Spontaneous mutations are the source of genetic variation required for evolutionary change, and are therefore important for many aspects of evolutionary biology. For example, the divergence between taxa at neutrally evolving sites in the genome is proportional to the per nucleotide mutation rate, u (ref. 1), and this can be used to date speciation events by assuming a molecular clock. The overall rate of occurrence of deleterious mutations in the genome each generation (U) appears in theories of nucleotide divergence and polymorphism2, the evolution of sex and recombination3, and the evolutionary consequences of inbreeding2. However, estimates of U based on changes in allozymes4 or DNA sequences5 and fitness traits are discordant6,7,8. Here we directly estimate u in Drosophila melanogaster by scanning 20 million bases of DNA from three sets of mutation accumulation lines by using denaturing high-performance liquid chromatography9. From 37 mutation events that we detected, we obtained a mean estimate for u of 8.4 × 10-9 per generation. Moreover, we detected significant heterogeneity in u among the three mutation-accumulation-line genotypes. By multiplying u by an estimate of the fraction of mutations that are deleterious in natural populations of Drosophila10, we estimate that U is 1.2 per diploid genome. This high rate suggests that selection against deleterious mutations may have a key role in explaining patterns of genetic variation in the genome, and help to maintain recombination and sexual reproduction.
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We thank D. Houle and C. López-Fanjul for providing samples of MA lines, P. Andolfatto for suggesting the use of PCR errors as positive controls, F. Oliver for help with DNA sequencing, and D. Charlesworth, J. Crow, J. Drake, A. Eyre-Walker, C. Haag, D. Houle and M. Lynch for comments on the manuscript. We are grateful to the Wellcome Trust for funding by a Functional Genomics Development Initiative grant.
Author Contributions S.M., C.H.-L. and M.D. performed the DHPLC analysis. M.D. cloned and sequenced putative variants. X.M. cloned and sequenced positive controls. D.L.H. analysed selective constraints on indel mutations. B.C. advised on Drosophila genetics and interpreting the data. P.D.K. conceived and designed the project. C.H.-L. and P.D.K. analysed the data and wrote the paper. All authors revised the draft manuscript.
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
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Haag-Liautard, C., Dorris, M., Maside, X. et al. Direct estimation of per nucleotide and genomic deleterious mutation rates in Drosophila. Nature 445, 82–85 (2007). https://doi.org/10.1038/nature05388
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