"Get a Grip on Hypertension": EXPLORING THE USE OF ISOMETRIC HANDGRIP TRAINING IN CARDIOPULMONARY REHABILITATION PATIENTS.

PURPOSE: Isometric handgrip (IHG) training lowers systolic and diastolic blood pressure (SBP and DBP, respectively), but the efficacy of IHG training in cardiopulmonary rehabilitation patients is unknown. The purpose of this study was to determine if IHG decreases blood pressure in cardiopulmonary rehabilitation patients. METHODS: Cardiopulmonary rehabilitation program participants (n = 11; 50-80 yr old) were randomized to IHG (n = 6) or control (CON; no treatment; n = 5) groups. IHG participants completed an IHG training program at 30% maximal voluntary contraction, 3 d/wk for 6 wk. Resting SBP, DBP, and heart rate were assessed weekly. RESULTS: Mean regression for SBP following IHG was negative (-1.04 ± 0.80). Mean regression in the CON group was positive (0.50 ± 0.88), but there was no significant difference between groups. Separate analysis of weeks 1 to 7 yielded a negative mean regression (-1.12 ± 0.54) in the IHG group, but positive (1.2 ± 0.60) in the CON group. A Wilcoxon test of these differences yielded significance for SBP (P = .009). In 3 of 6 IHG participants, SBP was lower (mean ± SD: -16 ± 11 mm Hg; P = .12), and in 2 IHG participants, DBP was lower (-9 ± 1 mm Hg; P = .06) compared with baseline. In 2 of 5 CON participants, SBP was not significantly lower (-11 ± 7 mm Hg) and, in 3 of 5 CON participants, DBP was lower (-7 ± 4 mm Hg; P = .04). CONCLUSIONS: Our data suggest that standard IHG training may be inadequate for blood pressure management immediately following a major cardiac or pulmonary event. Future work with a larger cohort and more developed training protocol to determine the efficacy of IHG training in patients with cardiopulmonary disease is warranted.

A comparison of blood pressure reductions following 12-weeks of isometric exercise training either in the laboratory or at home.

Isometric exercise training (IET)-induced reductions in resting blood pressure (RBP) have been achieved in laboratory environments, but data in support of IET outside the laboratory are scarce. The aim of this study was to compare 12 weeks of home-based (HOM) IET with laboratory-based, face-to-face (LAB) IET in hypertensive adults. Twenty-two hypertensive participants (24-60 years) were randomized to three conditions: HOM, LAB, or control (CON). IET involved isometric handgrip training (4 × 2 minutes at 30% maximum voluntary contraction, 3 days per week). RBP was measured every 6 weeks (0, 6, and 12 weeks) during training and 6 weeks after training (18 weeks). Clinically meaningful, but not statistically significant reductions in RBP were observed after 12 weeks of LAB IET (resting systolic blood pressure [SBP] -9.1 ± 4.1; resting diastolic blood pressure [DBP] -2.8 ± 2.1; P > .05), which was sustained for 6 weeks of detraining (SBP -8.2 ± 2.9; DBP -4 ± 2.9, P > .05). RBP was reduced in the HOM group after 12 weeks of training (SBP -9.7 ± 3.4; DBP -2.2 ± 2.0; P > .05), which was sustained for an additional 6 weeks of detraining (SBP -5.5 ± 3.4; DBP -4.6 ± 1.8; P > .05). Unsupervised home-based IET programs present an exciting opportunity for community-based strategies to combat hypertension, but additional work is needed if IET is to be used routinely outside the laboratory.

A genome-wide association study of seed composition traits in wild soybean (Glycine soja).

