NEW YORK — Researchers have used a new approach to refine the estimate of the average genome-wide mutation rate for humans, which they pegged at 1.24 x 10-8 per base pair per generation.
Previous approaches aimed at determining the genome-wide average human mutation rate have largely relied on sequencing data from parent-offspring trios, though newer methods have begun to use approaches that analyze segments of identity-by-descent (IBD), or stretches of the genome that are shared by individuals thought to be unrelated and can be used to gauge when they last had a common ancestor.
In a new paper appearing in the American Journal of Human Genetics on Friday, a University of Washington team described their approach, which draws on the IBD method. They first tested their method on simulated data before applying it to whole-genome sequencing data from more than 8,000 individuals from three Trans-Omics for Precision Medicine (TOPMed) program studies.
According to UW's Sharon Browning and colleagues, the rate they calculated "is consistent with our previous IBD-based estimates but has tighter confidence intervals because of the larger sample size enabled by the methodology presented here."
The researchers adapted a previous approach of theirs that used sets of three IBD haplotypes to estimate the mutation rate. Requiring three IBD haplotypes limited the effect of genotype error, as variants had to be observed at least twice. This previous approach, though, also required that the haplotypes be properly phased, but the new method instead can count IBD haplotypes from data even when the phase is uncertain.
The new method additionally takes the effects of gene conversion into consideration.
The researchers first applied their new method to estimate the average genome-wide mutation rate to a set of simulated data, which had a mutation rate of 1.3 x 10-8 per base pair per meiosis. With their method, they estimated a mutation rate of 1.31 x 10-8 per base pair per meiosis, with a 95 percent confidence interval stretching from 1.28 x 10-8 to 1.33 x 10-8.
When they did not incorporate that step to account for uncertain phasing, they estimated a mutation rate of 1.21 x 10-8 per base pair per meiosis with a 95 percent confidence interval. This indicated to the researchers that their method adjusts effecting for the uncertainty in phasing.
But when they compared the estimated gene conversion rates to the ones in the simulated data, the researchers noted a downward bias that they said is likely due to the effect of gene conversion events on phasing accuracy. They added that this means that for real population data where the true phase is not known, the gene conversion rate cannot be accurately determined. However, this does not seem to affect the accuracy of the mutation rate estimate.
The researchers then applied their method to estimate the average genome-wide mutation rate to three TOPMed datasets: 4,166 European American individuals from the TOPMed Framingham Heart Study; 2,996 European American individuals from the TOPMed My Life, Our Future study; and 1,586 African American individuals from the TOPMed Hypertension Genetic Epidemiology Network study.
Overall, they estimated the mutation rate to be 1.24 x 10-8 per base pair per generation with a 95 percent confidence interval of 1.18 x 10-8 to 1.33 x 10-8.
When they examined the three datasets separately, the researchers generated similar estimates of 1.2 x 10-8 per base pair per generation, 1.14 x 10-8 per base pair per generation, and 1.34 x 10-8 per base pair per generation, all with overlapping confidence intervals.
"Although mutation rates may differ between populations as a result of genetic factors, demographic factors such as average parental age, and environmental exposures, our results are consistent with equal genome-wide average mutation rates across these three populations," Browning and colleagues wrote.