Untangling HDL quantitative trait loci on mouse chromosome 5 and identifying Scarb1 and Acads as the underlying genes
Untangling HDL quantitative trait loci on mouse chromosome 5 and identifying Scarb1 and Acads as the underlying genes
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解开小鼠 5 号染色体上的 HDL 数量性状位点，并将 Scarb1 和 Acads 识别为潜在基因
DOI：
10.1194/jlr.m008110
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发表时间：
2010-09-01
影响因子：
6.5
通讯作者：
Paigen, Beverly
中科院分区：
文献类型：
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作者：
Su, Zhiguang;Leduc, Magalie S.;Paigen, Beverly
先前在小鼠远端 5 号染色体上鉴定出两个高密度脂蛋白胆固醇数量性状位点 (QTL)：125 Mb 处的 Hdlq1 和 113 Mb 处的 Hdlq8。我们的目标是鉴定潜在基因。我们首先使用生物信息学将 Hdlq1 位点缩小到 56 个基因。最有可能的候选者是 Scarb1（清道夫受体 B1），其基因表达数据与基因敲除和转基因小鼠模型一致。然后，我们通过在 NZB 和 NZW (LOD = 12.7) 之间的杂交中检测到 Hdlq8 是一个独立的 QTL，这两种小鼠品系具有相同的 Scarb1 基因型。单倍型分析将该 QTL 缩小到 9 个基因；最有可能的候选者是 Acads（酰基辅酶 A 脱氢酶，短链）。测序表明Acads在保守区域具有氨基酸多态性Gly94Asp；蛋白质印迹显示亲本菌株之间的蛋白质水平存在显着差异。先前已知的自发缺失会导致 BALB/cBy 小鼠 ACADS 活性丧失。我们发现，与 BALB/c 小鼠相比，BALB/cBy 小鼠的 HDL 水平显着升高，并且这种 HDL 差异与 Acads 突变共分离。我们证实 Hdlq1 和 Hdlq8 是小鼠 5 号染色体上的独立 QTL，并证明 Scarb1 和 Acads 是潜在基因。
Two high-density lipoprotein cholesterol quantitative trait loci (QTL), Hdlq1 at 125 Mb and Hdlq8 at 113 Mb, were previously identified on mouse distal chromosome 5. Our objective was to identify the underlying genes. We first used bioinformatics to narrow the Hdlq1 locus to 56 genes. The most likely candidate, Scarb1 (scavenger receptor B1), was supported by gene expression data consistent with knockout and transgenic mouse models. Then we confirmed Hdlq8 as an independent QTL by detecting it in an intercross between NZB and NZW (LOD = 12.7), two mouse strains that have identical genotypes for Scarb1. Haplotyping narrowed this QTL to 9 genes; the most likely candidate was Acads (acyl-coenzymeA dehydrogenase, short chain). Sequencing showed that Acads had an amino acid polymorphism, Gly94Asp, in a conserved region; Western blotting showed that protein levels were significantly different between parental strains. A previously known spontaneous deletion causes loss of ACADS activity in BALB/cBy mice. We showed that HDL levels were significantly elevated in BALB/cBy compared with BALB/c mice and that this HDL difference cosegregated with the Acads mutation. We confirmed that Hdlq1 and Hdlq8 are independent QTL on mouse chromosome 5 and demonstrated that Scarb1 and Acads are the underlying genes.