BACKGROUND: Cultivated soybean (Glycine max) is a major agricultural crop that provides a crucial source of edible protein and oil. Decreased amounts of saturated palmitic acid and increased amounts of unsaturated oleic acid in soybean oil are considered optimal for human cardiovascular health and therefore there has considerable interest by breeders in discovering genes affecting the relative concentrations of these fatty acids. Using a genome-wide association (GWA) approach with nearly 30,000 single nucleotide polymorphisms (SNPs), we investigated the genetic basis of protein, oil and all five fatty acid levels in seeds from a sample of 570 wild soybeans (Glycine soja), the progenitor of domesticated soybean, to identify quantitative trait loci (QTLs) affecting these seed composition traits. RESULTS: We discovered 29 SNPs located on ten different chromosomes that are significantly associated with the seven seed composition traits in our wild soybean sample. Eight SNPs co-localized with QTLs previously uncovered in linkage or association mapping studies conducted with cultivated soybean samples, while the remaining SNPs appeared to be in novel locations. Twenty-four of the SNPs significantly associated with fatty acid variation, with the majority located on chromosomes 14 (6 SNPs) and seven (8 SNPs). Two SNPs were common for two or more fatty acids, suggesting loci with pleiotropic effects. We also identified some candidate genes that are involved in fatty acid metabolism and regulation. For each of the seven traits, most of the SNPs produced differences between the average phenotypic values of the two homozygotes of about one-half standard deviation and contributed over 3% of their total variability. CONCLUSIONS: This is the first GWA study conducted on seed composition traits solely in wild soybean populations, and a number of QTLs were found that have not been previously discovered. Some of these may be useful to breeders who select for increased protein/oil content or altered fatty acid ratios in the seeds. The results also provide additional insight into the genetic architecture of these traits in a large sample of wild soybean, and suggest some new candidate genes whose molecular effects on these traits need to be further studied.

Back into the wild-Apply untapped genetic diversity of wild relatives for crop improvement.

Deleterious effects of climate change and human activities, as well as diverse environmental stresses, present critical challenges to food production and the maintenance of natural diversity. These challenges may be met by the development of novel crop varieties with increased biotic or abiotic resistance that enables them to thrive in marginal lands. However, considering the diverse interactions between crops and environmental factors, it is surprising that evolutionary principles have been underexploited in addressing these food and environmental challenges. Compared with domesticated cultivars, crop wild relatives (CWRs) have been challenged in natural environments for thousands of years and maintain a much higher level of genetic diversity. In this review, we highlight the significance of CWRs for crop improvement by providing examples of CWRs that have been used to increase biotic and abiotic stress resistance/tolerance and overall yield in various crop species. We also discuss the surge of advanced biotechnologies, such as next-generation sequencing technologies and omics, with particular emphasis on how they have facilitated gene discovery in CWRs. We end the review by discussing the available resources and conservation of CWRs, including the urgent need for CWR prioritization and collection to ensure continuous crop improvement for food sustainability.

Environmental versus geographical effects on genomic variation in wild soybean (Glycine soja) across its native range in northeast Asia.

A fundamental goal in evolutionary biology is to understand how various evolutionary factors interact to affect the population structure of diverse species, especially those of ecological and/or agricultural importance such as wild soybean (Glycine soja). G. soja, from which domesticated soybeans (Glycine max) were derived, is widely distributed throughout diverse habitats in East Asia (Russia, Japan, Korea, and China). Here, we utilize over 39,000 single nucleotide polymorphisms genotyped in 99 ecotypes of wild soybean sampled across their native geographic range in northeast Asia, to understand population structure and the relative contribution of environment versus geography to population differentiation in this species. A STRUCTURE analysis identified four genetic groups that largely corresponded to the geographic regions of central China, northern China, Korea, and Japan, with high levels of admixture between genetic groups. A canonical correlation and redundancy analysis showed that environmental factors contributed 23.6% to population differentiation, much more than that for geographic factors (6.6%). Precipitation variables largely explained divergence of the groups along longitudinal axes, whereas temperature variables contributed more to latitudinal divergence. This study provides a foundation for further understanding of the genetic basis of climatic adaptation in this ecologically and agriculturally important species.

Differential Expression of Inflammatory Cytokines and Stress Genes in Male and Female Mice in Response to a Lipopolysaccharide Challenge.

