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Science 301 (5633): 643-646

Copyright © 2003 by the American Association for the Advancement of Science

Evidence for Selective Advantage of Pathogenic FGFR2 Mutations in the Male Germ Line

Anne Goriely,1 Gilean A. T. McVean,3 Maria Röjmyr,4 Björn Ingemarsson,4 Andrew O. M. Wilkie1,2*

Abstract: Observed mutation rates in humans appear higher in male than female gametes and often increase with paternal age. This bias, usually attributed to the accumulation of replication errors or inefficient repair processes, has been difficult to study directly. Here, we describe a sensitive method to quantify substitutions at nucleotide 755 of the fibroblast growth factor receptor 2 (FGFR2) gene in sperm. Although substitution levels increase with age, we show that even high levels originate from infrequent mutational events. We propose that these FGFR2 mutations, although harmful to embryonic development, are paradoxically enriched because they confer a selective advantage to the spermatogonial cells in which they arise.

1 Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
2 Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
3 Department of Statistics, University of Oxford, South Parks Road, Oxford OX1 3TG, UK.
4 Pyrosequencing AB, Vallongatan 1, SE-752 28 Uppsala, Sweden.

* To whom correspondence should be addressed. E-mail: awilkie{at}

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