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Genetic architecture of voluntary exercise in an advanced intercross line of mice.

ABSTRACT: Exercise is essential for health, yet the amount, duration, and intensity that individuals engage in are strikingly variable, even under prescription. Our focus was to identify the locations and effects of quantitative trait loci (QTL) controlling genetic predisposition for exercise-related traits, utilizing a large advanced intercross line (AIL) of mice. This AIL (G(4)) population originated from a reciprocal cross between mice with genetic propensity for increased voluntary exercise [high-runner (HR) line, selectively bred for increased wheel running] and the inbred strain C57BL/6J. After adjusting for family structure, we detected 32 significant and 13 suggestive QTL representing both daily running traits (distance, duration, average speed, and maximum speed) and the mean of these traits on days 5 and 6 (the selection criteria for HR) of a 6-day test conducted at 8 wk of age, with many co-localizing to similar genomic regions. Additionally, seven significant and five suggestive QTL were observed for the slope and intercept of a linear regression across all 6 days of running, some representing a combination of the daily traits. We also observed two significant and two suggestive QTL for body mass before exercise. These results, from a well-defined animal model, reinforce a genetic basis for the predisposition to engage in voluntary exercise, dissect this predisposition into daily segments across a continuous time period, and present unique QTL that may provide insight into the initiation, continuation, and temporal pattern of voluntary activity in mammals.

SUBMITTER: Kelly SA

PROVIDER: S-EPMC3032284 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Genetic architecture of voluntary exercise in an advanced intercross line of mice.

Kelly Scott A SA Nehrenberg Derrick L DL Peirce Jeremy L JL Hua Kunjie K Steffy Brian M BM Wiltshire Tim T Pardo-Manuel de Villena Fernando F Garland Theodore T Pomp Daniel D

Physiological genomics 20100413 2

Exercise is essential for health, yet the amount, duration, and intensity that individuals engage in are strikingly variable, even under prescription. Our focus was to identify the locations and effects of quantitative trait loci (QTL) controlling genetic predisposition for exercise-related traits, utilizing a large advanced intercross line (AIL) of mice. This AIL (G(4)) population originated from a reciprocal cross between mice with genetic propensity for increased voluntary exercise [high-runn ...[more]

PMID: 20388837

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Project description:The advanced intercross line (AIL) that is created by successive generations of pseudo-random mating after the F2 generation is a valuable resource, especially in agricultural livestock and poultry species, because it improves the precision of quantitative trait loci (QTL) mapping compared with traditional association populations by introducing more recombination events. The growth traits of broilers have significant economic value in the chicken industry, and many QTLs affecting growth traits have been identified, especially on chromosomes 1, 4, and 27, albeit with large confidence intervals that potentially contain dozens of genes. To promote a better understanding of the underlying genetic architecture of growth trait differences, specifically body weight and bone development, in this study, we report a nine-generation AIL derived from two divergent outbred lines: High Quality chicken Line A (HQLA) and Huiyang Bearded (HB) chicken. We evaluate the genetic architecture of the F0, F2, F8, and F9 generations of AIL and demonstrate that the population of the F9 generation sufficiently randomized the founder genomes and has the characteristics of rapid linkage disequilibrium decay, limited allele frequency decline, and abundant nucleotide diversity. This AIL yielded a much narrower QTL than the F2 generations, especially the QTL on chromosome 27, which was reduced to 120 Kb. An ancestral haplotype association analysis showed that most of the dominant haplotypes are inherited from HQLA but with fluctuation of the effects between them. We highlight the important role of four candidate genes (PHOSPHO1, IGF2BP1, ZNF652, and GIP) in bone growth. We also retrieved a missing QTL from AIL on chromosome 4 by identifying the founder selection signatures, which are explained by the loss of association power that results from rare alleles. Our study provides a reasonable resource for detecting quantitative trait genes and tracking ancestor history and will facilitate our understanding of the genetic mechanisms underlying chicken bone growth.

