate of fixation by random genetic drift should be the same as the mutation rate.

The other study, by Roach et al. (2010), compared the genome sequences of two offspring and their parents. By adding up all the differences in the offspring they arrived at an estimate of 70 mutations in the offspring instead of the expected 130. This is half the expected value but the study is fraught with potential artifacts and it's best not to make a big deal of this discrepancy.
Now there's another paper that sequenced two sets of parents and a child (Conrad et al., 2011). You might think that the calculation is easy because all you have to do is count the number of new alleles in the child. But this doesn't work because you have to account for somatic mutations that arose in the tissue culture cells lines that are being used as a source of DNA. These can be eliminated by comparing the sequence with fresh DNA samples directly from the parents and child. In addition to false positives, you have to allow for some false negatives.

I don't understand all the mathematical manipulations but they are probably trustworthy. (Some of it was done by Reed Cartwright of Panda's Thumb.) The final estimates are 60 mutations in one of the children and 50 in the other. Both of these values are lower than the calculated rate and when you combine them with earlier results, it's beginning to look like the actual mutation rate is about half of the calculated value based on biochemistry. This could easily be due to a two-fold error in our estimate of repair efficiency. It could be that instead of repairing only 99/100 sites of damage the actual repair machinery fixes 199/200 damaged sites, for example.

The surprising result is that 92% of the new mutations in one of the children comes from the father but in the other family only 32% of the mutations were paternal. We expect that most of the mutations will occur during spermatogenesis so that part is not surprising. What's surprising is that in one case the majority come from the mother.

I suspect that this is an artifact of some kind, or a statistical outlier. The authors, however, take this as evidence of natural variation in male and female mutation rates. I'd like to see the estimates for other children of the same family in order to see if the result is reproducible.


Conrad, D.F., Keebler, J.E., DePristo, M.A., Lindsay, S.J., Zhang, Y., Casals, F., Idaghdour, Y., Hartl, C.L., Torroja, C., Garimella, K.V., Zilversmit, M., Cartwright, R., Rouleau, G.A., Daly, M., Stone, E.A., Hurles, M.E., Awadalla, P.; 1000 Genomes Project. (2011) Variation in genome-wide mutation rates within and between human families. Nat. Genet. 43:712-714. [doi: 10.1038/ng.862]

Nachman, M.W. and Crowell, S.L. (2000) Estimate of the mutation rate per nucleotide in humans. Genetics: 156:297-304.

13 comments :

  1. This is outside my area of expertise, so please excuse the questions if they are ignorant or naive...

    1) Is there any evidence that mutation rates (or DNA repair rates) vary greatly between humans. I would expect some variation, but to have such a large difference between two sets of parents would require either a pretty large difference in mutation/repair rates?

    2) I know in some "simple" organisms like yeast & e coli that there is pretty good evidence showing that mutations will accumulate more rapidly under stressed conditions (even if those conditions themselves wouldn't be expected to increase mutation rates - i.e. osmotic stress), and I've seen a few talks (although no papers) showing that yeast, at least, will downregulate some of their HSP after multi-generational stress; purportedly to enhance the effects of mutations. Is their any evidence of similar mechanisms in humans/mammals?

    ReplyDelete
  2. I would expect parental age to have an effect on mutation rate, particularly in males.

    ReplyDelete
  3. I can see why the number of mutations in the male line should vary with age, since spermatogenesis is a continuous process. But why the female line? Eggs haven't undergone any more cell generations in an older woman than in a younger one.

    ReplyDelete
    Replies
    1. Nevertheless, eggs are subject to lesions arising from oxidative damage etc. such that mutations will accumulate with time even in the absence of genomic replication and cell division.

      Delete
    2. Is that significant compared to replication errors, especially for tissues far from the common source of such damage, UV? My impression has always been that it isn't.

      Delete
    3. Ultraviolet Radiation is not the main or most damaging source of oxidative damage in cellular processes, RNA or DNA. Look up Reactive Oxygen Species and leukemia.

      Delete
    4. Is uv that prominent among mutagens? Cosmic rays, C14 decay, spontaneous hydrolysis, viruses and mechanical damage misrepair are all implicated in cancers, most of which are 'deep tissue' problems.

      There may also be issues relating to the differential preservation of diploidy. Following Meiosis 1, cells have no diploid complement from which to effect homologous repair. In the female, with meiosis 1 being completed pre-birth, the period of exposure to this risk is much greater. But in the male, cells up to primary spermatocytes retain the option.

      Mutation rates in some diploid germline tissues are significantly lower than in neighbouring somatic cells, and they actually decline as spermatogenesis proceeds, which may be indicative of a number of things - a preference for apoptosis over repair, or - just possibly - some kind of 'proof-reading' function. You can proof-read a diploid genome against a reference cell, but not a haploid one.

      Delete
    5. I vote for oxidative deamination of 5-methyl cytosine as most damaging to non-replicating cells, but that's a guess. Recombination between paraental homologs is nearly negligible as a DNA repair mechanism as most recombinational repair occurs between sister chromatids.

      Delete
    6. I believe oxidative deamination occurs mainly in the liver though. Slightly off-topic, while methylation levels are similar for the same genes in the liver and brain, brain DNA has much higher levels of hydroxymethylation compared to liver which is basically zero.

      Delete
  4. I think I remember depurination being easily the most common lesion. I don't know how often it leads to mutation, though, so it may not be the most damaging.

    ReplyDelete
    Replies
    1. Not particularly. Assuming that every C:T transition is caused by a 5-met-C deamination then it leads to a mutation roughly 1 out of 1,000 lesions.

      Delete
  5. My understanding is that the commonest source of reactive oxygen species is the action of UV radiation. No?

    ReplyDelete
    Replies
    1. No. It's the action of electron transfer chain. (That's why mitochondria are full of superoxide dismutase).

      Delete