Ultrafine mapping of SNPs from mouse strains C57BL/6J, DBA/2J, and C57BLKS/J for loci contributing to diabetes and atherosclerosis susceptibility
Ultrafine mapping of SNPs from mouse strains C57BL/6J, DBA/2J, and C57BLKS/J for loci contributing to diabetes and atherosclerosis susceptibility
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DOI：
10.2337/diabetes.54.4.1191
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发表时间：
2005-04-01
期刊：
影响因子：
7.7
通讯作者：
Lusis, AJ
中科院分区：
文献类型：
--
作者：
Davis, RC;Schadt, EE;Lusis, AJ
携带瘦素受体lepr(-/-) （BKS-db）突变的近交系小鼠C57BLKS/J （BKS）是典型的2型糖尿病小鼠模型。虽然BKS最初被认为是C57BL/6J的一个亚株（136），但很明显，它的基因组包含来自DBA/2 （DBA）样菌株和其他未知来源的渗入区域。据推测，与B6-db相比，BKS-db显著增强的糖尿病易感性是由这种DNA渗入所赋予的。利用高密度单核苷酸多态性，我们绘制了BKS中存在的DBA和其他污染DNA区域。因此，大约70%的基因组似乎来自136，大约20%来自DBA，另外9%来自一个身份不明的捐赠者。与56种不同的近交系进行比较表明，该供体可能是一种不太常见的近交系或远交系或野生株。利用B6与DBA杂交的表达数据，我们确定了这两个菌株之间的差异调控基因。这些位于BKS中ba样块上的顺式调控基因是BKS-db菌株中导致糖尿病易感性的基因的主要候选基因。为了进一步确定这些候选基因的优先级，我们确定了那些与糖尿病相关表型显著相关的顺式作用表达数量性状位点。
The inbred mouse strain C57BLKS/J (BKS) carrying a mutation of the leptin receptor lepr(-/-) (BKS-db) is a classic mouse model of type 2 diabetes. While BKS was originally presumed to be a substrain of C57BL/6J (136), it has become apparent that its genome contains introgressed regions from a DBA/2 (DBA)-like strain and perhaps other unidentified sources. It has been hypothesized that the strikingly enhanced diabetes susceptibility of BKS-db compared with B6-db is conferred by this introgressed DNA. Using high-density single nucleotide polymorphisms, we have mapped the DBA and other contaminating DNA regions present in BKS. Thus, similar to 70% of its genome appears to derive from 136, with similar to 20% from DBA and another 9% from an unidentified donor. Comparison with 56 diverse inbred strains suggests that this donor may be a less common inbred strain or an outbred or wild strain. Using expression data from a B6 x DBA cross, we identified differentially regulated genes between these two strains. Those cis-regulated genes located on DBA-like blocks in BKS constitute primary candidates for genes contributing to diabetes susceptibility in the BKS-db strain. To further prioritize these candidates, we identified those cis-acting expression quantitative trait loci whose expression significantly correlates with diabetes-related phenotypes.