Loci on chromosomes 2, 4, 9, and 16 for body weight, body length, and adiposity identified in a genome scan of an F2 intercross between the 129P3/J and C57BL/6ByJ mouse strains

Abstract

Mice have proved to be a powerful model organism for understanding obesity in humans. Single gene mutants and genetically modified mice have been used to identify obesity genes, and the discovery of loci for polygenic forms of obesity in the mouse is an important next step. To pursue this goal, the inbred mouse strains 129P3/J (129) and C57BL/6ByJ (B6), which differ in body weight, body length, and adiposity, were used in an F2 cross to identify loci affecting these phenotypes. Linkages were determined in a two-phase process. In the first phase, 169 randomly selected F2 mice were genotyped for 134 markers that covered all autosomes and the X Chromosome (Chr). Significant linkages were found for body weight and body length on Chr 2. In addition, we detected several suggestive linkages on Chr 2 (adiposity), 9 (body weight, body length, and adiposity), and 16 (adiposity), as well as two suggestive sex-dependent linkages for body length on Chrs 4 and 9. In the second phase, 288 additional F2 mice were genotyped for markers near these regions of linkage. In the combined set of 457 F2 mice, six significant linkages were found: Chr 2 (Bwq5, body weight and Bdln3, body length), Chr 4 (Bdln6, body length, males only), Chr 9 (Bwq6, body weight and Adip5, adiposity), and Chr 16 (Adip9, adiposity), as well as several suggestive linkages (Adip2, adiposity on Chr 2, Bdln4 and Bdln5, body length on Chr 9). In addition, there was a suggestive linkage to body length in males on Chr 9 (Bdln4). For adiposity, there was evidence for epistatic interactions between loci on Chr 9 (Adip5) and 16 (Adip9). These results reinforce the concept that obesity is a complex trait. Genetic loci and their interactions, in conjunction with sex, age, and diet, determine body size and adiposity in mice.

Fig. 1

Average adiposity (top), body length (middle), and body weight (bottom) of B6 (females N = 10, males N = 10), 129 (females N = 10, males N = 10), and F₂ (females N = 228, males N = 229) mice. Group means that share at least one letter in a superscript do not differ (p > 0.05, post-hoc test; LSD).

Fig. 2

Distribution of adjusted traits in the F₂ generation (N = 457).

Fig. 3

LOD scores (unconstrained model) from a genome scan with adjusted body weight, body length, and adiposity as phenotypes (N = 169). The lower line reflects the threshold for suggestive (LOD ≥ 2.8) linkage, and the upper line reflects the threshold for significant linkage (LOD ≥ 4.3) for an unconstrained model.

Fig. 4

Chr 2 LOD score curves (N = 457). For body weight, the confidence interval 1 extends from 24 to 84 cM; for body length, from 65 to 75 cM; for adiposity, from 48 cM to the telomere. LOD score traces are shown for unconstrained model to facilitate comparison across phenotypes.

Fig. 5

Chr 9 LOD score curves (N = 457). For body weight, the confidence interval extends from 68 cM to the telomere; for body length, from 30 cm to the telomere; for adiposity, from 6 to 54 cM. LOD score traces are shown for the modes of inheritance listed in Table 6 for each phenotype. Note that a second peak for body weight near D9Mit306 does not meet the criteria for suggestive linkage.

Fig. 6

Chr 16 LOD score curves (N = 457). For adiposity, the confidence interval extends from 35 to 64 cM. LOD score traces are shown for the unconstrained model to facilitate comparison across phenotypes.

Fig. 7

Epistatic effects on adiposity from loci on Chr 9 (Adip5) and Chr 16 (Adip9). F₂ mice homozygous for the 129 allele at marker D9Mit25 have higher adiposity if they are also homozygous for the B6 genotype at marker D16Mit9 compared with mice with all other genotypes at these loci.