Thursday, November 02, 2017

Parental age and the human mutation rate

Theme

Mutation

-definition
-mutation types
-mutation rates
-phylogeny
-controversies

Mutations are mostly due to errors in DNA replication. We have a pretty good idea of the accuracy of DNA replication—the overall error rate is about 10-10 per bp. There are about 30 cell divisions in females between zygote and formation of all egg cells. In males, there are about 400 mitotic cell divisions between zygote and formation of sperm cells. Using these average values, we can calculate the number of mutations per generation. It works out to about 130 mutations per generation [Estimating the Human Mutation Rate: Biochemical Method].

This value is similar to the estimate from comparing the sequences of different species (e.g. human and chimpanzee) based on the number of differences and the estimated time of divergence. This assumes that most of the genome is evolving at the rate expected for fixation of neutral alleles. This phylogenetic method give a value of about 112 mutations per generation [Estimating the Human Mutation Rate: Phylogenetic Method].

The third way of measuring the mutation rate is to directly compare the genome sequence of a child and both parents (trios). After making corrections for false positives and false negatives, this method yields values of 60-100 mutations per generation depending on how the data is manipulated [Estimating the Human Mutation Rate: Direct Method]. The lower values from the direct method call into question the dates of the split between the various great ape lineages. This controversy has not been resolved [Human mutation rates] [Human mutation rates - what's the right number?].

It's clear that males contribute more to evolution than females. There's about a ten-fold difference in the number of cell divisions in the male line compared to the female line; therefore, we expect there to be about ten times more mutations inherited from fathers. This difference should depend on the age of the father since the older the father the more cell divisions required to produce sperm.

This effect has been demonstrated in many publications. A maternal age effect has also been postulated but that's been more difficult to prove. The latest study of Icelandic trios helps to nail down the exact effect (Jónsson et al., 2017).

The authors examined 1,548 trios consisting of parents and at least one offspring. They analyzed 2.682 Mb of genome sequence (84% of the total genome) and discovered an average of 70 mutations events per child.1 This gives an overall mutation rate of 83 mutations per generation with an average generation time of 30 years. This is consistent with previous results.

Jónsson et al. looked at 225 cases of three generation data in order to make sure that the mutations were germline mutations and not somatic cell mutations. They plotted the numbers of mutations against the age of the father and mother to produce the following graph from Figure 1 of their paper.


Look at parents who are 30 years old. At this age, females contribute about 10 mutations and males contribute about 50. This is only a five-fold difference—much lees than we expect from the number of cell divisions. This suggests that the initial estimates of 400 cell divisions in males might be too high.

An age effect on mutations from the father is quite apparent and expected. A maternal age effect has previously been hypothesized but this is the first solid data that shows such an effect. The authors speculate that oocyotes accumulate mutations with age, particularly mutations due to strand breakage.


Of these, 93% were single nucleotide changes and 7% were small deletions or insertions.

Jónsson, H., Sulem, P., Kehr, B., Kristmundsdottir, S., Zink, F., Hjartarson, E., Hardarson, M.T., Hjorleifsson, K.E., Eggertsson, H.P., and Gudjonsson, S.A. (2017) Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature, 549:519-522. [doi: 10.1038/nature24018]

11 comments :

  1. Do you have anything on observed or calculated Y-chromosome or X-chromosome mutation/fixation rates as opposed to the (mostly) autosomal rates here?

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  2. I believe autism has some established degree of association with age of the father, and either a lesser degree of, a less well established, or both, association with the age of the mother.

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  3. Of course males also bear most of the responsibility for the unfortunate consequences of point mutations (genetic diseases, extinction...).

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  4. Steve Jones' Darwin's Ghost cites a study of the British peerage showing that the offspring of older fathers (who married late because they were waiting to inherit) had an average lifetime a year less than those of younger fathers. Consistent.

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  5. Males I think bear most of the responsibility for the unfortunate consequences of nearly everything. ;-)

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  6. "This is only a five-fold difference—much lees than we expect from the number of cell divisions. This suggests that the initial estimates of 400 cell divisions in males might be too high."

    Yes. But could a higher mortality due to mutation for male cells also be implied?

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  7. unrelated but intriguing... would appreciate a discussion if possible

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999464/

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  8. ... and of course Nick Lane's rebuttal
    https://www.researchgate.net/publication/316976894_Proton_gradients_at_the_origin_of_life

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  9. Hey remember Cornelius Hunter well he posted this. https://evolutionnews.org/2017/11/blindness-in-cave-fish-is-due-to-epigenetics/

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    1. Suggestion: Don't take Hunter's word for it, read the original article instead and then think for yourself.

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  10. Hi Larry..

    You wrote:

    "They discovered an average of 70 mutations events per child. This gives an overall mutation rate of 83 mutations per generation with an average generation time of 30 years."

    Could you explain to me how they get from 70 to 83?

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