Project description:While direct additive and dominance effects on complex traits have been mapped repeatedly, additional genetic factors contributing to the heterogeneity of complex traits have been scarcely investigated. To assess genetic background effects, we investigated transmission ratio distortions (TRDs) of alleles from parent to offspring using an advanced intercross line (AIL) of an initial cross between the mouse inbred strains C57BL/6NCrl (B6N) and BFMI860-12 [Berlin Fat Mouse Inbred (BFMI)]. A total of 341 males of generation 28 and their respective 61 parents and 66 grandparents were genotyped using Mega Mouse Universal Genotyping Arrays. TRDs were investigated using allele transmission asymmetry tests, and pathway overrepresentation analysis was performed. Sequencing data were used to test for overrepresentation of nonsynonymous SNPs (nsSNPs) in TRD regions. Genetic incompatibilities were tested using the Bateson-Dobzhansky-Muller two-locus model. A total of 62 TRD regions were detected, many in close proximity to the telocentric centromere. TRD regions contained 44.5% more nsSNPs than randomly selected regions (182 vs 125.9 ± 17.0, P < 1 × 10-4). Testing for genetic incompatibilities between TRD regions identified 29 genome-wide significant incompatibilities between TRD regions [P(BF) < 0.05]. Pathway overrepresentation analysis of genes in TRD regions showed that DNA methylation, epigenetic regulation of RNA, and meiotic/meiosis regulation pathways were affected independent of the parental origin of the TRD. Paternal BFMI TRD regions showed overrepresentation in the small interfering RNA biogenesis and in the metabolism of lipids and lipoproteins. Maternal B6N TRD regions harbored genes involved in meiotic recombination, cell death, and apoptosis pathways. The analysis of genes in TRD regions suggests the potential distortion of protein-protein interactions influencing obesity and diabetic retinopathy as a result of disadvantageous combinations of allelic variants in Aass, Pgx6, and Nme8. Using an AIL significantly improves the resolution at which we can investigate TRD. Our analysis implicates distortion of protein-protein interactions as well as meiotic drive as the underlying mechanisms leading to the observed TRD in our AIL. Furthermore, genes with large amounts of nsSNPs located in TRD regions are more likely to be involved in pathways that are related to the phenotypic differences between the parental strains. Genes in these TRD regions provide new targets for investigating genetic adaptation, protein-protein interactions, and determinants of complex traits such as obesity.

Project description:Genetic variability in the strength and precision of fear memory is hypothesised to contribute to the etiology of anxiety disorders, including post-traumatic stress disorder. We generated fear-susceptible (F-S) or fear-resistant (F-R) phenotypes from an F8 advanced intercross line (AIL) of C57BL/6J and DBA/2J inbred mice by selective breeding. We identified specific traits underlying individual variability in Pavlovian conditioned fear learning and memory. Offspring of selected lines differed in the acquisition of conditioned fear. Furthermore, F-S mice showed greater cued fear memory and generalised fear in response to a novel context than F-R mice. F-S mice showed greater basal corticosterone levels and hypothalamic corticotrophin-releasing hormone (CRH) mRNA levels than F-R mice, consistent with higher hypothalamic-pituitary-adrenal (HPA) axis drive. Hypothalamic mineralocorticoid receptor and CRH receptor 1 mRNA levels were decreased in F-S mice as compared with F-R mice. Manganese-enhanced magnetic resonance imaging (MEMRI) was used to investigate basal levels of brain activity. MEMRI identified a pattern of increased brain activity in F-S mice that was driven primarily by the hippocampus and amygdala, indicating excessive limbic circuit activity in F-S mice as compared with F-R mice. Thus, selection pressure applied to the AIL population leads to the accumulation of heritable trait-relevant characteristics within each line, whereas non-behaviorally relevant traits remain distributed. Selected lines therefore minimise false-positive associations between behavioral phenotypes and physiology. We demonstrate that intrinsic differences in HPA axis function and limbic excitability contribute to phenotypic differences in the acquisition and consolidation of associative fear memory. Identification of system-wide traits predisposing to variability in fear memory may help in the direction of more targeted and efficacious treatments for fear-related pathology.

Dataset Information

Genetic architecture of voluntary exercise in an advanced intercross line of mice.

Publications

Genetic architecture of voluntary exercise in an advanced intercross line of mice.

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