生物谷报道：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。
同时也是康奈尔的遗传学教授Schimenti还说：“我们还很少知道人类不育的遗传学原因。”
被称之为Dmc1的这个基因，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版本）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，但知道现在才有了确切的证据。”他还说到，人DNA序列的改变，是“良性”的、还是会破坏精子或卵子的产生，弄清这之间的区别，（借助）小鼠模型是重要的。研究者们制定了计划，最终要鉴定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。
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×.
原文出处：
Published April 10, 2007 - RESEARCH ARTICLE
A Dominant, Recombination-Defective Allele of Dmc1 Causing Male-Specific Sterility
Bannister LA, Pezza RJ, Donaldson JR, de Rooij DG, Schimenti KJ, et al. PLoS Biology Vol. 5, No. 5, e105 doi:10.1371/journal.pbio.0050105
相关基因：
DMC1
Official Symbol: DMC1 and Name: DMC1 dosage suppressor of mck1 homolog, meiosis-specific homologous recombination (yeast) [Homo sapiens]
Other Aliases: DMC1H, HsLim15, LIM15, MGC150472, MGC150473, dJ199H16.1
Other Designations: DMC1 dosage suppressor of mck1 homolog; DMC1 homologue; disrupted meiotic cDNA1, yeast, homolog of; meiotic recombination protein DMC1/LIM15 homolog
Chromosome: 22; Location: 22q13.1
MIM: 602721
GeneID: 11144
作者简介：
John Schimenti, Ph.D.
Professor of Genetics; Director, Center for Vertebrate Genomics
Research Interests
My laboratory uses the mouse as a model system to investigate the genetics of mammalian development, gametogenesis, and maintenance of genome integrity. We have used forward and reverse genetic technologies to mutagenize the mouse genome and identify novel genes involved in these processes.
In one project, we conducted a forward genetic screen for mice carrying mutations that cause chromosome instability (CIN). CIN is a hallmark of cancer cells, and in some cases, may be a causative defect leading to cancers. One of the mutations we recovered caused a 20 fold elevation in CIN. Positional cloning revealed that the mutation is a hypomorphic allele of an essential and highly conserved DNA replication gene called Mcm4. Whereas null mutations are lethal, our allele, called Chaos3, encodes a single amino acid change in an absolutely conserved residue, allowing the mice to be viable. However, female mice with this mutation are highly susceptible to mammary tumors exclusively; about 80% get aggressive mammary adenocarcinomas by 1 year of age. This mouse is a uniquenon-transgenic model of breast cancer, and suggests that variants in DNA replication genes may constitute a previously unrecognized basis for certain cancers. We are investigate the genomic anomolies in Chaos3 tumor cells that underlie the transformed phenotype, and are exploring the cause for the mammary specificity.
With respect to gametogenesis, we concentrate on the process of meiosis. During meiosis, DNA is replicated, homologous chromosomes pair, recombination occurs, and two rounds of divisions follow to create haploid gametes. We have isolated several mutants that disrupt these steps, using both forward (ENU mutagenesis) and reverse genetic (knockouts in ES cells) strategies. Among the novel genes we are studying are : Mei1, a vertebrate-specific gene required for initation of meiotic recombination; a male-specific dominant allele of the RecA-like meiotic recombination gene Dmc1; a novel gene called Mei4 that required for the formation of chiasmata; and a gene that is specifically required for noncrossover recombination. In addition to our collection of meiotic mutants, we are investigating infertility mutations that affect earlier stages of germ cell production as well as postmeiotic sperm development.
The final major project in the lab addresses the functional genomic content of proximal mouse Chromosome 5, representing about 2% of the genome. A region-specific ENU mutagenesis screen was conducted, yielding 37 embryonic lethal mutations. We have determined the timing and phenotypes of death for most of them, which range from pre-implantation lethality to a late-gestation homeotic-like skeletal transformation. To facilitate the mapping and cloning of these mutations in a systematic manner, we created a collection of nested chromosomal deletions in the region, using an ES cell-based technology. We have been positionally cloning the underlying mutant genes, which range from hypomorphic alleles of known genes to genes not previously studied at the functional level.
select Publications
Shima, N., Hartford, S., Duffy, T., Wilson, L., Schimenti, K. and Schimenti, J. (2003) Phenotype based identification of mouse chromosome instability mutants. Genetics, 163:1031-1040.
