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.

Original publication

DOI

10.1126/science.1085710

Type

Journal article

Journal

Science (New York, N.Y.)

Publication Date

08/2003

Volume

301

Pages

643 - 646

Addresses

Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.

Keywords

Spermatozoa, Spermatogonia, Stem Cells, Humans, Acrocephalosyndactylia, Receptor Protein-Tyrosine Kinases, Receptors, Fibroblast Growth Factor, Ligands, Models, Statistical, Amino Acid Substitution, Polymerase Chain Reaction, Sequence Analysis, DNA, DNA Mutational Analysis, Spermatogenesis, Aging, Paternal Age, Sex Characteristics, Heterozygote, Mutation, Point Mutation, Polymorphism, Single Nucleotide, Models, Genetic, Adult, Aged, Middle Aged, Female, Male, Receptor, Fibroblast Growth Factor, Type 2, Selection, Genetic