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

Abstract

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. We previously mapped multiple quantitative trait loci (QTL) that contribute to the biological control of voluntary exercise levels, body weight, and composition, as well as changes in body weight and composition in response to short-term exercise. Currently, using a subset of the G(4) population (n = 244), we examined the transcriptional landscape relevant to neurobiological aspects of voluntary exercise by means of global mRNA expression profiles from brain tissue. We identified genome-wide expression quantitative trait loci (eQTL) regulating variation in mRNA abundance and determined the mode of gene action and the cis- and/or trans-acting nature of each eQTL. Subsets of cis-acting eQTL, colocalizing with QTL for exercise or body composition traits, were used to identify candidate genes based on both positional and functional evidence, which were further filtered by correlational and exclusion mapping analyses. Specifically, we discuss six plausible candidate genes (Insig2, Socs2, DBY, Arrdc4, Prcp, IL15) and their potential role in the regulation of voluntary activity, body composition, and their interactions. These results develop a potential initial model of the underlying functional genomic architecture of predisposition to voluntary exercise and its effects on body weight and composition within a neurophysiological framework.

Figure 1

The number of statistically significant (P ≤ 0.05, adjusted for multiple comparisons) partial correlations, adjusted for sex and parent of origin, factors with known phenotypic effects (see Kelly et al. 2010a) between 17,571 significantly expressed transcripts, and exercise and body composition-related phenotypes. In total, 36 exercise-related phenotypes and 17 traits related to food consumption, body weight and composition, and change in body weight and composition as a result of 6 days of voluntary exercise on wheels were observed. Therefore, each of the phenotypes depicted above is composed of multiple traits (n depicted following each phenotype) that are each highly correlated with one another (see correlation analyses in Kelly et al. 2010b, 2011).

Figure 2

(A) The number of local or cis-acting (black bars) and distant or trans-acting (gray bars) eQTL across all chromosomes with a LOD ≥ 4.3. (B) Physical gene location as a function of mapped position of each QTL. The prominent diagonal band indicates cis-acting eQTL. A potential master regulatory region is observed on the distal end of chromosome 1, as indicated by a prominent vertical trans-band. Complete data file utilized to generate Figure 2B is provided in File S6. (C) Cis-acting eQTL were defined as falling within 10 Mb of the gene’s physical location, with the most significant eQTL generally being the closest to the gene’s midpoint.

Figure 3

Cis-acting eQTL colocalizing with exercise QTL. Colocalizing candidate genes that fell within the confidence intervals of the trait QTL are depicted. The LOD score of the eQTL is shown on the left y-axis, the phenotype (exercise trait) LOD score on the right y-axis, and the position of both on the x-axis. Each transcript is labeled, and color is used only for the purpose of demarcation. Inset lists of transcripts are in the corresponding order of their vertical position. (A) Mean running distance (Chr. 7) on days 5 and 6 of a 6-day test. (B) Running distance (Chr. 1) on each of days 1(black line) and 2 (gray line). (C) Mean running duration (Chr. 7) on days 5 and 6 of a 6-day test. (D) Average (black line) and maximum (gray line) running speed (Chr. 2) on days 5 and 6 of a 6-day test. (E) Average running speed (Chr. 14) on days 5 and 6 of a 6-day test. (F) Maximum running speed (Chr. 11) on days 5 and 6 of a 6-day test.

Figure 4

Cis-acting eQTL, colocalizing with QTL underlying changes in body weight and composition in response to 6 days of voluntary wheel running (Kelly et al. 2010b). Colocalizing candidate genes that fell within the confidence intervals of the trait QTL are depicted. The LOD score of the eQTL is shown on the left y-axis, the phenotype (exercise trait) LOD score on the right y-axis, and the position of both on the x-axis. Each transcript is labeled, and color is used only for the purpose of demarcation. Inset lists of transcripts are in the corresponding order of their vertical position. (A) Percentage change in body mass (Chr. 11). (B) Percentage change in percentage fat mass (Chr. 1). (C) Percentage change in percentage fat mass (Chr. 5). (D) Percentage change in percentage lean mass (Chr. 5).