September 04, 2014

Everything you ever wanted to know about mutation rate in humans

Annual Review of Genomics and Human Genetics Vol. 15: 47-70 (Volume publication date August 2014)

Determinants of Mutation Rate Variation in the Human Germline

Laure Ségurel, Minyoung J. Wyman, and Molly Przeworski

Because germline mutations are the source of all evolutionary adaptations and heritable diseases, characterizing their properties and the rate at which they arise across individuals is of fundamental importance for human genetics. After decades during which estimates were based on indirect approaches, notably on inferences from evolutionary patterns, it is now feasible to count de novo mutations in transmissions from parents to offspring. Surprisingly, this direct approach yields a mutation rate that is twofold lower than previous estimates, calling into question our understanding of the chronology of human evolution and raising the possibility that mutation rates have evolved relatively rapidly. Here, we bring together insights from studies of human genetics and molecular evolution, focusing on where they conflict and what the discrepancies tell us about important open questions. We begin by outlining various methods for studying the properties of mutations in humans. We review what we have learned from their applications about genomic factors that influence mutation rates and the effects of sex, age, and other sources of interindividual variation. We then consider the mutation rate as a product of evolution and discuss how and why it may have changed over time in primates.



Mark Moore (Moderator) said...

Maybe not "everything" we wanted to know, but a lot. I wanted to know if position relative to the equator and amount of time in the sun affected mutation rates in humans. There was a hint in the paper that it did, but that was all. If so, it would explain a lot- like why the mutation rate was twice as low as expected- if their measurements were from typical affluent Westerner's who live far north of the equator and don't spend much time in the full sun anyway.

eurologist said...

Many are rejoicing and are feeling vindicated that their many arguments are finally being heard and being taken seriously.

And Chimpanzees' ancestors from 8 - 10 million years ago are now resting peacefully.

Fiend of 9 worlds said...

One invalid math approach substituted for another.

If something is selected against it will always fall out in a decent sized population. The only way something becomes fixed is positive selection or else bottleneck in a small population.

LivoniaG said...

“A more direct approach, which has only recently become feasible, is to survey most of the genome, or a small subset of the genome (e.g., exomes), in pedigrees and identify mutations as variants present in children but not their parents (118, 137). This pedigree-based method provides an estimate of the mutation rate in each gamete and can be used to quantify variation among parents...”

This is admirable work by Ségurel, Wyman, Przeworski and even more so given the caution they give with their conclusions.

Another problem that might be worth mentioning is the kind of mutation that is being counted in a pedigree-based method.

Not all mutations will be seen in living children. A certain category of mutation will not be viable. The child will not be born or will not survive. Another set will not be seen in the third generation because the child will not reach the age to reproduce.

These are “mutations” in the actual sense. The mutation does not enter the statistical population. They are selected against, but that selection is immediate and so it doesn’t show up between two generations.

This kind of mutation may be highly meaningful historically. If there is variation in genetic mutability between populations, then the changing occurrence of non-viable mutations could have a large impact on population size and could affect the accuracy of estimated rates of mutation.

Mutation is the raw material of change in evolution. But that not only applies to mutations that survive to make an appearance in a second generation or in a population profile. The brutal machinery of evolution also creates -- must creates -- mutations that hit wider of the mark and don’t even survive.

It’s possible you can’t accurately measure a true rate of mutation unless you include mutations that are non-viable. Especially because it does not accurately reflect how evolution works.