I have made several attempts here to estimate the number of somatic mutations: 3,93 mutations / Mb(2007), the long fuse (2007), about the cancer the legacy (2010) or 1/day in the life of a mutation (2010) but the best summary now comes from the 1000 genomes
From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10^-8 per base pair per generation.
along with the fact that
on average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders.
which raises some doubts that these 50 to 100 have only been implicated but not proven…
The AJHG preprint server has an important paper about the effect of rare missense alleles. By combining information from HGMD, human – chimpanzee divergence and 4 other datasets (NIEHS-EGP, Seattle SNPs, JSNP and a resequencing approach of 58 genes in >1,500 chromosomes) they attack the Chakravarti hypothesis of “common diseases – commmon variants”
It remains uncertain why such polymorphisms can persist without being eliminated by purifying selection. Currently, two major lines of reasoning exist that explain this apparent paradox. The first considers various complex evolutionary scenarios and treats positive or balancing selection as a major force that can drive medically detrimental mutations to high frequencies. The second line of reasoning postulates a high mutation rate as a major factor that determines the cumulative frequency of detrimental polymorphisms in the population.
Anyway, here is the main outcome
Mutation accumulation in the human genome is a largely neglected research field. Most mutations have a very small effect (if any) and may be compensated by environmental improvements. I have already argued in that way in the 2003 Triple T paper and will reiterate it soon in PLOS medicine (just found that James Crow 1997 in PNAS and 2000 in nat gen rev had the same opinion). In principle, the improvement of sanitation and better medical care is leading to a retention of mutations that would be otherwise subject of purifying selection.
Another important factor seems to be the increase of parental age in Western societies. A 20 year old man had about 150 chromosome replications while a 40 year old had about 610 replications. To count the number of your somatic mutations, you need to add all events of your lifetime plus the age of your father at birth minus 9 months … Even with the high fidelity of polymerases, DNA replication remains an error prone process leading eventually to an increase of germline mutations (as may be seen with achondroplasia, Apert syndrome, neurofibromatosis and prostate cancer). With the increasing age of fathers we are now nearly doubling the absolute number of mutations every generation – and we keep them in the pool in contrast to previous centuries. Crow in PNAS 1997 even said
I do regard mutation accumulation as a problem. It is something like the population bomb, but it has a much longer fuse
Addendum 20 Nov 2013
In another post, I detailed the 3,93 figure derived from cancer tissues. The best human estimate at the moment is in this Cell paper that shows a rate between 2.0 and 3.8 x 10^-8 cells. Sperm sequencing may not represent a good model as there are so many degenerate cells.
Addendum 1 Jan 2021
Here is a new nature medicine paper on cell turnover. What I do not understand – shouldn’t we have a much higher leukemia rate in the population? Leukemia is only on the11th place.