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Proc Natl Acad Sci U S A. 2010 Jan 19;107(3):961-8. doi: 10.1073/pnas.0912629107. Epub 2010 Jan 4.

Rate, molecular spectrum, and consequences of human mutation.

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1
Department of Biology, Indiana University, Bloomington, IN 47405, USA. milynch@indiana.edu

Abstract

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.

PMID:
20080596
PMCID:
PMC2824313
DOI:
10.1073/pnas.0912629107
[Indexed for MEDLINE]
Free PMC Article
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