Body Composition QTLs Identified in Intercross Populations Are Reproducible in Consomic Mouse Strains.

Genetic variation contributes to individual differences in obesity, but defining the exact relationships between naturally occurring genotypes and their effects on fatness remains elusive. As a step toward positional cloning of previously identified body composition quantitative trait loci (QTLs) from F2 crosses of mice from the C57BL/6ByJ and 129P3/J inbred strains, we sought to recapture them on a homogenous genetic background of consomic (chromosome substitution) strains. Male and female mice from reciprocal consomic strains originating from the C57BL/6ByJ and 129P3/J strains were bred and measured for body weight, length, and adiposity. Chromosomes 2, 7, and 9 were selected for substitution because previous F2 intercross studies revealed body composition QTLs on these chromosomes. We considered a QTL confirmed if one or both sexes of one or both reciprocal consomic strains differed significantly from the host strain in the expected direction after correction for multiple testing. Using these criteria, we confirmed two of two QTLs for body weight (Bwq5-6), three of three QTLs for body length (Bdln3-5), and three of three QTLs for adiposity (Adip20, Adip26 and Adip27). Overall, this study shows that despite the biological complexity of body size and composition, most QTLs for these traits are preserved when transferred to consomic strains; in addition, studying reciprocal consomic strains of both sexes is useful in assessing the robustness of a particular QTL

Data for Mouse Phenome Database_Reed_Bachmanov_June_2015

Contains body composition data for consomic mic

Data from: Body composition QTLs identified in intercross populations are reproducible in consomic mouse strains

Genetic variation contributes to individual differences in obesity, but defining the exact relationships between naturally occurring genotypes and their effects on fatness remains elusive. As a step toward positional cloning of previously identified body composition quantitative trait loci (QTLs) from F2 crosses of mice from the C57BL/6ByJ and 129P3/J inbred strains, we sought to recapture them on a homogenous genetic background of consomic (chromosome substitution) strains. Male and female mice from reciprocal consomic strains originating from the C57BL/6ByJ and 129P3/J strains were bred and measured for body weight, length, and adiposity. Chromosomes 2, 7, and 9 were selected for substitution because previous F2 intercross studies revealed body composition QTLs on these chromosomes. We considered a QTL confirmed if one or both sexes of one or both reciprocal consomic strains differed significantly from the host strain in the expected direction after correction for multiple testing. Using these criteria, we confirmed two of two QTLs for body weight (Bwq5-6), three of three QTLs for body length (Bdln3-5), and three of three QTLs for adiposity (Adip20, Adip26 and Adip27). Overall, this study shows that despite the biological complexity of body size and composition, most QTLs for these traits are preserved when transferred to consomic strains; in addition, studying reciprocal consomic strains of both sexes is useful in assessing the robustness of a particular QTL

QTL confirmation from the consomic strains.

<p>Confirmation criterion–one or more sexes and one or more reciprocal strains differed in the expected direction using a p-value threshold adjusted for multiple testing (see <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141494#pone.0141494.t003" target="_blank">Table 3</a></b>). <i>Bdln4</i> and <i>Bdln5</i> are combined because they are both on chromosome 9.</p

QTLs detection in consomic mice: Average values of body size and composition measures in inbred and consomics strains.

<p>Body weight (top), body length (middle), and adiposity (bottom) in inbred and consomic strains (means ± SEM). Left panels: Strains with 129 genetic background. Right panels: Strains with B6 genetic background. Asterisks (*) indicate a nominal difference between consomic strain and its inbred host (p < .0.05), # indicates significant after correction for multiple testing (p<0.0056). ^~p = 0.0545. ^&borderline significance. ^§mice are heavier (top panel) but have similar gonadal weight, thus are leaner after adjustment for body weight.</p

Comparison of sex-specific QTLs between F₂ crosses and consomic strains.

<p>Differences between consomic and inbred host strains are indicated by:</p><p>x, p≥0.05 (no significant differences)</p><p>√, p<0.05 (a nominal p-value)</p><p>√√. p = 0.0545 (an adjusted p-value; <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141494#pone.0141494.t003" target="_blank">Table 3</a></b>).</p><p>QTL type was determined in F₂ crosses.</p

Inbred and consomic mouse strains used in this study.

<p>* Identification numbers (ID) are shown for strains available from the Jackson Laboratory (JAX; <a href="http://jaxmice.jax.org/" target="_blank">http://jaxmice.jax.org</a>) and the Mutant Mouse Regional Resource Center (MMRRC; <a href="https://www.mmrrc.org/" target="_blank">https://www.mmrrc.org</a>).</p><p>^# ‘Mon’ within mouse strain name is a laboratory code for the Monell Chemical Senses Center issued by the Institute for Laboratory Animal Research (ILAR; <a href="http://dels.nas.edu/ilar_n/ilarhome/labcode.shtml" target="_blank">http://dels.nas.edu/ilar_n/ilarhome/labcode.shtml</a>).</p><p>Abbreviations: F = female; M = male; M = mean; SD = standard deviation; d = days; n/a = not applicable</p

QTLs originally detected in F₂ hybrids.

<p>* Adiposity is defined as the weight of the gonadal adipose depot relative to body size [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141494#pone.0141494.ref019" target="_blank">19</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141494#pone.0141494.ref021" target="_blank">21</a>]. However a study using percent body fat [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141494#pone.0141494.ref022" target="_blank">22</a>] is included here for reference because both these fatness measures are closely related and thus informative.</p><p><i># cM</i> positions as provided in the original report.</p><p>^<i>§</i> formerly referred to as <i>Adip5</i> [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141494#pone.0141494.ref019" target="_blank">19</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141494#pone.0141494.ref020" target="_blank">20</a>].</p><p>^ observed when mice were fed a high-fat diet (mice ate a low-fat mouse chow diet in the other studies referenced in this table).</p><p>F₂%var = % trait variance in F₂ explained by the QTL; estimates are not available (NA) for all QTLs from all prior studies. Ref = reference.</p