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

Laura A Bannister,R Daniel Camerini-Otero,Dirk G De Rooij,Kerry J Schimenti,John C Schimenti,Janet R Donaldson,Roberto J Pezza,Scott Keeney

doi:10.1371/journal.pbio.0050105

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.

Highlights

Genetic recombination occurs in all organisms and is critical for repair of DNA damage, proper chromosome segregation during meiosis, and genetic diversification
Basis for Sexual Dimorphisms in Meiotic Recombination Uncovered by Dmc1Mei11
Whereas mutant oocytes can proceed into pachynema and even undergo the first meiotic division, spermatocytes deficient for these genes and double-strand breaks (DSBs) repair genes such as Dmc1 arrest earlier, at the zygotene/pachytene transition [4,30,31]

Summary

Introduction

Genetic recombination occurs in all organisms and is critical for repair of DNA damage, proper chromosome segregation during meiosis, and genetic diversification. Meiotic DSBs are repaired by proteins that mediate homologous strand exchange, mismatch repair, and resolution of recombination intermediates. As these activities are occurring, homologous chromosomes undergo pairing and synapsis, which are completed by the pachytene stage of meiosis. The ability of germ cells to complete meiosis, and to undergo proper segregation of chromosomes in the subsequent meiotic divisions, hinges on the fidelity of these events. Defects in recombination and meiosis have been shown to underlie aneuploidy syndromes such as Downs [1] and azoospermia in men [2]

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Conclusion