A Dominant, Recombination-Defective Allele of Dmc1 Causing Male-Specific Sterility

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Abstract
DMC1 is a meiosis-specific homolog of bacterial RecA and eukaryotic RAD51 that can catalyze homologous DNA strand invasion and D-loop formation in vitro. DMC1-deficient mice and yeast are sterile due to defective meiotic recombination and chromosome synapsis. The authors identified a male dominant sterile allele of Dmc1, Dmc1Mei11, encoding a missense mutation in the L2 DNA binding domain that abolishes strand invasion activity. Meiosis in male heterozygotes arrests in pachynema, characterized by incomplete chromosome synapsis and no crossing-over. Young heterozygous females have normal litter sizes despite having a decreased oocyte pool, a high incidence of meiosis I abnormalities, and susceptibility to premature ovarian failure. Dmc1Mei11 exposes a sex difference in recombination in that a significant portion of female oocytes can compensate for DMC1 deficiency to undergo crossing-over and complete gametogenesis. Importantly, these data demonstrate that dominant alleles of meiosis genes can arise and propagate in populations, causing infertility and other reproductive consequences due to meiotic prophase I defects. About 10%–15% of couples are infertile due to defects in meiosis (the process by which egg or sperm cells containing a single copy of each chromosome are produced). Because studying the genetics of meiosis in humans is difficult, we performed genetic screens in mice and identified a novel mutation in Dmc1 that causes male-specific infertility due to defects in meiosis. Dmc1 encodes a key protein required for meiotic recombination; the mutation causes a single amino acid change that prevents genetic exchange, or crossing-over, in males, abolishes its recombination activity, and abrogates the production of sperm. Though heterozygous females are fertile, they have fewer oocytes due to a high incidence of meiosis I abnormalities, and show susceptibility to premature ovarian failure. Importantly, these data demonstrate that dominant alleles of meiosis genes can arise and propagate in populations, and produce meiotic prophase I defects that cause infertility and other reproductive abnormalities.

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