QTL mapping in an advance intercross line of the Berlin Fat Mouse identifies candidate genes for the metabolic syndrome

Background and aim The Berlin Fat Mouse Inbred line (BFMI) is a model for obesity and related pathologies such as insulin resistance and fatty liver. The aim of this study was to identify genetic variants associated with traits of the metabolic syndrome using two sub-strains of the BFMI (BFMI861-S1 and BFMI861-S2). These lines are genetically close related but differ in several phenotypes (e. g. insulin resistance and body weight).

Methods An advanced intercross line (AIL) was generated from the cross BFMI861-S1 x BFMI861-S2. In generation 10, 397 male mice were extensively phenotyped over 25 weeks. To perform QTL-analysis, selective genotyping of 200 mice was performed using the GigaMUGA SNP chip. For candidate prioritization, ranking was performed using whole genome sequencing data and gene expression data of the parental lines.

Results Overlapping QTLs were detected on chromosome 3 (93,516,258–101,097,858) for gonadal adipose tissue weight and final blood glucose, and on chromosome 17 (7,725,897–26,054,796) for gonadal adipose tissue weight, liver weight, and final blood glucose. Additional QTLs are located on chromosome 7 (16,692,359–17,022,025) for liver triglycerides and on chromosome 16 (3,892,297-21,355,904) for final body weight. The highest ranked candidate genes are Hsd3b2, Fmo5 and Notch2 (chr 3); Ptgir and Pnmal1 (chr 7); Trap1 and Rrn3 (chr 16); Fam120b, Map3k4, Plg, Acat2, and Ift140 (chr 17) of which several were confirmed by literature.

Conclusion The combination of QTL mapping with a detailed prioritization approach allowed us to identify candidate genes that could contribute for the development of the metabolic syndrome.

Publication History

Article published online:
06 May 2021