An advanced intercross line resolves Eae18 into two narrow quantitative trait loci syntenic to multiple sclerosis candidate loci
An advanced intercross line resolves Eae18 into two narrow quantitative trait loci syntenic to multiple sclerosis candidate loci
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DOI：
10.4049/jimmunol.173.2.1366
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发表时间：
2004-07-15
影响因子：
4.4
通讯作者：
Olsson, T
中科院分区：
文献类型：
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作者：
Jagodic, M;Becanovic, K;Olsson, T
识别调控炎症性疾病的多态基因可能会揭开关键的致病机制。然而，在F、杂交或回交群体中使用连锁分析来定位这些基因的最初步骤，会导致包含数百个基因的广泛的数量性状基因座(QTL)。本研究利用先进的异交系与同源菌株相结合，对髓鞘少突胶质细胞糖蛋白诱导的实验性自身免疫性脑脊髓炎(EAE)大鼠10号染色体上的Eae18进行了精细定位。髓鞘少突胶质细胞糖蛋白诱导的EAE是一种慢性复发性疾病，与多发性硬化症的关键特征非常相似。同源DA.ACI大鼠品系将Eae18定位于类似于30-Mb的大区域。然后对由(DA×PVG.1AV1)F-7杂交组合组成的高级杂交组合进行精细定位，得到两个相邻的EAE调控QTL，分别命名为Eae18a和Eae18b。两个QTL的跨度分别为5.5和3Mb，而3-Mb的Eae18b只包含10个基因，包括一组趋化因子基因(CCL1、CCL2、CCL7和CCL11)。Eae18a和Eae18b分别与人类染色体17p13和17q11同线，两者都与多发性硬化症连锁。因此，Eae18至少由两个EAE调控基因组成，为疾病调控基因在QTL中的聚集是一种重要现象提供了进一步的证据。Eae18a和Eae18b与先前在人类和小鼠中发现的QTL之间的重叠进一步支持了炎症性疾病的易感等位基因在物种之间进化保守的观点。
Identification of polymorphic genes regulating inflammatory diseases may unravel crucial pathogenic mechanisms. Initial steps to map such genes using linkage analysis in F, intercross or backcross populations, however, result in broad quantitative trait loci (QTLs) containing hundreds of genes. In this study, an advanced intercross-line in combination with congenic strains, was used to fine-map Eae18 on rat chromosome 10 in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE). Myelin oligodendrocyte glycoprotein-induced EAE is a chronic relapsing disease that closely mimics key features of multiple sclerosis. Congenic DA.ACI rat strains localized Eae18 to an similar to30-Mb large region. Fine-mapping was then performed in an advanced intercross line consisting of a (DA X PVG.1AV1)F-7 intercross, resulting in two adjacent EAE-regulating QTLs designated Eae18a and Eae18b. The two QTLs span 5.5 and 3 Mb, respectively, and the 3-Mb Eae18b contains as few as 10 genes, including a cluster of chemokine genes (CCL1, CCL2, CCL7, and CCL11). Eae18a and Eae18b are syntenic to human chromosome 17p13 and 17q11, respectively, which both display linkage to multiple sclerosis. Thus, Eae18 consists of at least two EAE-regulating genes, providing additional evidence that clustering of disease-regulating genes in QTLs is an important phenomenon. The overlap between Eae18a and Eae18b with previously identified QTLs in humans and mice further supports the notion that susceptibility alleles in inflammatory disease are evolutionary conserved between species.