Multiple linked mouse chromosome 7 loci influence body fat mass

Abstract

BACKGROUND: Congenic mouse strains contain donor mouse strain DNA in genomes otherwise identical to a background strain. They can be used to identify defined chromosomal regions containing obesity genes with small effects. OBJECTIVE: The objective of this study was to discover congenic strains containing genes that influence body fat in mice and to examine interactions between these genes. DESIGN: A survey of congenic strains showed that the B6.C-Tyr c H1 b Hbb d /By (B6.C-H1) congenic strain, with a 24 centiMorgan (cM) donor region from strain BALB/cBy on chromosome 7, had 50% less fat than background C57BL/6By (B6By) mice. The congenic donor region was then divided into 11 smaller overlapping subcongenic regions. Genotype effects on obesity traits in the subcongenics were determined by breeding heterozygotes for each line and comparing phenotypes of littermates with different donor genotypes. RESULTS: At least three subcongenic strains, two with overlapping donor regions and one with a nonoverlapping donor strain region, were found to exhibit significant influences of donor region genotype on obesity. A cross of the two overlapping subcongenics demonstrated that a single gene in the overlap region could not account for the observed obesity effects. We also observed significant obesity differences between genetically identical progeny that were contingent on the genotype of their subcongenic mothers.CONCLUSIONS: These results demonstrate the existence of at least three genes influencing obesity in three subcongenic strains with donor strain chromosomal regions whose size ranges from 0.5 to 5 cM. A maternal effect gene influencing obesity may be present in some subcongenic strains. IntroductionIdentification of natural alleles for complex traits such as obesity remains difficult but important because these studies survey the cumulative effects of evolution. While quantitative trait locus (QTL) mapping can identify broad chromosomal regions containing genes influencing complex traits, isolation of the specific underlying genes requires production of monogenic models. Congenic mouse strains can be used as monogenic models of complex traits. 1 Breeding two inbred strains to each other, and repeatedly backcrossing the progeny to the background strain for at least 10 generations produce congenic strains. The final congenic strain is identical to the background strain except for a selected donor region of highly variable size, and any unintended passenger donor regions (perhaps on other chromosomes) and spontaneous mutations occurring during breeding of the congenics. Although size, number and frequency of passenger donor chromosomal regions are usually unknown, their existence cannot be ruled out except by appropriate control experiments, such as those described in this manuscript.The congenic mouse strains surveyed for obesity traits in this study were originally produced by investigators studying histocompatability responses. 2 Historically, genes underlying the complex trait of tissue rejection were identified in...

A meta-analysis of quantitative trait loci associated with body weight and adiposity in mice

“…71 Thus, in addition to clustering of QTL, there is a striking Meta-analysis of QTL for body weight and adiposity S Wuschke et al overlap of these regions with candidate genes and markers implicated in control of body weight and body composition in rodents and humans. QTL mapping of complex traits is a promising technique, and the generation of novel rodent models, congenic and consomic lines [72][73][74][75] as well as application of bioinformatics methods, 76 including comparative genomics and genomewide haplotype analysis have provided progress towards identification of the genes responsible for the effects of a QTL. Our study may provide guidance for a further systematic investigation of candidate genes within the consensus QTL regions, and application of high-density single nucleotide polymorphism (SNP) maps.…”

Prolylcarboxypeptidase regulates food intake by inactivating α-MSH in rodents

“…Recently, we identified a B6.C-D7Mit353 subcongenic mouse line with less body fat than its B6By background control line (7). Phenotypic differences (such as obesity) between these background and congenic strains are due to polymorphisms in genes located in the congenic donor region located on chromosome 7.…”

“…PRCP initiates the degradation and inactivation of extracellular α-MSH [1][2][3][4][5][6][7][8][9][10][11][12][13] . We found that Prcp was expressed in neuronal populations that send efferents to areas where α-MSH [1][2][3][4][5][6][7][8][9][10][11][12][13] is released from axon terminals.…”

“…5). Once produced, α-MSH 1-13 undergoes a maturation process: desacetylated α-MSH 1-13 (Des-α-MSH [1][2][3][4][5][6][7][8][9][10][11][12][13] ) is converted to N-acetylated α-MSH [1][2][3][4][5][6][7][8][9][10][11][12][13] (Act-α-MSH [1][2][3][4][5][6][7][8][9][10][11][12][13] ) by an N-acetyltransferase that has not yet been identified (5,6). The acetylation of α-MSH 1-13 may serve as a protective measure that stabilizes the peptide against degradation to prolong its action on target cells.…”

Complex Inheritance of the 5-Lipoxygenase Locus Influencing Atherosclerosis in Mice

“…This, coupled with the growing evidence that some of the QTL for complex traits consist of multiple closely linked causal genes (Legare and Frankel 2000;Rogner et al 2001;Liu et al 2002;Diament and Warden 2004;Yalcin et al 2004;Flint et al 2005), lead us to hypothesize that the chromosome 6 locus may also represent such a multigenic region. To examine this, we created a panel of overlapping and reciprocal subcongenic lines from CON6.Ldlr À/À mice and characterized each line for development of atheroma in the proximal aorta.…”