BACKGROUND: Sex plays a key role in an individual's immune response against pathogenic challenges such that females fare better when infected with certain pathogens. It is thought that sex hormones impact gene expression in immune cells and lead to sexually dimorphic responses to pathogens. We predicted that, in the presence of E. coli gram-negative lipopolysaccharide (LPS), there would be a sexually dimorphic response in proinflammatory cytokine production and acute phase stress gene expression and that these responses might vary among different mouse strains and times in a pattern opposite to that of body temperature associated with LPS-induced shock. MATERIALS AND METHODS: Interleukin-6 (IL-6), macrophage inflammatory protein-Iß (MIP-1ß), tumor necrosis factor alpha (TNF-α) and interleukin-1ß (IL-1ß) as well as beta-fibrinogen (Fgb) and metallothionein-1 (Mt-1) mRNA expression were measured at four time points (0, 2, 4 and 7 hours) after injection of E. coli LPS in mice from three inbred strains. RESULTS: Statistical analysis using analyses of variance (ANOVAs) showed that the levels of the all six traits changed over time, generally peaking at 2 hours after LPS injection. Mt-1, Fgb, and IL-6 showed differences among strains, although these were time-specific. Sexual dimorphism was seen for Fgb and IL6, and was most pronounced at the latest time period (7 hours) where male levels exceeded those for females. Trends for all six cytokine/gene expression traits were negatively correlated with those for body temperatures. DISCUSSION: The higher levels of expression of Fgb and IL6 in males compared with females are consistent with the greater vulnerability of males to infection and subsequent inflammation. Temperature appears to be a useful proxy for mortality in endotoxic shock, but sexual dimorphism in cytokine and stress gene expression levels may persist after an LPS challenge even if temperatures in the two sexes are similar and have begun to stabilize.

Host genetics and diet, but not immunoglobulin A expression, converge to shape compositional features of the gut microbiome in an advanced intercross population of mice.

BACKGROUND: Individuality in the species composition of the vertebrate gut microbiota is driven by a combination of host and environmental factors that have largely been studied independently. We studied the convergence of these factors in a G10 mouse population generated from a cross between two strains to search for quantitative trait loci (QTLs) that affect gut microbiota composition or ileal Immunoglobulin A (IgA) expression in mice fed normal or high-fat diets. RESULTS: We found 42 microbiota-specific QTLs in 27 different genomic regions that affect the relative abundances of 39 taxa, including four QTL that were shared between this G10 population and the population previously studied at G4. Several of the G10 QTLs show apparent pleiotropy. Eight of these QTLs, including four at the same site on chromosome 9, show significant interaction with diet, implying that diet can modify the effects of some host loci on gut microbiome composition. Utilization patterns of IghV variable regions among IgA-specific mRNAs from ileal tissue are affected by 54 significant QTLs, most of which map to a segment of chromosome 12 spanning the Igh locus. Despite the effect of genetic variation on IghV utilization, we are unable to detect overlapping microbiota and IgA QTLs and there is no significant correlation between IgA variable pattern utilization and the abundance of any of the taxa from the fecal microbiota. CONCLUSIONS: We conclude that host genetics and diet can converge to shape the gut microbiota, but host genetic effects are not manifested through differences in IgA production

Large-scale adaptive divergence in Boechera fecunda, an endangered wild relative of Arabidopsis.

Many biological species are threatened with extinction because of a number of factors such as climate change and habitat loss, and their preservation depends on an accurate understanding of the extent of their genetic variability within and among populations. In this study, we assessed the genetic divergence of five quantitative traits in 10 populations of an endangered cruciferous species, Boechera fecunda, found in only several populations in each of two geographic regions (WEST and EAST) in southwestern Montana. We analyzed variation in quantitative traits, neutral molecular markers, and environmental factors and provided evidence that despite the restricted geographical distribution of this species, it exhibits a high level of genetic variation and regional adaptation. Conservation efforts therefore should be directed to the preservation of populations in each of these two regions without attempting transplantation between regions. Heritabilities and genetic coefficients of variation estimated from nested ANOVAs were generally high for leaf and rosette traits, although lower (and not significantly different from 0) for water-use efficiency. Measures of quantitative genetic differentiation, Q ST, were calculated for each trait from each pair of populations. For three of the five traits, these values were significantly higher between regions compared with those within regions (after adjustment for neutral genetic variation, F ST). This suggested that natural selection has played an important role in producing regional divergence in this species. Our analysis also revealed that the B. fecunda populations appear to be locally adapted due, at least in part, to differences in environmental conditions in the EAST and WEST regions.

