Genetics of colitis susceptibility in IL-10-deficient mice:: Backcross versus F2 results contrasted by principal component analysis
Genetics of colitis susceptibility in IL-10-deficient mice:: Backcross versus F2 results contrasted by principal component analysis
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DOI：
10.1006/geno.2002.6840
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发表时间：
2002-09-01
期刊：
影响因子：
4.4
通讯作者：
Churchill, GA
中科院分区：
文献类型：
--
作者：
Mähler, M;Most, C;Churchill, GA
C3H/HeJBir 遗传背景的白细胞介素 10 缺陷 (I/10(-/-)) 小鼠比 C57BL/6J 背景的小鼠患上更严重的结肠炎。我们使用源自这两个菌株的两个第一回交群体，对该模型系统中调节结肠炎易感性的数量性状位点（QTL）进行基因组筛选。为了降低该分析的复杂性，通过主成分分析总结了来自多种组织学表型的信息。将类似的方法应用于之前发表的 F2 杂交数据（涉及相同的祖细胞株），这使我们能够确定所有 6 个之前报告的细胞因子缺乏诱导的结肠炎易感位点 (Cdcs1-6)，这些位点对 3、1、2、8、17 和 18 号染色体具有主要和/或相互作用的影响。Cdcs1 的致结肠炎作用在与 C3H/HeJBir-I/10(-/-)。其效应被12号染色体上的另一个基因座上位性修饰。此外，在与C57BL/6J-I/10(-/-)回交中鉴定了4、5和12号染色体上的三个主效应QTL。对这些杂交中遗传模式的分析揭示了双亲基因组对结肠炎的贡献。这些发现显示了结肠炎易感性遗传的复杂性，并说明了为什么人类炎症性肠病基因座的检测如此困难。
Interleukin-10-deficient (I/10(-/-)) mice on a C3H/HeJBir genetic background develop more severe colitis than those on a C57BL/6J background. We performed genome screens for quantitative trait loci (QTLs) regulating colitis susceptibility in this model system using two first backcross populations derived from these two strains. To reduce the complexity of this analysis, the information from numerous histologic phenotypes was summarized by principal component analysis. A similar approach was applied to previously published data from an F2 intercross (involving the same progenitor strains), which allowed us to ascertain all six previously reported cytokine-deficiency-induced colitis susceptibility loci (Cdcs1-6) with main and/or interacting effects on chromosomes 3, 1, 2, 8, 17, and 18. The colitogenic effect of Cdcs1 was confirmed in the backcross to C3H/HeJBir-I/10(-/-). Its effect was epistatically modified by another locus on chromosome 12. In addition, three main effect QTLs on chromosomes 4, 5, and 12 were identified in the backcross to C57BL/6J-I/10(-/-). Analyses of the modes of inheritance in these crosses revealed colitogenic contributions by both parental genomes. These findings show the complexity of inheritance underlying susceptibility to colitis and illustrate why detection of human inflammatory bowel disease loci has proven to be so difficult.