A locus on mouse Chromosome 9 (Adip5) affects the relative weight of the gonadal but not retroperitoneal adipose depot

Abstract

To identify the gene or genes on mouse Chromosome 9 that contribute to strain differences in fatness, we conducted an expanded mapping analysis to better define the region where suggestive linkage was found, using the F(2 )generation of an intercross between the C57BL/6ByJ and 129P3/J mouse strains. Six traits were studied: the summed weight of two adipose depots, the weight of each depot, analyzed individually (the gonadal and retroperitoneal depot), and the weight of each depot (summed and individual) relative to body size. We found significant linkage (LOD = 4.6) that accounted for the relative weight of the summed adipose depots, and another for the relative weight of the gonadal (LOD = 5.3) but not retroperitoneal (LOD = 0.9) adipose depot. This linkage is near marker rs30280752 (61.1 Mb, Build 34) and probably is equivalent to the quantitative trait locus (QTL) Adip5. Because the causal gene is unknown, we identified and evaluated several candidates within the confidence interval with functional significance to the body fatness phenotype (Il18, Acat1, Cyp19a1, Crabp1, Man2c1, Neil1, Mpi1, Csk, Lsm16, Adpgk, Bbs4, Hexa, Thsd4, Dpp8, Anxa2, and Lipc). We conclude that the Adip5 locus is specific to the gonadal adipose depot and that a gene or genes near the linkage peak may account for this QTL.

Fig. 1

Mapping results for absolute and relative adipose depot weight. RP = retroperitoneal adipose depot, GON = gonadal adipose depot, BOTH = sum of the RP and GON depot. RP, GON, and BOTH are expressed either as absolute adipose-depot weights or relative to body size (bs). LOD scores plotted are obtained using unconstrained (free) model. Peaks for the absolute weight of the depots near the telomere do not reach threshold for suggestive linkage (observed LOD = 2.3; criterion LOD = 2.8 for an unconstrained model).

Fig. 2

Means for each trait expressed as z scores with the standard error of the mean. “129” refers to the alleles of the 129P3/J strain and “B6” refers to alleles of the C57BL/6ByJ strain. Data are grouped by genotype at marker rs30280752. The means of groups with different subscripts differ by post hoc analysis. See text for significance tests and other details.

Fig. 3

Detailed map of linkage peak region (50–70 Mb). The linkage peak was anchored to markers within 10 Mb from the peak. The haplotype blocks are displayed under the linkage map with light blue demonstrating discordant regions and purple demonstrating regions of concordance. Markers used in mapping the chromosome are displayed in pink immediately under the haplotype blocks. Beneath the markers, candidate genes that were chosen for their functional significance (Table 4) are displayed as follows: gene names in red are lower-priority candidates, gene names in black are medium-priority candidates, and gene names in blue are the highest-priority candidates. Directly beneath the candidate genes are the known cSNPs located within the sequence of the highest priority candidates. The amino acid residue changes and their positions within the polypeptide sequence of the resulting protein are also in blue under the SNP identifier. The approximate position of the map is shown in 5-Mb increments (bottom).