Abstract
It is still challenging to identify causal genes governing obesity. Pbwg1.5, a quantitative trait locus (QTL) for resistance to obesity, was previously discovered from wild Mus musculus castaneus mice and was fine-mapped to a 2.1-Mb genomic region of mouse chromosome 2, where no known gene with an effect on white adipose tissue (WAT) has been reported. The aim of this study was to identify a strong candidate gene for Pbwg1.5 by an integration approach of transcriptome analysis (RNA-sequencing followed by real-time PCR analysis) and the causal inference test (CIT), a statistical method to infer causal relationships between diplotypes, gene expression and trait values. Body weight, body composition and biochemical traits were measured in F2 mice obtained from an intercross between the C57BL/6JJcl strain and a congenic strain carrying Pbwg1.5 on the C57BL/6JJcl background. The F2 mice showed significant diplotype differences in 12 traits including body weight, WAT weight and serum cholesterol/triglyceride levels. The transcriptome analysis revealed that Ly75, Pla2r1, Fap and Gca genes were differentially expressed in the liver and that Fap, Ifih1 and Grb14 were differentially expressed in WAT. However, CITs indicated statistical evidence that only the liver Ly75 gene mediated between genotype and WAT. Ly75 expression was negatively associated with WAT weight. The results suggested that Ly75 is a putative quantitative trait gene for the obesity-resistant Pbwg1.5 QTL discovered from the wild M. m. castaneus mouse. The finding provides a novel insight into a better understanding of the genetic basis for prevention of obesity.
Highlights
Genome-wide quantitative trait locus (QTL) mapping is performed on the basis of either association analysis in outbred populations (called a genome-wide association study (GWAS)) or linkage analysis in three-generation pedigrees or designed crosses
We previously revealed 24 QTLs with main effects and/or epistatic interaction effects on postnatal body weight and growth in mice by genome-wide QTL analyses with an intersubspecific backcross population between C57BL/6JJcl (B6), a commonly used inbred strain prone to obesity and type 2 diabetes [8], and wild Mus musculus castaneus mice trapped live in Luzon Island, the Philippines [9,10,11]
The integration approach of gene expression and the causal inference test (CIT) clearly demonstrated that the Ly75 gene is the mediator between diplotype and white adipose tissue (WAT) weight, indicating that Ly75 is a strong candidate gene for the Pbwg1.5 QTL discovered from an untapped natural resource of wild M. m. castaneus mice in the Philippines
Summary
The aim of this study was to identify a strong candidate gene for Pbwg1.5 by an integration approach of transcriptome analysis (RNA-sequencing followed by real-time PCR analysis) and the causal inference test (CIT), a statistical method to infer causal relationships between diplotypes, gene expression and trait values. The aim of the present study was to identify strong candidate genes for two QTLs using an integration approach of transcriptome analysis and the causal inference test (CIT) [18], a statistical method to infer causal relationships between genotype, gene expression and phenotypic difference
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