Congenic and bioinformatics analyses resolved a major-effect Fob3b QTL on mouse Chr 15 into two closely linked loci

Abstract

We previously identified a Chr 15 quantitative trait locus (QTL) Fob3b in lines of mice selected for high (Fat line) and low (Lean line) body fat content that represent a unique model of polygenic obesity. Here we genetically dissected the Fob3b interval by analyzing the phenotypes of eight overlapping congenic lines and four F(2) congenic intercrosses and prioritized candidates by bioinformatics approaches. Analyses revealed that the Fob3b QTL consists of at least two separate linked QTLs Fob3b1 and Fob3b2. They exhibit additive inheritance and are linked in coupling with alleles originating from the Lean line, decreasing obesity-related traits. In further analyses, we focused on Fob3b1 because it had a larger effect on obesity-related traits than Fob3b2, e.g., the difference between homozygotes for adiposity index (ADI) percentage was 1.22 and 0.77% for Fob3b1 and Fob3b2, respectively. A set of bioinformatics tools was used to narrow down positional candidates from 85 to 4 high-priority Fob3b1 candidates. A previous single Fob3b QTL was therefore resolved into another two closely linked QTLs, confirming the fractal nature of QTLs mapped at low resolution. The interval of the original Fob3b QTL was narrowed from 22.39 to 4.98 Mbp for Fob3b1 and to 7.68 Mbp for Fob3b2, which excluded the previously assigned candidate squalene epoxidase (Sqle) as the causal gene because it maps proximal to refined Fob3b1 and Fob3b2 intervals. A high-resolution map along with prioritization of Fob3b1 candidates by bioinformatics represents an important step forward to final identification of the Chr 15 obesity QTL.

Fine Mapping Reveals That Promotion Susceptibility Locus 1 (Psl1) Is a Compound Locus With Multiple Genes That Modify Susceptibility to Skin Tumor Development

“…In addition, GSTA4 has been shown to be a modifier of susceptibility to nonmelanoma skin cancer in humans (Abel et al 2010). As described in the current study, analyses of skin tumor promotion susceptibility using interval specific subcongenic mouse strains indicate that Psl1 is a compound locus made up of a cluster of subloci (see Figure 1), similar to other QTL affecting complex traits such as blood pressure (reviewed in Rapp and Joe 2012), diabetes (Granhall et al 2006), body composition (Diament and Warden 2004; Farber and Medrano 2007; Ishikawa et al 2007; Prevorsek et al 2010), and cancer (Samuelson et al 2005, 2007). Inheritance of Psl1.1a , Psl1.2a , Psl1.2b , and Gsta4 from DBA/2 results in increased susceptibility to skin tumor promotion whereas inheritance of Psl1.1b and Psl1.2c from DBA/2 results in decreased susceptibility.…”

Genome-wide association study for feed efficiency and growth traits in U.S. beef cattle

“…The largest-effect DMI QTL region (14_17 Mb; Table 4) included genes that have previously been associated with several aspects of feed efficiency ( NDUFB9 , RNF139 ) in beef cattle [28, 82] and Type 2 diabetes ( MTSS1 ) in humans [83]. Moreover, all of the positional candidate genes near the largest-effect DMI QTL (14_17 Mb; Table 4) were also immediately flanked by SQLE (14_16.7 Mb), a cholesterol biosynthesis enzyme previously implicated as a primary positional candidate for a large-effect obesity QTL in mice [84, 85]. Proximal to the second largest-effect SimAngus DMI QTL, we detected SV2B (21_16 Mb; Table 4), which may be involved in aspects of regulated insulin secretion [86], and has been associated with human weight-loss across a diverse array of dietary regimes [87].…”

Genetic identification of thiosulfate sulfurtransferase as an adipocyte-expressed antidiabetic target in mice selected for leanness

“…Lean mice (4% of body weight is fat mass) exhibit metabolically healthy leanness 4 , not lipodystrophy. The major quantitative trait loci (QTL) underlying divergent adiposity between Lean mice and their counter-selected Fat mouse line (23% of body weight is fat mass) were described 5, 6 , facilitating our search for positional candidate lean genes. Direct experimental evidence 7 and QTL mapping also ruled out known brain-regulated appetite and energy expenditure ( Lep , Lepr , Npy , Mc4r ) systems as driving adiposity divergence.…”