Abstract

Human infertility is a major worldwide health problem for individuals and their partners (1). Because genetic defects are thought to underlie many of the unexplained pathologies in infertility cases, animal models are expected to provide valuable clues to the underlying defects. More than 200 infertile or subfertile genetic mouse models have already been generated, defining key DNA repair and signaling pathways and other processes involved in mammalian reproduction (2). Many of these models were generated by targeted disruption of known genes or were fortuitously identified as spontaneously arising mutants. Because of the complexity of reproduction, however, this number almost certainly represents only a small fraction of the genes controlling this process (3). To discover new genes in gametogenesis, John Schimenti and colleagues have undertaken an ambitious phenotypebased screen in mice based on chemical mutagenesis of either embryonic stem cells (ethylmethanesulfonate) or whole animals (ethylnitrosourea). In a pilot study, 11 mouse fertility mutants have thus far been generated that affect several different stages of gametogenesis in one or both sexes, including meiosis (4). In this issue of PNAS, Libby et al. (5) report the positional cloning of the first of the mutant genes, Mei1 (meiosis defective 1). Mei1 is expressed almost exclusively in the gonads, in particular, in the testis of prepubertal and adult males and in the ovary of late embryonic females (i.e., embryonic day 17.5), the time of meiotic prophase. The human MEI1 gene is predicted to encode a protein with 79% identity to the mouse protein, and other vertebrate homologs have also been identified. However, the encoded protein contains no significant homology to previously described proteins, and homologs are not evident in yeast, worms, or flies. Thus, with this forward genetic approach, a novel vertebrate meiosis gene has been identified, highlighting the power of the chemical mutagenesis …

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