Candidate lung tumor susceptibility genes identified through whole-genome association analyses in inbred mice
Candidate lung tumor susceptibility genes identified through whole-genome association analyses in inbred mice
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DOI：
10.1038/ng1849
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发表时间：
2006-08-01
期刊：
影响因子：
30.8
通讯作者：
You, Ming
中科院分区：
文献类型：
--
作者：
Liu, Pengyuan;Wang, Yian;You, Ming
我们在近交系小鼠中使用密集SNP图谱（类似于每20 kb 1个SNP）进行了肺肿瘤易感性的全基因组关联分析。我们复制了在以前的连锁研究中确定的肺腺瘤易感性1（Pas 1）位点，并进一步将该数量性状位点（QTL）缩小到小于0.5 Mb的区域，其中至少有两个基因，Kras 2（Kirsten大鼠肉瘤癌基因2）和Casc 1（癌症易感性候选者1;也称为Las 1），是强有力的候选者。Casc 1基因敲除小鼠肿瘤生物测定表明，Casc 1缺陷小鼠对化学诱导的肺肿瘤敏感。我们还发现了另外三个肺腺瘤发生的基因位点。这些候选基因座之一的分析确定了一个以前未表征的基因Lasc 1，轴承非同义取代（D102 E）。我们发现Lasc 1 Glu 102等位基因优先促进肺肿瘤细胞生长。我们的研究结果展示了在实验室小鼠中使用密集SNP图谱来改进先前的QTL区域并识别复杂性状的遗传决定因素的前景。
We performed a whole-genome association analysis of lung tumor susceptibility using dense SNP maps (similar to 1 SNP per 20 kb) in inbred mice. We reproduced the pulmonary adenoma susceptibility 1 (Pas1) locus identified in previous linkage studies and further narrowed this quantitative trait locus (QTL) to a region of less than 0.5 Mb in which at least two genes, Kras2 (Kirsten rat sarcoma oncogene 2) and Casc1 (cancer susceptibility candidate 1; also known as Las1), are strong candidates. Casc1 knockout mouse tumor bioassays showed that Casc1-deficient mice were susceptible to chemical induction of lung tumors. We also found three more genetic loci for lung adenoma development. Analysis of one of these candidate loci identified a previously uncharacterized gene Lasc1, bearing a nonsynonymous substitution (D102E). We found that the Lasc1 Glu102 allele preferentially promotes lung tumor cell growth. Our findings demonstrate the prospects for using dense SNP maps in laboratory mice to refine previous QTL regions and identify genetic determinants of complex traits.