Ward, J., Reinholdt, L., Hartford, S., Wilson, L., Munroe, R., Schimenti, K., Libby, B., O'Brien, M., Pendola, J., Eppig, J. and Schimenti, J. (2003) Towards the genetics of mammalian reproduction: induction and mapping of gametogenesis mutants in mice. Biology of Reproduction, 69, 1615-25.
Libby, B., Reinholdt, L., and Schimenti, J. (2003) Positional cloning and characterization of Mei1, a novel, vertebrate-specific gene required for normal meiotic chromosome synapsis in mice. PNAS, 100: 15706-15711.
Munroe, R., Ackerman, S. and Schimenti, J. (2004) Genome-wide two generation screens for recessive mutations by ES cell mutagenesis. Mammalian Genome, 15:.960-965.
Shima, N. Munroe, R. and Schimenti, J. (2004) The mouse genomic instability mutation chaos1 is an allele of Polq that exhibits genetic interaction with Atm. Mol. Cell. Biol. 24: 10381-9.
Bannister , L, Reinholdt, L. Munroe, R. and Schimenti, J. (2004) Positional cloning and characterization of mouse mei8, a disrupted allele of the meiotic cohesin Rec8. Genesis, 40: 184-194. (Cover).
Schimenti, J., Reynolds, J. and Planchart, A. (2005) Mutations in Serac1 or Synj2 cause proximal t haplotype -mediated male mouse sterility, but not transmission ratio distortion. PNAS 102: 3342-3347.
Reinholdt, L. and Schimenti, J. (2005) Mei1 is epistatic to Dmc1 in mouse meiosis. Chromosoma, 114: 127-134.
Wilson, L, Ching, Y., Farias, M., Hartford, S., Howell, G., Shao, H., Bucan, M. and Schimenti, J. (2005) ENU mutagenesis of proximal mouse Chromosome 5 uncovers predominantly embryonic lethal mutations. Genome Research. 15:1095-1105.
Howell, G., Munroe, R. and Schimenti, J. (2005) Transgenic rescue of the mouse t complex haplolethal locus Thl1. Mammalian Genome 16: 838-846. (cover).
Zan, H., Shima, N., Wu, Z., Al-Qahtani, A., Evinger, A., Zhong, Y., Schimenti , J. and Casali, P. (2005) The translesion DNA Polymerase Theta plays a dominant role in immunoglobulin gene somatic hypermutation. EMBO 24: 3757-59.
Handel, M.A., Lessard, C., Reinholdt, L., Schimenti, J. and Eppig, J. (2006) Mutagenesis as an unbiased approach to identify novel contraceptive targets. Mol. Cell. Endocrinol., 250:201-5.
Reinholdt, L., Munroe, R., Kamdar, S. and Schimenti, J. (2006) The mouse gcd2 mutation causes primordial germ cell depletion. Mechanisms of Development 123: 559-569.
Lessard, C., Lothrop, H., Schimenti, J. and Handel, M.A. (2007) Mutagenesis-generated mouse models of human infertility with abnormal sperm. Human Reproduction, 22: 159-166.
Shima, N., Alcaraz, A., Liachko, I., Buske, T., Andrews, C., Munroe, R., Hartford, S., Tye, B., and Schimenti, J. (2007) A viable mutation of Mcm4 causes genomic instability and mammary adenocarcinoma in mice. Nature Genetics 19: 93-98.
Howell, G., Shindo, M., Murray, S., Gridley, T. Wilson, L. and Schimenti, J. (2007) Mutation of an ubiquitously-expressed mouse transmembrane protein (Tapt1) causes specific skeletal homeotic transformations. Genetics 175:699-707.
Bannister, L., Pezza, R., Donaldson, J., de Rooij, D., Schimenti, K., Camerini-Otero, D. and Schimenti, J. (2007) Male-specific sterility in mice carrying a dominant, recombination-defective allele of the RecA homolog Dmc1. PLoS Biology, in press.
