Identification of positional candidate genes for body weight and adiposity in subcongenic mice

• Published in: Physiological genomics Vol. 31; no. 1; pp. 75 - 85
• Main Authors: Chiu, Sally, Kim, Kyoungmi, Haus, Kari A, Espinal, Glenda M, Millon, Lee V, Warden, Craig H
• Format: Journal Article
• Language: English
• Published: United States Am Physiological Soc 19-09-2007
• Subjects: Adipose Tissue - metabolism; Alleles; Animals; Body Weight; Chromosomes - ultrastructure; Genetic Techniques; Genotype; Heterozygote; Homozygote; Mice; Mice, Congenic; Mice, Inbred C57BL; Obesity; Oligonucleotide Array Sequence Analysis; Quantitative Trait Loci
• ISSN: 1094-8341; 1531-2267
• DOI: 10.1152/physiolgenomics.00267.2006

1 Rowe Program in Genetics, University of California, Davis, California
2 School of Veterinary Medicine, University of California, Davis, California
3 Section of Neurobiology, Physiology, and Behavior, University of California, Davis, California
We previously constructed a congenic mouse, B6.S- D2Mit194-D2Mit311 (B6.S-2) with 27 Mb of SPRET/Ei donor DNA on distal chromosome 2 in a C57BL/6J background that captured an obesity quantitative trait locus (QTL). Mice homozygous for SPRET/Ei alleles at the donor region had decreased body weight and obesity-related phenotypes (Diament AL, Farahani P, Chiu S, Fisler J, Warden CH. Mamm Genome 15: 452–459, 2004). In this study, we constructed five overlapping subcongenics with smaller SPRET/Ei donor regions to fine map the underlying gene(s). One of the five subcongenic lines derived from the B6.S-2 founding congenic, B6.S-2A, captured the body weight and adiposity phenotypes in a donor region with a maximum size of 7.4 Mb. Homozygous SPRET/Ei donor alleles in both the founding congenic and the derived B6.S-2A subcongenic exhibited significant decreases in body weight, multiple fat pad weights, and adiposity index (total fat pad weight divided by body weight). Interval-specific microarray analysis in four tissues for donor region genes from the founding B6.S-2 congenic identified several differentially expressed genes mapping to the B6.S-2A subcongenic donor region, including prohormone convertase 2 (PC2; gene name: Pcsk2 ). Quantitative real-time PCR confirmed a modest decrease of PC2 expression in brains of mice homozygous for SPRET/Ei donor alleles. Analysis of the relative levels of mRNA for B6 and SPRET/Ei in heterozygous congenic mice showed differentially higher expression of the C57BL/6J allele over the SPRET/Ei allele, indicating a cis regulation of differential expression. Using subcongenic mapping, we successfully narrowed a body weight and obesity QTL interval and identified PC2 as a positional candidate gene.
quantitative trait locus mapping; mouse chromosome 2; congenic strains; microarray