Variation in genome-wide mutation rates within and between human families : Nature Genetics : Nature Publishing Group

Nature Genetics | Letter
Variation in genome-wide mutation rates within and between human families
Donald F Conrad,1, 2 Jonathan E M Keebler,3, 4 Mark A DePristo,5 Sarah J Lindsay,1 Yujun Zhang,1 Ferran Casals,3 Youssef Idaghdour,3 Chris L Hartl,5 Carlos Torroja,1 Kiran V Garimella,5 Martine Zilversmit,3 Reed Cartwright,6 Guy A Rouleau,7 Mark Daly,5 Eric A Stone,4, 6 Matthew E Hurles1 & Philip Awadalla3 for the 1000 Genomes Project8


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.

Variation in genome-wide mutation rates within and between human families : Nature Genetics : Nature Publishing Group