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IMMUNOGENETICS OF SEX DETERMINATION

性别决定的免疫遗传学

基本信息

批准号：
3135639
负责人：
STEPHEN S WACHTEL
金额：
$ 19.43万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-03-01 至 1990-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3135639
关键词：
HY antigen gene expression genetic mapping glycopeptides human population genetics human subject immunogenetics monoclonal antibody sex linked trait

项目摘要

Studies under this grant have been concerned with elucidation of the mechanisms of sex determination in the vertebrates, and with evaluation of the hypothesis that the molecule bearing serologically-defined H-Y antigen is the determinant of the heterogametic (XY) gonad. H-Y genes have been located on the Y chromosome and on the X; evidence has been provided that development of the XY gonad is secondary to reaction of H-Y and a gonadal receptor; and H-Y minus and H-Y plus classes have been discovered among clinical cases of XY gonadal dysgenesis, of which the latter may be at risk for gonadal tumors. Current research is moving toward evaluation of further theory: that testis-determining structural loci of the mammal are autosomal and regulated by the sex chromosomes; that structural H-Y loci comprise a system of genes of which some are absent in XX males; and that H-Y phenotype is predictive for heterogamety among the vertebrates in general, and for malignancy in cases of XY gonadal dysgenesis in the human. Technical advances are likely to be central to this work. We have devised a sensitive ELISA for detection of H-Y at the cell surface or in solution. The ELISA is based on reaction of biotin-conjugated monoclonal H-Y antibody and a plated antigen source followed by addition of avidinbiotin-enzyme complex and substrate. The result is scored for optical density in an ELISA plate reader. By use of this method, free H-Y has been demonstrated in the supernatant fluids of cultured Sertoli cells and cultured Daudi cells, and cell-surface H-Y has been measured by quantitative absorption in the chicken and mouse. The method will be applied to the study of H-Y in normal populations, and the data obtained will be used as a statistical foundation for the study of H-Y in clinical cases of abnormal sex differentiation and in subjects with aberrant sex chromosome constitutions. Our phylogenetic survey has revealed H-Y antigens in 32 new species and has provided evidence that male and female heterogamety and sex-specific expression of H-Y have evolved several times -- independently in the different species. It is proposed to further extend that survey with emphasis on temperature-controlled sex determination and on systems characterizing transition from male to female heterogamety, the latter evidently governed by a single mutation. The expectation is that analysis of sex determining systems in the different vertebrate classes will provide a comprehensive base for further elucidation of the evolution, genetics and function of the putative inducer molecule.

这项拨款下的研究一直致力于澄清脊椎动物性别决定的机制，以及对假设携带血清学定义的H-Y抗原的分子是异性恋(XY)性腺的决定因素。H-Y基因已经被位于Y染色体和X染色体上；证据已经提供 XY性腺的发育次于H-Y和性腺的反应受体；以及H-Y减号和H-Y+类已在 XY性腺发育不全的临床病例，后者可能存在风险性腺肿瘤的治疗。目前的研究正在向评估的方向发展进一步的理论：决定哺乳动物睾丸结构的基因是常染色体，受性染色体调控；结构H-Y基因座包括一个基因系统，其中一些基因在XX个男性中不存在； H-Y表型可预测脊椎动物之间的异配性一般情况下，以及在XY性腺发育不良病例中的恶性肿瘤人类。技术进步很可能是这项工作的核心。我们有设计了一种灵敏的检测细胞表面或细胞内H-Y的酶联免疫吸附试验解决方案。酶联免疫吸附试验是基于生物素标记的单抗反应。 H-Y抗体和平板抗原源，然后加入亲和素-酶复合体和底物。结果是为酶联免疫吸附试验平板阅读器的光密度。通过使用这种方法，自由H-Y 已在培养的Sertoli细胞的上清液中发现和培养的Daudi细胞，细胞表面的H-Y被测量在鸡和小鼠体内的定量吸收。该方法将是应用于正常人群的H-Y研究，得到的数据将作为临床研究H-Y的统计学基础性分化异常和性行为异常的病例染色体构成。我们的系统发育调查揭示了H-Y 在32个新物种中发现了抗原，并提供了雄性和雌性 H-Y的异性配偶性和性别特异性表达已经进化了几次 --在不同物种中独立存在。建议进一步扩大调查范围，重点是温控性行为关于从男性向女性转变的决定和系统特征异性配偶制，后者明显受单一突变控制。这个期望是对不同性别决定系统的分析脊椎动物课程将为进一步推测的诱导物的进化、遗传学和功能的阐明分子。