Fine Mapping and Candidate Gene Search of Quantitative Trait Loci for Growth and Obesity Using Mouse Intersubspecific Subcongenic Intercrosses and Exome Sequencing

<div><p>Although growth and body composition traits are quantitative traits of medical and agricultural importance, the genetic and molecular basis of those traits remains elusive. Our previous genome-wide quantitative trait locus (QTL) analyses in an intersubspecific backcross population between C57BL/6JJcl (B6) and wild <i>Mus musculus castaneus</i> mice revealed a major growth QTL (named <i>Pbwg1</i>) on a proximal region of mouse chromosome 2. Using the B6.Cg-<i>Pbwg1</i> intersubspecific congenic strain created, we revealed 12 closely linked QTLs for body weight and body composition traits on an approximately 44.1-Mb wild-derived congenic region. In this study, we narrowed down genomic regions harboring three (<i>Pbwg1.12</i>, <i>Pbwg1.3</i> and <i>Pbwg1.5</i>) of the 12 linked QTLs and searched for possible candidate genes for the QTLs. By phenotypic analyses of F₂ intercross populations between B6 and each of four B6.Cg-<i>Pbwg1</i> subcongenic strains with overlapping and non-overlapping introgressed regions, we physically defined <i>Pbwg1.12</i> affecting body weight to a 3.8-Mb interval (61.5–65.3 Mb) on chromosome 2. We fine-mapped <i>Pbwg1.3</i> for body length to an 8.0-Mb interval (57.3–65.3) and <i>Pbwg1.5</i> for abdominal white fat weight to a 2.1-Mb interval (59.4–61.5). The wild-derived allele at <i>Pbwg1.12</i> and <i>Pbwg1.3</i> uniquely increased body weight and length despite the fact that the wild mouse has a smaller body size than that of B6, whereas it decreased fat weight at <i>Pbwg1.5</i>. Exome sequencing and candidate gene prioritization suggested that <i>Gcg</i> and <i>Grb14</i> are putative candidate genes for <i>Pbwg1.12</i> and that <i>Ly75</i> and <i>Itgb6</i> are putative candidate genes for <i>Pbwg1.5</i>. These genes had nonsynonymous SNPs, but the SNPs were predicted to be not harmful to protein functions. These results provide information helpful to identify wild-derived quantitative trait genes causing enhanced growth and resistance to obesity.</p>