Rate, molecular spectrum, and consequences of human mutation

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551 Scopus citations


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 novomutations formonogenic disorders are used to estimate the rateandmolecular spectrumof spontaneously arisingmutations 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/Tcomposition,andleads to thehypothesis 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 inmutation 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 humanfitness can be expected over the next few centuries in industrialized societies unless novel means of genetic intervention are developed.

Original languageEnglish (US)
Pages (from-to)961-968
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number3
StatePublished - Jan 19 2010
Externally publishedYes


  • Base substitutions
  • Human genetic disorders
  • Introns
  • Mutation rate
  • Mutational spectrum

ASJC Scopus subject areas

  • General


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