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2011 June 20

Human mutation rates

Filed under: Uncategorized — gasstationwithoutpumps @ 10:02
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I just finished reading an article on human mutation rates:

Variation in genome-wide mutation rates within and between human families by Donald F Conrad, Jonathan E M Keebler, Mark A DePristo, Sarah J Lindsay, Yujun Zhang, Ferran Casals, Youssef Idaghdour, Chris L Hartl, Carlos Torroja, Kiran V Garimella, Martine Zilversmit, Reed Cartwright, Guy A RouleauMark Daly, Eric A Stone, Matthew E Hurles,& Philip Awadalla for the 1000 Genomes Project
Nature Genetics
(2011) Published online 12 June 2011

The article computes mutation rates for two triples (father, mother, and child) who have been thoroughly re-sequenced as part of the 1000 genomes project.  For each triple, they identify possible sites of de novo mutations (appearing in the child but not inherited from either parent) using different methods, then re-examine each of the possible candidates with further sequencing, to try to separate out germ-line (inheritable) mutations from somatic (in the body) or cell-culture mutations.

They found that few of the observed de novo mutations in the sequencing were actually germ-line mutations (only about one in 20).  The final mutation rates they get were about 1e-8 (one change in 108 bases).  This rate is comparable with sex-averaged rates from other more population-based estimates, but at the low end.  They point out that mutation rates may vary between individuals (based on age and environmental conditions), and that a few high-mutation-rate individuals may  make the mean rate over many generations higher than the most frequently observed rate at the current time, so both the 1e-8 rate and the highest estimates (4e-8 for paternal mutations estimated from species-divergence from chimps) may still be consistent.  Other possible explanations for the wide spread are given—for example, that the divergence from chimp may be further back in time than the current best estimates.

If we take the 1e-8 error rate as typical, we would expect to see about 60 de novo mutations in each individual (remember that the 3Gbase human genome size is the haploid size, but humans are diploid, so we inherit about 6Gbases from our parents).  The variation from person to person could be quite wide though, even if there were no environmental factors affecting the mutation rate—a Poisson process has a standard deviation of the square root of the mean, so  mean 60 implies a standard deviation of about 8.

One surprising result they got was that for one of the triples, the paternal mutation rate was lower than the maternal one (most estimates have the paternal mutation rate around 4 times the maternal rate, attributed to higher numbers of replications of DNA in the male germ line).  The ages of the parents at conception was not recorded for either triple, but age almost certainly plays a major role in mutation rate. The 4 estimates of mutation rate they got (2 maternal and 2 paternal) had about an 8-to-1 range (much wider than the error bars on the individual estimates), so clearly many more triples need to be examined to get a broader picture of maternal and paternal mutation rates in the population as a whole.  It would be good to have triples in which the ages of the parents are recorded, and to have further generations sequenced to make germline/non-germline mutations easier to separate.

Estimated mutation rates, with previously published estimates above the green line, and new ones below it. Figure copied from the article.

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