Architecture of energy balance traits in emerging lines of the Collaborative Cross

Abstract

The potential utility of the Collaborative Cross (CC) mouse resource was evaluated to better understand complex traits related to energy balance. A primary focus was to examine if genetic diversity in emerging CC lines (pre-CC) would translate into equivalent phenotypic diversity. Second, we mapped quantitative trait loci (QTL) for 15 metabolism- and exercise-related phenotypes in this population. We evaluated metabolic and voluntary exercise traits in 176 pre-CC lines, revealing phenotypic variation often exceeding that seen across the eight founder strains from which the pre-CC was derived. Many phenotypic correlations existing within the founder strains were no longer significant in the pre-CC population, potentially representing reduced linkage disequilibrium (LD) of regions harboring multiple genes with effects on energy balance or disruption of genetic structure of extant inbred strains with substantial shared ancestry. QTL mapping revealed five significant and eight suggestive QTL for body weight (Chr 4, 7.54 Mb; CI 3.32-10.34 Mb; Bwq14), body composition, wheel running (Chr 16, 33.2 Mb; CI 32.5-38.3 Mb), body weight change in response to exercise (1: Chr 6, 77.7Mb; CI 72.2-83.4 Mb and 2: Chr 6, 42.8 Mb; CI 39.4-48.1 Mb), and food intake during exercise (Chr 12, 85.1 Mb; CI 82.9-89.0 Mb). Some QTL overlapped with previously mapped QTL for similar traits, whereas other QTL appear to represent novel loci. These results suggest that the CC will be a powerful, high-precision tool for examining the genetic architecture of complex traits such as those involved in regulation of energy balance.

Fig. 1.

Body weights (BW) and body fat percentages (BFP) in pre-CC and founder lines prior to running wheel access. A: phenotypic variation among founder strains exceeded the variation among the pre-CC lines for BW. BW for all pre-CC lines fell within the low and high extreme values of WSB/EiJ and NZO/H1LtJ, respectively. B: variation in BFP in pre-CC lines was comparable to that of founder strains. Although several pre-CC lines held extreme low BFP values, extreme high BFP were determined solely by NZO/H1LtJ. Group means for each founder line are indicated in black with appropriate color-coded asterisk above to indicate strain being depicted.

Fig. 2.

Nocturnal respiratory exchange ration (RER) in founder and pre-CC lines prior to exercise. RER (V̇co₂/V̇o₂), a measure of energy utilization, was far more variable in pre-CC lines than in founders. RER values of 0.7 ad 1.0 represent using pure fat or carbohydrate, respectively, as energy. Mixed diets tend to produce RER values between 0.8 and 0.9. Extreme values beyond 1.0 may indicate hyperactivity, anxiety, or stress. Several pre-CC lines demonstrated extreme low or high RER vs. founder lines. Group means for each founder line are indicated in black with appropriate color-coded asterisk above to indicate strain being depicted.

Fig. 3.

Average running distances in pre-CC and founder lines on days 5 and 6 (D56) and days 11 and 12 (D12) of ad libitum running wheel access. Mice were given 12 days of ad libitum running wheel access. Running distances and speeds were recorded continuously over 24 h in 1-min increments. Mean distances for D56 (A) and D12 (B) were exceedingly more variable among pre-CC lines than founder lines. Group means for each founder line are indicated in black with appropriate color-coded asterisk above to indicate strain being depicted.

Fig. 4.

Average daily food intake in founder and pre-CC mice during wheel access. Food intake was measured every other day during 12 days of running wheel access. Intakes were averaged across the 12 days and corrected for BW. Intakes are expressed as kcal·day⁻¹·BW⁻¹. Although NZO/H1LtJ held the extremely low food intake values, food intake among pre-CC lines varied greatly, with a few of the pre-CC lines representing extremely high food intake values. Group means for each founder line are indicated in black with appropriate color-coded asterisk above to indicate strain being depicted.

Fig. 5.

Net change in BW and BFP in pre-CC and founder lines after ad libitum access to running wheels for 12 days. BW (A) and BF (B) change in response to exercise was again more variable in pre-CC lines than in founders. Group means for each founder line are indicated in black with appropriate color-coded asterisk above to indicate strain being depicted.

Fig. 6.

Quantitative trait loci (QTL) maps for novel QTL identified on Chr 16 for average wheel running distances on days 5 and 6 (blue) and days 11 and 12 (red) in pre-CC mice. Dashed red and blue lines designate genome-wide significance threshold, P < 0.05. Select functionally relevant genes with colocalized expression (e)QTL are listed in their approximate locations within the region.