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.
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