康奈爾大學(xué)的研究者們鑒定了一個(gè)能夠?qū)е滦坌孕∈蟛挥幕蛲蛔?。因?yàn)檫@是在哺乳動(dòng)物中首次發(fā)現(xiàn)引起不育的顯性突變,，研究者們說，他們現(xiàn)在能夠?qū)ふ也挥巳褐械念愃艱NA突變,?？的螤柎髮W(xué)脊椎動(dòng)物基因組中心主任,、發(fā)表在本期《公共科學(xué)圖書館》（PLoS）文章的作者John Schimenti說：“如果你認(rèn)為不育是一種疾病,，你不能像其他的疾病一樣去研究它，因?yàn)槭芩绊懙娜藗儾荒芊敝澈蟠?rdquo; Schemati實(shí)驗(yàn)室的Laura Bannister,，是文章的第一作者,。同是康奈爾教授的遺傳學(xué)家Schimenti還說：“我們還很少知道人類不育的遺傳學(xué)原因。”
這個(gè)被稱之為Dmc1的基因,，是編碼減數(shù)分裂過程中的一個(gè)關(guān)鍵蛋白,。減數(shù)分裂制造生殖所必需的精子和卵細(xì)胞。這些性細(xì)胞各含一套染色體,，形成胚胎細(xì)胞時(shí),，來自父本和母本的染色體則組合在一起。Dmc1基因的突變,，導(dǎo)致一個(gè)氨基酸的變化,，從而會(huì)阻止減數(shù)分裂的進(jìn)行，不能產(chǎn)生精子,。這個(gè)突變體等位基因（遺傳自父本母本一對(duì)基因副本）是顯性的,；雌性小鼠帶有這一突變?nèi)匀豢梢陨菚?huì)將這一缺陷傳至下一代,。但是,，研究者們發(fā)現(xiàn),，帶有這一突變的雌性小鼠，減數(shù)分裂過程中會(huì)出現(xiàn)更多的異常情況,，可能導(dǎo)致染色體不平衡和生殖缺陷,。研究者們還發(fā)現(xiàn)，Dmc1突變的雌性小鼠會(huì)伴隨卵細(xì)胞數(shù)量減少,、卵細(xì)胞早熟——研究者們幽默地認(rèn)為這將造成小鼠的“絕經(jīng)期”提前,。
為取得實(shí)驗(yàn)結(jié)果，研究者們對(duì)小鼠的染色體進(jìn)行隨機(jī)誘變,，然后在變異小鼠中尋找不育小鼠,。他們分析了不育雄性小鼠的DNA，鑒定出導(dǎo)致不育的等位基因,。小鼠不育的遺傳學(xué)研究,，大多習(xí)慣于采用“基因敲除”技術(shù)，而這項(xiàng)研究則首次揭示了導(dǎo)致哺乳動(dòng)物明確不育的一個(gè)顯性突變,。研究者們相信,，這種顯性效應(yīng)與人類不育的實(shí)際情況非常接近。
“人們測(cè)定了包括Dmc1基因在內(nèi)的人基因序列,，試圖將序列的改變和不育聯(lián)系起來,，” Schimenti說,，“有少數(shù)的報(bào)道稱,，Dmc1或其它減數(shù)分裂相關(guān)基因的序列改變可能引起顯性的不育缺陷，但直到現(xiàn)在才有了確切的證據(jù),。”研究者們已經(jīng)制定了計(jì)劃,，要鑒定出小鼠所有的不育基因，并將這些信息應(yīng)用于人類不育的研究,。
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×.
英文全文鏈接：
http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0050105
