Epistatic interactions of genes influence within-individual variation of physical activity traits in mice

A number of quantitative trait loci (QTLs) recently have been discovered that affect various activity traits in mice, but their collective impact does not appear to explain the consistently moderate to high heritabilities for these traits. We previously suggested interactions of genes, or epistasis, might account for additional genetic variability of activity, and tested this for the average distance, duration and speed run by mice during a 3 week period. We found abundant evidence for epistasis affecting these traits, although, recognized that epistatic effects may well vary within individuals over time. We therefore conducted a full genome scan for epistatic interactions affecting these traits in each of seven three-day intervals. Our intent was to assess the extent and trends in epistasis affecting these traits in each of the intervals. We discovered a number of epistatic interactions of QTLs that influenced the activity traits in the mice, the majority of which were not previously found and appeared to affect the activity traits (especially distance and speed) primarily in the early or in the late age intervals. The overall impact of epistasis was considerable, its contribution to the total phenotypic variance varying from an average of 22–35% in the three traits across all age intervals. It was concluded that epistasis is more important than single-locus effects of genes on activity traits at specific ages and it is therefore an essential component of the genetic architecture of physical activity

Sex-, Diet-, and Cancer-Dependent Epistatic Effects on Complex Traits in Mice

The genetic basis of quantitative traits such as body weight and obesity is complex, with several hundred quantitative trait loci (QTLs) known to affect these and related traits in humans and mice. It also has become increasingly evident that the single-locus effects of these QTLs vary considerably depending on factors such as the sex of the individuals and their dietary environment, and we were interested to know whether this context-dependency also applies to two-locus epistatic effects of QTLs as well. We therefore conducted a genome scan to search for epistatic effects on 13 different weight and adiposity traits in an F2 population of mice (created from an original intercross of the FVB strain with M16i, a polygenic obesity model) that were fed either a control or a high-fat diet and half of which harbored a transgene (PyMT) that caused the development of metastatic mammary cancer. We used a conventional interval mapping approach with SNPs to scan all 19 autosomes, and found extensive epistasis affecting all of these traits. More importantly, we also discovered that the majority of these epistatic effects exhibited significant interactions with sex, diet, and/or presence of PyMT. Analysis of these interactions showed that many of them appeared to involve QTLs previously identified as affecting these traits, but whose single-locus effects were variously modified by two-locus epistatic effects of other QTLs depending on the sex, diet, or PyMT environment. It was concluded that this context-dependency of epistatic effects is an important component of the genetic architecture of complex traits such as those contributing to weight and obesity

Genetic variation for body weight change in mice in response to physical exercise

Abstract Background Physical activity is beneficial in reducing the weight gain and associated health problems often experienced by individuals as they age, but the association of weight change with physical activity remains complex. We tested for a possible genetic basis for this association between 9-12-week body weight change (WTC) and the distance, duration, and speed voluntarily run by 307 mice in an F2 population produced from an intercross of two inbred strains (C57L/J and C3H/HeJ) that differed dramatically in their physical activity levels. Results In this population WTC did show the expected negative association with the physical activity traits, but only the phenotypic correlation of WTC with speed (-0.18) reached statistical significance. Using an interval mapping approach with single-nucleotide polymorphism markers, we discovered five (four suggestive and one significant) quantitative trait loci (QTLs) affecting body weight change, only one of which appeared to show pleiotropic effects on the physical activity traits as well. Genome-wide epistasis scans also detected several pairwise interactions of QTLs with pleiotropic effects on WTC and the physical activity traits, but these effects made a significant contribution (51%) only to the covariance of WTC with speed. Conclusion It was concluded that the genetic contribution to the phenotypic association between WTC and the physical activity traits in this population of mice was primarily epistatic in origin, restricted to one measure of physical activity, and could be quite variable among different populations depending on the genetic background, experimental design and traits assessed

