Intersubspecific subcongenic mouse strain analysis reveals closely linked QTLs with opposite effects on body weight

Abstract

A previous genome-wide QTL study revealed many QTLs affecting postnatal body weight and growth in an intersubspecific backcross mouse population between the C57BL/6J (B6) strain and wild Mus musculus castaneus mice captured in the Philippines. Subsequently, several closely linked QTLs for body composition traits were revealed in an F(2) intercross population between B6 and B6.Cg-Pbwg1, a congenic strain on the B6 genetic background carrying the growth QTL Pbwg1 on proximal chromosome 2. However, no QTL affecting body weight has been duplicated in the F(2) population, except for mapping an overdominant QTL that causes heterosis of body weight. In this study, we developed 17 intersubspecific subcongenic strains with overlapping and nonoverlapping castaneus regions from the B6.Cg-Pbwg1 congenic strain in order to search for and genetically dissect QTLs affecting body weight into distinct closely linked loci. Phenotypic comparisons of several developed subcongenic strains with the B6 strain revealed that two closely linked but distinct QTLs that regulate body weight, named Pbwg1.11 and Pbwg1.12, are located on an 8.9-Mb region between D2Mit270 and D2Mit472 and on the next 3.6-Mb region between D2Mit205 and D2Mit182, respectively. Further analyses using F(2) segregating populations obtained from intercrosses between B6 and each of the two selected subcongenic strains confirmed the presence of these two body weight QTLs. Pbwg1.11 had an additive effect on body weight at 6, 10, and 13 weeks of age, and its castaneus allele decreased it. In contrast, the castaneus allele at Pbwg1.12 acted in a dominant fashion and surprisingly increased body weight at 6, 10, and 13 weeks of age despite the body weight of wild castaneus mice being 60% of that of B6 mice. These findings illustrate the complex genetic nature of body weight regulation and support the importance of subcongenic mouse analysis to dissect closely linked loci.

Linkage Relationships Among Multiple QTL for Horticultural Traits and Late Blight (P. infestans) Resistance on Chromosome 5 Introgressed from Wild TomatoSolanum habrochaites

“…Plant shape had the most complex genetic architecture, being controlled by four QTL with alternating direction of allelic effect. Similar genetic complexity, including multiple closely linked QTL with varying direction of allelic effects, has previously been reported for higher-resolution mapping of QTL in maize (Graham et al 1997), Drosophila melanogaster (Pasyukova et al 2000; De Luca et al 2003), mice (Mollah and Ishikawa 2011), and rat (Granhall et al 2006). …”

Genetics of Rapid and Extreme Size Evolution in Island Mice

“…Although our judgment of QTL overlap is rough, this result suggests that the evolution of body size involved different genetic changes in GI mice and laboratory strains. This conclusion is bolstered by comparisons to other QTL known to affect body weight in mice (Dragani et al 1995;Cheverud et al 1996;Keightley et al 1996;Rance et al 1997;Brockmann et al 1998Brockmann et al , 2004Kirkpatrick et al 1998;Morris et al 1999;Vaughn et al 1999;Corva and Medrano 2001;Rocha et al 2004;Bennett et al 2005;Kenney-Hunt et al 2006;Shao et al 2007;Casellas et al 2009;Mollah and Ishikawa 2011;Ishikawa and Okuno 2014). Although a few of these QTL overlap with those we identified, most do not.…”

“…Genetic correlations between age-specific body weights decline with increasing time between ages (Cheverud et al 1983a;Riska et al 1984). Many QTL that contribute to body weight differences between laboratory mouse strains have been identified (Dragani et al 1995;Cheverud et al 1996;Keightley et al 1996;Rance et al 1997;Brockmann et al 1998Brockmann et al , 2004Kirkpatrick et al 1998;Morris et al 1999;Vaughn et al 1999;Corva and Medrano 2001;Rocha et al 2004; Bennett et al 2005; KenneyHunt et al 2006;Shao et al 2007;Casellas et al 2009;Mollah and Ishikawa 2011;Ishikawa and Okuno 2014). A common pattern is that strain differences in weight and growth rate are due to a large number of loci with modest phenotypic effects.…”

Nonrandom X Chromosome Inactivation Is Influenced by Multiple Regions on the Murine X Chromosome

“…Our results could be explained by an Xce locus that promotes preferential XCI of the Cast allele rather than the 129S1 allele [ Figure 5B(3)]. Closely linked loci may have opposite effects as was reported for QTL on chromosome 2 that affect body weight (Mollah and Ishikawa 2011). We cannot rule out that this trend is due to background effects in the RX1-and RX2-derived mice but because we observed this trend in both RX1-and RX2-derived mice, which were generated and maintained in different backgrounds (Figure 1), an X-linked locus may best explain our observation.…”