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.

Quantitative trait loci for bone mineral density and femoral morphology in an advanced intercross population of mice.

Osteoporosis, characterized by low levels of bone mineral density (BMD), is a prevalent medical condition in humans. We investigated its genetic and environmental basis by searching for quantitative trait loci (QTLs) affecting six skeletal (including three BMD) traits in a G10 advanced intercross population produced from crosses of mice from the inbred strain C57BL/6J with mice from a strain selected for high voluntary wheel running. The mice in this population were fed either a high-fat or a matched control diet throughout the study, allowing us to test for QTL by diet interactions for the skeletal traits. Our genome scan uncovered a number of QTLs, the great majority of which were different from QTLs previously found for these same traits in an earlier (G4) generation of the same intercross. Further, the confidence intervals for the skeletal trait QTLs were reduced from an average of 18.5 Mb in the G4 population to an equivalent of about 9 Mb in the G10 population. We uncovered a total of 50 QTLs representing 32 separate genomic sites affecting these traits, with a distal region on chromosome 1 harboring several QTLs with large effects on the BMD traits. One QTL was located on chromosome 5 at 4.0 Mb with a confidence interval spanning from 4.0 to 4.6 Mb. Only three protein coding genes reside in this interval, and one of these, Cyp51, is an attractive candidate as others have shown that developing Cyp51 knockout embryos exhibit shortened and bowed limbs and synotosis of the femur and tibia. Several QTLs showed significant interactions with sex, although only two QTLs interacted with diet, both affecting only mice fed the high-fat diet.

Exercise and diet affect quantitative trait loci for body weight and composition traits in an advanced intercross population of mice.

Driven by the recent obesity epidemic, interest in understanding the complex genetic and environmental basis of body weight and composition is great. We investigated this by searching for quantitative trait loci (QTLs) affecting a number of weight and adiposity traits in a G(10) advanced intercross population produced from crosses of mice in inbred strain C57BL/6J with those in a strain selected for high voluntary wheel running. The mice in this population were fed either a high-fat or a control diet throughout the study and also measured for four exercise traits prior to death, allowing us to test for pre- and postexercise QTLs as well as QTL-by-diet and QTL-by-exercise interactions. Our genome scan uncovered a number of QTLs, of which 40% replicated QTLs previously found for similar traits in an earlier (G(4)) generation. For those replicated QTLs, the confidence intervals were reduced from an average of 19 Mb in the G(4) to 8 Mb in the G(10). Four QTLs on chromosomes 3, 8, 13, and 18 were especially prominent in affecting the percentage of fat in the mice. About of all QTLs showed interactions with diet, exercise, or both, their genotypic effects on the traits showing a variety of patterns depending on the diet or level of exercise. It was concluded that the indirect effects of these QTLs provide an underlying genetic basis for the considerable variability in weight or fat loss typically found among individuals on the same diet and/or exercise regimen.

Epistatic Control of Mammary Cancer Susceptibility in Mice may Depend on the Dietary Environment.

