康奈尔大学的研究者们鉴定了一个能够导致雄性小鼠不育的基因突变。因为这是在哺乳动物中首次发现引起不育的显性突变，研究者们说，他们现在能够寻找不育人群中的类似DNA突变。康奈尔大学脊椎动物基因组中心主任、发表在本期《公共科学图书馆》（PLoS）文章的作者John Schimenti说：“如果你认为不育是一种疾病，你不能像其他的疾病一样去研究它，因为受它影响的人们不能繁殖后代。” Schemati实验室的Laura Bannister，是文章的第一作者。同是康奈尔教授的遗传学家Schimenti还说：“我们还很少知道人类不育的遗传学原因。”
这个被称之为Dmc1的基因，是编码减数分裂过程中的一个关键蛋白。减数分裂制造生殖所必需的精子和卵细胞。这些性细胞各含一套染色体，形成胚胎细胞时，来自父本和母本的染色体则组合在一起。Dmc1基因的突变，导致一个氨基酸的变化，从而会阻止减数分裂的进行，不能产生精子。这个突变体等位基因（遗传自父本母本一对基因副本）是显性的；雌性小鼠带有这一突变仍然可以生育，但是会将这一缺陷传至下一代。但是，研究者们发现，带有这一突变的雌性小鼠，减数分裂过程中会出现更多的异常情况，可能导致染色体不平衡和生殖缺陷。研究者们还发现，Dmc1突变的雌性小鼠会伴随卵细胞数量减少、卵细胞早熟——研究者们幽默地认为这将造成小鼠的“绝经期”提前。
为取得实验结果，研究者们对小鼠的染色体进行随机诱变，然后在变异小鼠中寻找不育小鼠。他们分析了不育雄性小鼠的DNA，鉴定出导致不育的等位基因。小鼠不育的遗传学研究，大多习惯于采用“基因敲除”技术，而这项研究则首次揭示了导致哺乳动物明确不育的一个显性突变。研究者们相信，这种显性效应与人类不育的实际情况非常接近。
“人们测定了包括Dmc1基因在内的人基因序列，试图将序列的改变和不育联系起来，” Schimenti说，“有少数的报道称，Dmc1或其它减数分裂相关基因的序列改变可能引起显性的不育缺陷，但直到现在才有了确切的证据。”研究者们已经制定了计划，要鉴定出小鼠所有的不育基因，并将这些信息应用于人类不育的研究。
部分英文原文：
PLoS Biology，Published: April 10, 2007
A Dominant, Recombination-Defective Allele of Dmc1 Causing Male-Specific Sterility
Laura A. Bannister1,2, Roberto J. Pezza3, Janet R. Donaldson3, Dirk G. de Rooij4,5, Kerry J. Schimenti1,2, R. Daniel Camerini-Otero3, John C. Schimenti1,2*
1 Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America, 2 The Jackson Laboratory, Bar Harbor, Maine, United States of America, 3 Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America, 4 Department of Endocrinology, Utrecht University, Utrecht, The Netherlands, 5 Department of Cell Biology, University Medical Center Utrecht, Utrecht, The Netherlands
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.
Author Summary
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.
Figure 1. Histopathology of Mei11 Mutant Testes
Paraffin-embedded adult testes sections were stained with hematoxylin and eosin (A–D) or periodic acid–Schiff (E and F). Genotypes are indicated.
(A, B, and D) Images are at 20×, except for inset (60×).
(C) Dying spermatocytes (arrows) are in an epithelial stage IV seminiferous tubule (60×).
(E) Incomplete meiotic arrest. The seminiferous tubule marked with an asterisk contains mid-pachytene spermatocytes (arrows). 60×.
(F) A rare tubule (asterisk) containing round spermatids (blue arrows) and elongating spermatids (black arrows). 60×.
英文全文链接：
http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0050105
