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Genetic control of testicular germ cell tumor susceptibility in mice.

机译：小鼠睾丸生殖细胞肿瘤易感性的遗传控制。

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摘要

Testicular germ cell tumors (TGCTs) are the most common types of testicular cancer as well as the most common tumor in men aged 15--34. Despite their prevalence, the genetic control of susceptibility is poorly understood. Family history suggests a strong genetic component to TGCT susceptibility, but studies have found only one rare, weakly associated Y-linked locus. The 129 family of inbred mouse strains is an established animal model of TGCTs. Linkage studies in mice have been largely unsuccessful, and no genes controlling susceptibility have been found.;The goal of my research was to identify chromosomes and chromosomal regions containing TGCT QTLs (quantitative trait loci) using chromosome substitution strains (CSSs). My analysis showed that three CSSs have TGCT QTLs. To map the QTLs on chromosome 18, I made a panel of eight congenic strains from 129-Chr 18MOLF. I surveyed congenic males for TGCTs and found evidence for three previously unknown TGCT QTLs on chromosome 18.;Because studies have shown conflicting evidence for a Y-linked factor(s) promoting TGCTs in humans, I tested the role of this chromosome on TGCT development in mice. Sry, the master sex-determining gene in mammals, is on the Y chromosome and is normally required for testis formation and male development. In the absence of the Y chromosome, mice develop as fertile females. To bypass the requirement for Sry in sexual development, I took advantage of the Odd Sex mutation that causes XX animals to develop as males without the Y chromosome. Sex-reversed XX males develop testes with PGCs, which enabled tests of whether the Y chromosome was required for TGCT tumorigenesis. Although normal males developed TGCTs at an appreciable rate, no TGCTs were found in sex-reversed males. I concluded that at least one factor on the Y chromosome was required for TGCT initiation.;The results of my research support the theory that TGCTs are a highly complex trait, and that CSSs are an effective tool for mapping QTLs with weak effects. A more thorough understanding of the heritable component of TGCTs in mice will improve our understanding of the genetic control of susceptibility to complex diseases.
机译：睾丸生殖细胞肿瘤（TGCT）是15--34岁男性中最常见的睾丸癌类型，也是最常见的肿瘤。尽管它们很普遍，但是人们对遗传易感性的遗传控制知之甚少。家族史表明TGCT易感性具有很强的遗传成分，但是研究发现只有一个罕见的，弱关联的Y连锁基因座。 129个自交系小鼠品系是已建立的TGCT动物模型。在小鼠中的连锁研究在很大程度上没有成功，也没有发现控制敏感性的基因。我的研究目标是使用染色体替代菌株（CSS）鉴定含有TGCT QTL（定量性状基因座）的染色体和染色体区域。我的分析表明，三个CSS具有TGCT QTL。为了将QTL定位在18号染色体上，我从129-Chr 18MOLF中提取了8个同系菌株。我调查了TGCT的同系雄性，并发现了18号染色体上三个先前未知的TGCT QTL的证据;由于研究表明在人中促进TGCT的Y相关因子存在矛盾的证据，我测试了该染色体在TGCT发育中的作用在小鼠中。 Sry是哺乳动物的主要性别决定基因，位于Y染色体上，通常是睾丸形成和雄性发育所必需的。在没有Y染色体的情况下，小鼠发育为可育的雌性。为了避免性发育中对Sry的要求，我利用了Odd Sex突变的优势，该突变导致XX种动物发育为没有Y染色体的雄性。性别相反的XX雄性会用PGC发育睾丸，从而可以测试TGCT的肿瘤发生是否需要Y染色体。尽管正常男性以可观的速度发展了TGCT，但在性别反转的男性中未发现TGCT。我的结论是，TGCT启动至少需要一个Y染色体上的因子。我的研究结果支持TGCT是一种高度复杂的性状，而CSS是绘制QTL效果较弱的有效工具的理论。对小鼠中TGCT的遗传成分的更透彻的了解将增进我们对复杂疾病易感性的遗传控制的了解。

著录项

  • 作者

    Anderson, Philip David.;

  • 作者单位

    Case Western Reserve University.;

  • 授予单位 Case Western Reserve University.;
  • 学科 Biology Genetics.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 132 p.
  • 总页数 132
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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