Recent studies have linked a high fat diet to the development of breast cancer, but any genetic basis for this association is poorly understood. We investigated this association with an epistatic analysis of seven cancer traits in a segregating population of mice with metastatic mammary cancer that were fed either a control or a high-fat diet. We used an interval mapping approach with single nucleotide polymorphisms to scan all 19 autosomes, and discovered a number of diet-independent epistatic interactions of quantitative trait loci (QTLs) affecting these traits. More importantly, we also discovered significant epistatic by diet interactions affecting some of the traits that suggested these epistatic effects varied depending on the dietary environment. An analysis of these interactions showed some were due to epistasis that occurred in mice fed only the control diet or only the high-fat diet whereas other interactions were generated by differential effects of epistasis in the two dietary environments. Some of the epistatic QTLs appeared to colocalize with cancer QTLs mapped in other mouse populations and with candidate genes identified from eQTLs previously mapped in this population, but others represented novel modifying loci affecting these cancer traits. It was concluded that these diet-dependent epistatic QTLs contribute to a genetic susceptibility of dietary effects on breast cancer, and their identification may eventually lead to a better understanding that will be needed for the design of more effective treatments for this disease.

Disentangling prenatal and postnatal maternal genetic effects reveals persistent prenatal effects on offspring growth in mice.

Mothers are often the most important determinant of traits expressed by their offspring. These "maternal effects" (MEs) are especially crucial in early development, but can also persist into adulthood. They have been shown to play a role in a diversity of evolutionary and ecological processes, especially when genetically based. Although the importance of MEs is becoming widely appreciated, we know little about their underlying genetic basis. We address the dearth of genetic data by providing a simple approach, using combined genotype information from parents and offspring, to identify "maternal genetic effects" (MGEs) contributing to natural variation in complex traits. Combined with experimental cross-fostering, our approach also allows for the separation of pre- and postnatal MGEs, providing rare insights into prenatal effects. Applying this approach to an experimental mouse population, we identified 13 ME loci affecting body weight, most of which (12/13) exhibited prenatal effects, and nearly half (6/13) exhibiting postnatal effects. MGEs contributed more to variation in body weight than the direct effects of the offsprings' own genotypes until mice reached adulthood, but continued to represent a major component of variation through adulthood. Prenatal effects always contributed more variation than postnatal effects, especially for those effects that persisted into adulthood. These results suggest that MGEs may be an important component of genetic architecture that is generally overlooked in studies focused on direct mapping from genotype to phenotype. Our approach can be used in both experimental and natural populations, providing a widely practicable means of expanding our understanding of MGEs.

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 F(2) 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.

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

BACKGROUND: 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 F2 population 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. RESULTS: 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. CONCLUSIONS: 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.

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

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.

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

BACKGROUND: 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 F2 generation produced from an intercross of two inbred lines that differed dramatically in their physical activity levels. METHODS: 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 (relQTLs), or chromosomal regions that affected an activity trait variably depending on the phenotypic value of body weight. RESULTS: 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 relQTLs 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 relQTLs produced these varying associations through differential epistatic interactions with a number of other epistatic QTLs throughout the genome. CONCLUSION: It was concluded that individuals with specific combinations of genotypes at the relQTLs and epiQTLs might account for some of the variation typically seen in plots of the association of physical activity with body weight.

Genetic differences in sensitivity to alterations of mandible structure caused by the teratogen 2,3,7,8-tetrachlorodibenzo-p-dioxin.

The contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an environmental pollutant and teratogen that has been shown to alter craniofacial development. Differences in sensitivity to TCDD are attributed primarily to differences in alleles at the Ahr locus coding for the aryl-hydrocarbon receptor (AHR) that binds TCDD and mediates its effects by altering gene expression. The authors used geometric morphometric methods to evaluate differences in the effects of small in utero exposures of TCDD on adult mandible size and shape in five different inbred mouse strains with the same Ahr alleles. Because of the known effects of this toxicant on bone and craniofacial structures, the authors hypothesized that TCDD would decrease mandible size and alter mandible shape, but that the effects of TCDD exposure would differ among the inbred strains. The authors found that TCDD did alter mandible size and shape, but these effects were limited to specific strains and also differed between the sexes. The relative sensitivity to TCDD's effects on mandibles did not correspond with the previously reported sensitivity to TCDD's effects on molars. The authors hypothesize that beyond Ahr-related effects, variation in response to TCDD reflects differences in the genetic architecture controlling the trait being evaluated, thus explaining the species, strain, and trait specificity of TCDD.

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.