Fine mapping reveals multiple loci and a possible epistatic interaction within the mammary carcinoma susceptibility quantitative trait locus, Mcs5.
Fine mapping reveals multiple loci and a possible epistatic interaction within the mammary carcinoma susceptibility quantitative trait locus, Mcs5.
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精细作图揭示了乳腺癌易感性数量性状基因座 Mcs5 内的多个基因座和可能的上位相互作用。
DOI：
10.1158/0008-5472.can-05-1498
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Gould,MichaelN
中科院分区：
文献类型：
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作者：
Samuelson,DavidJ;Aperavich,BethA;Haag,JillD;Gould,MichaelN
为了鉴定高频、低外显率的乳腺癌修饰基因，我们建立了一个大鼠遗传模型，该模型使用Wistar-Kyoto （WKy）自交系作为基因供体，而易感Wistar-Furth （WF）菌株作为受体，该菌株对7,12-二甲基苯[a]蒽诱导的乳腺癌具有抗性。本研究利用含有mcs55数量性状位点区域较小WKy基因组间隔的基因大鼠系的数据，精细绘制了三个独立作用的mcs5亚位点。定义mcs5a、Mcs5b和mcs55基因系的wky纯合子雌性小鼠平均每只大鼠患乳腺癌的概率分别为4.0±0.4、11.6±0.6和3.5±0.4。这些表型值与wf纯合表型值（8.0±0.4）有统计学差异，wf纯合表型值是这些实验使用的基线表型。我们发现likelyMcs5a×Mcs5bepistatic相互作用导致theMcs5bWKy等位基因被theMcs5aWKy等位基因掩盖。我们还提供了aMcs5a×Mcs5cinteraction的证据，该证据表明，在每个位点的WKy等位基因单独的加性作用下，协同降低乳腺癌易感性。cs5亚位点目前定位于大鼠5号染色体的1.0、7.5和4.5 Mb，同源区域位于人9号染色体和小鼠4号染色体上。这些基因座将为人类病例对照关联研究的评估提供公正的候选基因座。
To identify high-frequency, low-penetrance breast cancer modifier genes, we have developed a rat genetic model that uses the Wistar-Kyoto (WKy) inbred strain, resistant to developing 7,12-dimethylbenz[a]anthracene–induced mammary carcinogenesis, as a congenic donor and the susceptible Wistar-Furth (WF) strain as the recipient. Here, data from congenic rat lines containing smaller WKy genomic intervals of theMcs5quantitative trait locus region are presented to fine map three independently actingMcs5subloci. WKy-homozygous females from congenic lines definingMcs5a, Mcs5b, andMcs5caveraged, respectively, 4.0 ± 0.4, 11.6 ± 0.6, and 3.5 ± 0.4 mammary carcinomas per rat. These phenotypic values are statistically different from the WF-homozygous phenotype value of 8.0 ± 0.4, which is the baseline phenotype used for these experiments. We identified a likelyMcs5a×Mcs5bepistatic interaction that results in masking the increased susceptibility effect of theMcs5bWKy allele by theMcs5aWKy allele. We also provide evidence for aMcs5a×Mcs5cinteraction that is synergistic to decrease mammary carcinoma susceptibility below the additive effects of WKy alleles at each locus independently. TheMcs5subloci are currently localized to 1.0, 7.5, and 4.5 Mb of rat chromosome5, and the orthologous regions are on human chromosome9and mouse chromosome4. These loci will provide unbiased candidate gene loci for evaluation in human case-control association studies.