Department for Crop and Animal Sciences, Albrecht Daniel Thaer-Institute of Agricultural and Horticultural Sciences Humboldt-Universität Zu Berlin, Unter den Linden 6, 10099, Berlin, Germany.
Sci Rep. 2022 Jun 21;12(1):10471. doi: 10.1038/s41598-022-14316-5.
The Berlin Fat Mouse Inbred line (BFMI) is a model for obesity and the metabolic syndrome. This study aimed to identify genetic variants associated with liver weight, liver triglycerides, and body weight using the obese BFMI sub-line BFMI861-S1. BFMI861-S1 mice are insulin resistant and store ectopic fat in the liver. In generation 10, 58 males and 65 females of the advanced intercross line (AIL) BFMI861-S1xB6N were phenotyped under a standard diet over 20 weeks. QTL analysis was performed after genotyping with the MiniMUGA Genotyping Array. Whole-genome sequencing and gene expression data of the parental lines was used for the prioritization of positional candidate genes. Three QTLs associated with liver weight, body weight, and subcutaneous adipose tissue (scAT) weight were identified. A highly significant QTL on chromosome (Chr) 1 (157-168 Mb) showed an association with liver weight. A QTL for body weight at 20 weeks was found on Chr 3 (34.1-40 Mb) overlapping with a QTL for scAT weight. In a multiple QTL mapping approach, an additional QTL affecting body weight at 16 weeks was identified on Chr 6 (9.5-26.1 Mb). Considering sequence variants and expression differences, Sec16b and Astn1 were prioritized as top positional candidate genes for the liver weight QTL on Chr 1; Met and Ica1 for the body weight QTL on Chr 6. Interestingly, all top candidate genes have previously been linked with metabolic traits. This study shows once more the power of an advanced intercross line for fine mapping. QTL mapping combined with a detailed prioritization approach allowed us to identify additional and plausible candidate genes linked to metabolic traits in the BFMI861-S1xB6N AIL. By reidentifying known candidate genes in a different crossing population the causal link with specific traits is underlined and additional evidence is given for further investigations.
柏林肥胖小鼠近交系(BFMI)是肥胖和代谢综合征的模型。本研究旨在使用肥胖 BFMI 亚系 BFMI861-S1 鉴定与肝重、肝甘油三酯和体重相关的遗传变异。BFMI861-S1 小鼠存在胰岛素抵抗,并且异位储存脂肪在肝脏中。在第 10 代,65 只雄性和 58 只雌性 BFMI861-S1xB6N 先进的近交系(AIL)在标准饮食下进行表型分析,为期 20 周。使用 MiniMUGA 基因分型阵列进行基因分型后,进行了 QTL 分析。对亲本系的全基因组测序和基因表达数据进行了优先级排序,以确定位置候选基因。鉴定出与肝重、体重和皮下脂肪组织(scAT)重量相关的三个 QTL。第 1 号染色体(Chr)1(157-168 Mb)上的一个高度显著 QTL 与肝重相关。在 Chr 3(34.1-40 Mb)上发现了一个与 scAT 重量相关的 20 周体重 QTL。在多 QTL 映射方法中,在 Chr 6(9.5-26.1 Mb)上鉴定出了另一个影响 16 周体重的 QTL。考虑到序列变异和表达差异,Sec16b 和 Astn1 被优先考虑为 Chr 1 上肝重 QTL 的最佳位置候选基因;Met 和 Ica1 为 Chr 6 上体重 QTL 的最佳位置候选基因。有趣的是,所有的顶级候选基因以前都与代谢特征有关。本研究再次展示了先进的近交系进行精细作图的强大功能。QTL 作图与详细的优先级排序方法相结合,使我们能够鉴定出与 BFMI861-S1xB6N AIL 代谢特征相关的其他和合理的候选基因。通过在不同的杂交群体中重新鉴定已知的候选基因,强调了与特定特征的因果关系,并为进一步的研究提供了更多的证据。