microRNA-146a-5p association with the cardiometabolic disease risk factor TMAO.

Trimethylamine-N-oxide (TMAO), a microbial choline metabolism byproduct that is processed in the liver and excreted into circulation, is associated with increased atherosclerotic lesion formation and cardiovascular disease risk. Genetic regulators of TMAO levels are largely unknown. In the present study, we used 288 mice from a genetically heterogeneous mouse population [Diversity Outbred (DO)] to determine hepatic microRNA associations with TMAO in the context of an atherogenic diet.

Correction to: Quantitative trait mapping in Diversity Outbred mice identifies two genomic regions associated with heart size.

The original article has been published with an incorrect text in Materials and Methods section. The corrected text should read as.

CC002/Unc females are mouse models of exercise-induced paradoxical fat response.

Exercise results in beneficial health outcomes and protects against a variety of chronic diseases. However, U.S.

Developmental constraint through negative pleiotropy in the zygomatic arch.

Background: Previous analysis suggested that the relative contribution of individual bones to regional skull lengths differ between inbred mouse strains. If the negative correlation of adjacent bone lengths is associated with genetic variation in a heterogeneous population, it would be an example of negative pleiotropy, which occurs when a genetic factor leads to opposite effects in two phenotypes. Confirming negative pleiotropy and determining its basis may reveal important information about the maintenance of overall skull integration and developmental constraint on skull morphology.

Quantitative trait mapping in Diversity Outbred mice identifies two genomic regions associated with heart size.

Heart size is an important factor in cardiac health and disease. In particular, increased heart weight is predictive of adverse cardiovascular outcomes in multiple large community-based studies. We use two cohorts of Diversity Outbred (DO) mice to investigate the role of genetics, sex, age, and diet on heart size.

Improving Metabolic Health Through Precision Dietetics in Mice.

The incidence of diet-induced metabolic disease has soared over the last half-century, despite national efforts to improve health through universal dietary recommendations. Studies comparing dietary patterns of populations with health outcomes have historically provided the basis for healthy diet recommendations. However, evidence that population-level diet responses are reliable indicators of responses across individuals is lacking.

Systems genetics identifies a co-regulated module of liver microRNAs associated with plasma LDL cholesterol in murine diet-induced dyslipidemia.

Chronically altered levels of circulating lipids, termed dyslipidemia, is a significant risk factor for a number of metabolic and cardiovascular morbidities. MicroRNAs (miRNAs) have emerged as important regulators of lipid balance, have been implicated in dyslipidemia, and have been proposed as candidate therapeutic targets in lipid-related disorders including atherosclerosis. A major limitation of most murine studies of miRNAs in lipid metabolic disorders is that they have been performed in just one (or very few) inbred strains, such as C57BL/6.

Aerobic exercise prevents rarefaction of pial collaterals and increased stroke severity that occur with aging.

Variation in extent of the brain's collateral circulation is an important determinant of variation in the severity of stroke and efficacy of revascularization therapies. However, the number and diameter of pial collateral "arterioles" decrease with aging in associated with reduced eNOS and increased oxidative stress. We tested whether exercise reduces this aging-induced rarefaction.

Prevention of tumorigenesis in mice by exercise is dependent on strain background and timing relative to carcinogen exposure.

Among cancer diagnoses, colorectal cancer (CRC) is prevalent, with a lifetime risk of developing CRC being approximately 5%. Population variation surrounding the mean risk of developing CRCs has been associated with both inter-individual differences in genomic architecture and environmental exposures. Decreased risk of CRC has been associated with physical activity, but protective responses are variable.

Long-term exercise in mice has sex-dependent benefits on body composition and metabolism during aging.

Aging is associated with declining exercise and unhealthy changes in body composition. Exercise ameliorates certain adverse age-related physiological changes and protects against many chronic diseases. Despite these benefits, willingness to exercise and physiological responses to exercise vary widely, and long-term exercise and its benefits are difficult and costly to measure in humans.

R2d2 Drives Selfish Sweeps in the House Mouse.

A selective sweep is the result of strong positive selection driving newly occurring or standing genetic variants to fixation, and can dramatically alter the pattern and distribution of allelic diversity in a population. Population-level sequencing data have enabled discoveries of selective sweeps associated with genes involved in recent adaptations in many species. In contrast, much debate but little evidence addresses whether "selfish" genes are capable of fixation-thereby leaving signatures identical to classical selective sweeps-despite being neutral or deleterious to organismal fitness.

