Rate, molecular spectrum, and consequences of human mutation

Contributed by Michael Lynch, December 3, 2009 (sent for review September 13, 2009)
January 4, 2010
107 (3) 961-968
Profile of Michael Lynch
Beth Azar


Although mutation provides the fuel for phenotypic evolution, it also imposes a substantial burden on fitness through the production of predominantly deleterious alleles, a matter of concern from a human-health perspective. Here, recently established databases on de novo mutations for monogenic disorders are used to estimate the rate and molecular spectrum of spontaneously arising mutations and to derive a number of inferences with respect to eukaryotic genome evolution. Although the human per-generation mutation rate is exceptionally high, on a per-cell division basis, the human germline mutation rate is lower than that recorded for any other species. Comparison with data from other species demonstrates a universal mutational bias toward A/T composition, and leads to the hypothesis that genome-wide nucleotide composition generally evolves to the point at which the power of selection in favor of G/C is approximately balanced by the power of random genetic drift, such that variation in equilibrium genome-wide nucleotide composition is largely defined by variation in mutation biases. Quantification of the hazards associated with introns reveals that mutations at key splice-site residues are a major source of human mortality. Finally, a consideration of the long-term consequences of current human behavior for deleterious-mutation accumulation leads to the conclusion that a substantial reduction in human fitness can be expected over the next few centuries in industrialized societies unless novel means of genetic intervention are developed.

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The author thanks M. Ackerman, C. Baer, J. Drake, A. Kondrashov, and S. Yi for helpful comments, and M. Ackerman for assistance in some key computations. This work was funded by National Institutes of Health Grant GM36827, National Science Foundation Grant EF-0827411, and the MetaCyte program derived from Lilly Foundation funding to Indiana University.

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Published in

Go to Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences
Vol. 107 | No. 3
January 19, 2010
PubMed: 20080596


Submission history

Published online: January 4, 2010
Published in issue: January 19, 2010


  1. base substitutions
  2. human genetic disorders
  3. introns
  4. mutation rate
  5. mutational spectrum


The author thanks M. Ackerman, C. Baer, J. Drake, A. Kondrashov, and S. Yi for helpful comments, and M. Ackerman for assistance in some key computations. This work was funded by National Institutes of Health Grant GM36827, National Science Foundation Grant EF-0827411, and the MetaCyte program derived from Lilly Foundation funding to Indiana University.



Michael Lynch1 [email protected]
Department of Biology, Indiana University, Bloomington, IN 47405


Author contributions: M.L. designed research; performed research; analyzed data; and wrote the paper.
This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2009.

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    Rate, molecular spectrum, and consequences of human mutation
    Proceedings of the National Academy of Sciences
    • Vol. 107
    • No. 3
    • pp. 949-1254







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