June 13, 2011

Autosomal mutation rate from family trios

Razib points me to a new 1000 Genomes Project paper which measures the autosomal mutation directly by looking at trios of individuals (offspring+parents). I don't have much to add except:
  1. The authors find substantial family-related variability of the mutation rate. It may be worthwhile to determine whether the mutation rate is a constant across the geographical range of H. sapiens; it is not inconceivable that, if there are family differences in mutability, there may also be population differences.
  2. The authors estimate the human-chimp divergence at 7 million years. This is reasonably close to the 6.5 million years in last year's papers about Neandertal/Denisovan admixture in modern years, but it is worthwhile to re-examine all past papers with dates dependent on this calibration point. Until now, we had to "fix" human/chimp divergence, and express divergences within Homo and within Homo sapiens as a fraction of that divergence, but our newfound ability to study whole genomes of 1st degree relatives -and soon many more of those- will make it possible to measure the rate directly and not depend on any calibration based on paleontological data.
Nature Genetics (2011) doi:10.1038/ng.862

Variation in genome-wide mutation rates within and between human families

Donald F Conrad et al.

J.B.S. Haldane proposed in 1947 that the male germline may be more mutagenic than the female germline1. Diverse studies have supported Haldane's contention of a higher average mutation rate in the male germline in a variety of mammals, including humans2, 3. Here we present, to our knowledge, the first direct comparative analysis of male and female germline mutation rates from the complete genome sequences of two parent-offspring trios. Through extensive validation, we identified 49 and 35 germline de novo mutations (DNMs) in two trio offspring, as well as 1,586 non-germline DNMs arising either somatically or in the cell lines from which the DNA was derived. Most strikingly, in one family, we observed that 92% of germline DNMs were from the paternal germline, whereas, in contrast, in the other family, 64% of DNMs were from the maternal germline. These observations suggest considerable variation in mutation rates within and between families.


  1. The gender differences in germline mutation rates isn't unexpected. Males continually produce new germline cells, women produce their eggs early and as a result their germline cells aren't impacted by subsequent environmental exposures to the same degree.

    Advanced paternal age is implicated as a major factor in a great many genetic conditions probably through increased mutation rates in older men (something to some extent shown directly), and there is also evidence that germline cell mutations are impacted by environmental exposures of fathers (it is pregnancy and nursing exposures that women are most vulnerable to for environmental impacts). For example, one study from California showed pre-conception pestiside exposure of men, but not women as having an impact on birth defects and abnomalities.

    This mechanism suggests that male environmental exposure rates and paternal age should be closely scrutinized before one jumps to the conclusion that individuals themselves are inherently more or less mutagenic. Similarities in advanced paternal age affects from one population to another internationally, at least in developed world samples, suggest that between population differences in mutation rates may be modest.

  2. Surprising result. Basically the experiment did not work. Variable results. Higher in the paternal side in one family lower in another. I agree with Andrew, overall this must balance out as we dont appear to see this in populations.

    Still 92% in one family through the father? What was he 70+? I am surprised by such a huge difference.

  3. I agree with the importance of environmental factors. Also, as I mentioned at Razib's, Utah is high altitude and may in addition have higher levels of water and ground radioactivity than Nigeria.

  4. "Still 92% in one family through the father? What was he 70+?"

    Background radiation and cosmic rays are greater here in the high country than in Nigeria, but I'd put my money on environmental exposures being due to work related events -- the differences in background levels aren't anywhere near high enough to be clinically significant and create that kind of difference in mutation rates. Work related possibilities include the fact the center of the U.S. uranium mining and processing industry is on the Utah-Colorado border, the Rocky Mountain region was a center of nerve gas and chemical weapon production, and lots of people in the region are military veterans who may have been exposed to Agent Orange during Vietnam or former farmers who may have been exposed to agricultural chemicals.


Stay on topic. Be polite. Use facts and arguments. Be Brief. Do not post back to back comments in the same thread, unless you absolutely have to. Don't quote excessively. Google before you ask.