Sex dependent imprinting effects on complex traits in mice

BACKGROUND: Genomic imprinting is an epigenetic source of variation in quantitative traits that results from monoallelic gene expression, where commonly either only the paternally- or the maternally-derived allele is expressed. Imprinting has been shown to affect a diversity of complex traits in a variety of species. For several such quantitative traits sex-dependent genetic effects have been discovered, but whether imprinting effects also show such sex-dependence has yet to be explored. Moreover, theoretical work on the evolution of sex-dependent genomic imprinting effects makes specific predictions about the phenotypic patterns of such effects, which, however, have not been assessed empirically to date. RESULTS: Using a genome-scan for loci affecting a set of complex growth and body composition traits from an intercross between two divergent mouse strains, we investigated possible sex-dependent imprinting effects. Our results demonstrate for the first time the existence of genomic imprinting effects that depend on sex and are not related to sex-chromosome effects. We detected a total of 13 loci on 11 chromosomes that showed significant differences between the sexes in imprinting effects. Most loci showed imprinting effects in only one sex, with eight imprinted effects found in males and six in females. One locus showed sex-dependent imprinting effects in both sexes for different traits. The absence of an imprinting effect in one sex was not necessarily indicative of the overall inactivity of the locus in that sex, as for several loci a significant additive or dominance effect was detected. Moreover, three loci exhibited significant additive effects in both sexes but their imprinting effect was restricted to one sex. CONCLUSION: Our results clearly show that imprinting effects can be sex-dependent and also suggest that new candidate imprinted loci can be detected when taking account of sex-specific imprinting effects. However, predictions made about the evolution of sex-dependent imprinting effects and associated phenotypic patterns cannot be unequivocally supported at present and further research into the selection pressures applied to the strains of mice used in our study is required

Quantitative trait loci for physical activity traits in mice

The genomic locations and identities of the genes that regulate voluntary physical activity are presently unknown. The purpose of this study was to search for quantitative trait loci (QTL) that are linked with daily mouse running wheel distance, duration, and speed of exercise. F2 animals (n = 310) derived from high active C57L/J and low active C3H/HeJ inbred strains were phenotyped for 21 days. After phenotyping, genotyping with a fully informative single-nucleotide polymorphism panel with an average intermarker interval of 13.7 cM was used. On all three activity indexes, sex and strain were significant factors, with the F2 animals similar to the high active C57L/J mice in both daily exercise distance and duration of exercise. In the F2 cohort, female mice ran significantly farther, longer, and faster than male mice. QTL analysis revealed no sex-specific QTL but at the 5% experimentwise significance level did identify one QTL for duration, one QTL for distance, and two QTL for speed. The QTL for duration (DUR13.1) and distance (DIST13.1) colocalized with the QTL for speed (SPD13.1). Each of these QTL accounted for ∼6% of the phenotypic variance, whereas SPD9.1 (chromosome 9, 7 cM) accounted for 11.3% of the phenotypic variation. DUR13.1, DIST13.1, SPD13.1, and SPD9.1 were subsequently replicated by haplotype association mapping. The results of this study suggest a genetic basis of voluntary activity in mice and provide a foundation for future candidate gene studies

Quantitative trait loci for energy balance traits in an advanced intercross line derived from mice divergently selected for heat loss