Maternal exercise before and during pregnancy does not impact offspring exercise or body composition in mice.

Background: The genome, the environment, and their interactions simultaneously regulate complex traits such as body composition and voluntary exercise levels. One such environmental influence is the maternal milieu (i.e.

A multi-megabase copy number gain causes maternal transmission ratio distortion on mouse chromosome 2.

Significant departures from expected Mendelian inheritance ratios (transmission ratio distortion, TRD) are frequently observed in both experimental crosses and natural populations. TRD on mouse Chromosome (Chr) 2 has been reported in multiple experimental crosses, including the Collaborative Cross (CC). Among the eight CC founder inbred strains, we found that Chr 2 TRD was exclusive to females that were heterozygous for the WSB/EiJ allele within a 9.

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.

High-resolution genetic mapping in the diversity outbred mouse population identifies Apobec1 as a candidate gene for atherosclerosis.

Inbred mice exhibit strain-specific variation in susceptibility to atherosclerosis and dyslipidemia that renders them useful in dissecting the genetic architecture of these complex diseases. Traditional quantitative trait locus (QTL) mapping studies using inbred strains often identify large genomic regions, containing many genes, due to limited recombination and/or sample size. This hampers candidate gene identification and translation of these results into possible risk factors and therapeutic targets.

Functional characterization of cytochrome P450-derived epoxyeicosatrienoic acids in adipogenesis and obesity.

Adipogenesis plays a critical role in the initiation and progression of obesity. Although cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) have emerged as a potential therapeutic target for cardiometabolic disease, the functional contribution of EETs to adipogenesis and the pathogenesis of obesity remain poorly understood. Our studies demonstrated that induction of adipogenesis in differentiated 3T3-L1 cells (in vitro) and obesity-associated adipose expansion in high-fat diet (HFD)-fed mice (in vivo) significantly dysregulate the CYP epoxygenase pathway and evoke a marked suppression of adipose-derived EET levels.

Quantitative genomics of voluntary exercise in mice: transcriptional analysis and mapping of expression QTL in muscle.

Motivation and ability both underlie voluntary exercise, each with a potentially unique genetic architecture. Muscle structure and function are one of many morphological and physiological systems acting to simultaneously determine exercise ability. We generated a large (n = 815) advanced intercross line of mice (G4) derived from a line selectively bred for increased wheel running (high runner) and the C57BL/6J inbred strain.

A novel intronic single nucleotide polymorphism in the myosin heavy polypeptide 4 gene is responsible for the mini-muscle phenotype characterized by major reduction in hind-limb muscle mass in mice.

Replicated artificial selection for high levels of voluntary wheel running in an outbred strain of mice favored an autosomal recessive allele whose primary phenotypic effect is a 50% reduction in hind-limb muscle mass. Within the High Runner (HR) lines of mice, the numerous pleiotropic effects (e.g.

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.

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.

Functional genomic architecture of predisposition to voluntary exercise in mice: expression QTL in the brain.

The biological basis of voluntary exercise is complex and simultaneously controlled by peripheral (ability) and central (motivation) mechanisms. The accompanying natural reward, potential addiction, and the motivation associated with exercise are hypothesized to be regulated by multiple brain regions, neurotransmitters, peptides, and hormones. We generated a large (n = 815) advanced intercross line of mice (G(4)) derived from a line selectively bred for increased wheel running (high runner) and the C57BL/6J inbred strain.

Identification of quantitative trait loci influencing skeletal architecture in mice: emergence of Cdh11 as a primary candidate gene regulating femoral morphology.

Bone strength is influenced by many properties intrinsic to bone, including its mass, geometry, and mineralization. To further advance our understanding of the genetic basis of bone-strength-related traits, we used a large (n = 815), moderately (G(4) ) advanced intercross line (AIL) of mice derived from a high-runner selection line (HR) and the C57BL/6J inbred strain. In total, 16 quantitative trait loci (QTLs) were identified that affected areal bone mineral density (aBMD) and femoral length and width.

Exercise, weight loss, and changes in body composition in mice: phenotypic relationships and genetic architecture.

The regulation of body weight and composition is complex, simultaneously affected by genetic architecture, the environment, and their interactions. We sought to analyze the complex phenotypic relationships between voluntary exercise, food consumption, and changes in body weight and composition and simultaneously localize quantitative trait loci (QTL) controlling these traits. A large (n = 815) murine advanced intercross line (G(4)) was created from a reciprocal cross between a high-running line and the inbred strain C57BL/6J.