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

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. Rouleau; Mark Daly; Eric A. Stone; Matthew E. Hurles; Philip Awadalla

doi:10.1038/ng.862

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

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. Rouleau, Mark Daly, Eric A. Stone, Matthew E. Hurles, Philip Awadalla

Research output: Contribution to journal › Article › peer-review

417 Scopus citations

Abstract

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 humans. 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.

Original language	English (US)
Pages (from-to)	712-714
Number of pages	3
Journal	Nature Genetics
Volume	43
Issue number	7
DOIs	https://doi.org/10.1038/ng.862
State	Published - Jul 2011
Externally published	Yes

ASJC Scopus subject areas

Genetics

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Conrad, D. F., Keebler, J. E. M., Depristo, M. A., Lindsay, S. J., Zhang, Y., Casals, F., Idaghdour, Y., Hartl, C. L., Torroja, C., Garimella, K. V., Zilversmit, M., Cartwright, R., Rouleau, G. A., Daly, M., Stone, E. A., Hurles, M. E., & Awadalla, P. (2011). Variation in genome-wide mutation rates within and between human families. Nature Genetics, 43(7), 712-714. https://doi.org/10.1038/ng.862

Conrad, DF, Keebler, JEM, Depristo, MA, Lindsay, SJ, Zhang, Y, Casals, F, Idaghdour, Y, Hartl, CL, Torroja, C, Garimella, KV, Zilversmit, M, Cartwright, R, Rouleau, GA, Daly, M, Stone, EA, Hurles, ME & Awadalla, P 2011, 'Variation in genome-wide mutation rates within and between human families', Nature Genetics, vol. 43, no. 7, pp. 712-714. https://doi.org/10.1038/ng.862

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title = "Variation in genome-wide mutation rates within and between human families",

abstract = "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 humans. 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.",

author = "Conrad, {Donald F.} and Keebler, {Jonathan E.M.} and Depristo, {Mark A.} and Lindsay, {Sarah J.} and Yujun Zhang and Ferran Casals and Youssef Idaghdour and Hartl, {Chris L.} and Carlos Torroja and Garimella, {Kiran V.} and Martine Zilversmit and Reed Cartwright and Rouleau, {Guy A.} and Mark Daly and Stone, {Eric A.} and Hurles, {Matthew E.} and Philip Awadalla",

note = "Funding Information: We would like to thank A. Kernytsky, G. McVean, T. Massingham, J. Thorne, J. Hussin, A. Motsinger, Coriell Cell Repositories and members of the 1000 Genomes analysis group for their help and support. D.F.C., S.J.L., Y.Z., C.T. and M.E.H. were funded by the Wellcome Trust (grant number 077014/Z/05/Z). J.E.M.K., F.C., Y.I., M.Z., G.A.R. and P.A. were funded by the Ministry of Development, Exploration and Innovation (grant number PSR-SIIRI-195) in Quebec and a Genome Quebec Award for Population and Medical Genomics to P.A.",

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AU - Conrad, Donald F.

AU - Keebler, Jonathan E.M.

AU - Depristo, Mark A.

AU - Lindsay, Sarah J.

AU - Zhang, Yujun

AU - Casals, Ferran

AU - Idaghdour, Youssef

AU - Hartl, Chris L.

AU - Torroja, Carlos

AU - Garimella, Kiran V.

AU - Zilversmit, Martine

AU - Cartwright, Reed

AU - Rouleau, Guy A.

AU - Daly, Mark

AU - Stone, Eric A.

AU - Hurles, Matthew E.

AU - Awadalla, Philip

N1 - Funding Information: We would like to thank A. Kernytsky, G. McVean, T. Massingham, J. Thorne, J. Hussin, A. Motsinger, Coriell Cell Repositories and members of the 1000 Genomes analysis group for their help and support. D.F.C., S.J.L., Y.Z., C.T. and M.E.H. were funded by the Wellcome Trust (grant number 077014/Z/05/Z). J.E.M.K., F.C., Y.I., M.Z., G.A.R. and P.A. were funded by the Ministry of Development, Exploration and Innovation (grant number PSR-SIIRI-195) in Quebec and a Genome Quebec Award for Population and Medical Genomics to P.A.

PY - 2011/7

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N2 - 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 humans. 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.

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

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