Obesity in human populations, currently a serious health concern, is considered to be the consequence of an energy imbalance in which more energy in calories is consumed than is expended. We used interval mapping techniques to investigate the genetic basis of a number of energy balance traits in an F11 advanced intercross population of mice created from an original intercross of lines selected for increased and decreased heat loss. We uncovered a total of 137 quantitative trait loci (QTLs) for these traits at 41 unique sites on 18 of the 20 chromosomes in the mouse genome, with X-linked QTLs being most prevalent. Two QTLs were found for the selection target of heat loss, one on distal chromosome 1 and another on proximal chromosome 2. The number of QTLs affecting the various traits generally was consistent with previous estimates of heritabilities in the same population, with the most found for two bone mineral traits and the least for feed intake and several body composition traits. QTLs were generally additive in their effects, and some, especially those affecting the body weight traits, were sex-specific. Pleiotropy was extensive within trait groups (body weights, adiposity and organ weight traits, bone traits) and especially between body composition traits adjusted and not adjusted for body weight at sacrifice. Nine QTLs were found for one or more of the adiposity traits, five of which appeared to be unique. The confidence intervals among all QTLs averaged 13.3 Mb, much smaller than usually observed in an F2 cross, and in some cases this allowed us to make reasonable inferences about candidate genes underlying these QTLs. This study combined QTL mapping with genetic parameter analysis in a large segregating population, and has advanced our understanding of the genetic architecture of complex traits related to obesity.Peer reviewe

A search for quantitative trait loci controlling within-individual variation of physical activity traits in mice

<p>Abstract</p> <p>Background</p> <p>In recent years it has become increasingly apparent that physical inactivity can predispose individuals to a host of health problems. While many studies have analyzed the effect of various environmental factors on activity, we know much less about the genetic control of physical activity. Some studies in mice have discovered quantitative trait loci (QTL) influencing various physical activity traits, but mostly have analyzed inter-individual variation rather than variation in activity within individuals over time. We conducted a genome scan to identify QTLs controlling the distance, duration, and time run by mice over seven consecutive three-day intervals in an F₂population created by crossing two inbred strains (C57L/J and C3H/HeJ) that differed widely (average of nearly 300%) in their activity levels. Our objectives were (a) to see if we would find QTLs not originally discovered in a previous investigation that assessed these traits over the entire 21-day period and (b) to see if some of these QTLs discovered might affect the activity traits only in the early or in the late time intervals.</p> <p>Results</p> <p>This analysis uncovered 39 different QTLs, over half of which were new. Some QTLs affected the activity traits only in the early time intervals and typically exhibited significant dominance effects whereas others affected activity only in the later age intervals and exhibited less dominance. We also analyzed the regression slopes of the activity traits over the intervals, and found several QTLs affecting these traits that generally mapped to unique genomic locations.</p> <p>Conclusions</p> <p>It was concluded that the genetic architecture of physical activity in mice is much more complicated than has previously been recognized, and may change considerably depending on the age at which various activity measures are assessed.</p

Genetic variation in the pleiotropic association between physical activity and body weight in mice

<p>Abstract</p> <p>Background</p> <p>A sedentary lifestyle is often assumed to lead to increases in body weight and potentially obesity and related diseases but in fact little is known about the genetic association between physical activity and body weight. We tested for such an association between body weight and the distance, duration, and speed voluntarily run by 310 mice from the F₂generation produced from an intercross of two inbred lines that differed dramatically in their physical activity levels.</p> <p>Methods</p> <p>We used a conventional interval mapping approach with SNP markers to search for QTLs that affected both body weight and activity traits. We also conducted a genome scan to search for relationship QTLs (<it>rel</it>QTLs), or chromosomal regions that affected an activity trait variably depending on the phenotypic value of body weight.</p> <p>Results</p> <p>We uncovered seven quantitative trait loci (QTLs) affecting body weight, but only one co-localized with another QTL previously found for activity traits. We discovered 19 <it>rel</it>QTLs that provided evidence for a genetic (pleiotropic) association of physical activity and body weight. The three genotypes at each of these loci typically exhibited a combination of negative, zero, and positive regressions of the activity traits on body weight, the net effect of which was to produce overall independence of body weight from physical activity. We also demonstrated that the <it>rel</it>QTLs produced these varying associations through differential epistatic interactions with a number of other epistatic QTLs throughout the genome.</p> <p>Conclusion</p> <p>It was concluded that individuals with specific combinations of genotypes at the <it>rel</it>QTLs and <it>epi</it>QTLs might account for some of the variation typically seen in plots of the association of physical activity with body weight.</p