Data for Mouse Phenome Database_Reed_Bachmanov_June_2015

Contains body composition data for consomic mic

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 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

Adiposity QTL <i>Adip20</i> decomposes into at least four loci when dissected using congenic strains

<div><p>An average mouse in midlife weighs between 25 and 30 g, with about a gram of tissue in the largest adipose depot (gonadal), and the weight of this depot differs between inbred strains. Specifically, C57BL/6ByJ mice have heavier gonadal depots on average than do 129P3/J mice. To understand the genetic contributions to this trait, we mapped several quantitative trait loci (QTLs) for gonadal depot weight in an F₂ intercross population. Our goal here was to fine-map one of these QTLs, <i>Adip20</i> (formerly <i>Adip5</i>), on mouse chromosome 9. To that end, we analyzed the weight of the gonadal adipose depot from newly created congenic strains. Results from the sequential comparison method indicated at least four rather than one QTL; two of the QTLs were less than 0.5 Mb apart, with opposing directions of allelic effect. Different types of evidence (missense and regulatory genetic variation, human adiposity/body mass index orthologues, and differential gene expression) implicated numerous candidate genes from the four QTL regions. These results highlight the value of mouse congenic strains and the value of this sequential method to dissect challenging genetic architecture.</p></div

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

Human genome-wide associations within mouse QTLs for adiposity and body mass index.

<p>Human genome-wide associations within mouse QTLs for adiposity and body mass index.</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

QTL effects.

<p>The least square means (dark red lines) and 95% lower and upper confidence limits (blue lines) for QTL genotypes were obtained from the general linear model with body weight as covariate in the congenic mouse data used for the sequential analyses. We selected one marker in the middle of each QTL to plot each QTL effect. The host (A) comprised littermates homozygous for B6/B6 from all strains; we selected appropriate congenic mice (H) as suggested by the results of the sequential analysis.</p

Gonadal adipose depot.

<p>Anatomical location of the gonadal adipose depot in a male mouse.</p

Detection of gonadal adipose depot weight QTLs on chromosome 9 by association analyses of a pooled congenic population.

<p>(<b>A</b>) Location of the markers in Mb on mouse chromosome 9 (mChr9); the y-axis is the—log p-values (black line) obtained in a general linear regression model analysis with body weight and strain as covariates (red line, significant threshold; gray line, suggestive). We defined the QTL confidence intervals by two units of—log10 p-value drop from the peak (blue line). For QTL1-QTL4 (Q1-Q4), the shaded peak areas correspond to QTL regions defined by the sequential method. (<b>B and C</b>) Average weight of the gonadal adipose depot by genotype (B6/B6, B6/129; <b>B</b>) and Cohen’s <i>D</i> effect size (<b>C</b>) of <i>rs3723670</i>, the most associated marker (i.e., the marker with the lowest p value). *p<0.0001, difference between genotypes.</p