International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

E3 Neurpeptide Y is a Candidate Gene for an Obesity QTL

B. A. Taylor, C. Wnek, D. Schroeder, and S. J. Phillips. The Jackson Laboratory, Bar Harbor, ME 04609

We have extended the mapping of obesity QTLs to a 327-member intercross between the obese, diabetes-prone NZO/HlLt strain and the relatively lean, normoglycemic SM/J strain. Mice were weaned onto an 10.5% fat diet. At 16 weeks of age, mice were weighed, fasted overnight, then bled and killed. An adiposity index (AI) was defined as the sum of inguinal, gonadal, retroperitoneal and mesenteric fat pad weights, expressed as a percentage of body weight. Genome-wide screening revealed significant AI QTLs on Chromosomes 1, 2, 5, 6, 7, and 17. Jointly, these QTLs account for nearly half of the phenotypic variance. One striking feature of the data is the selective effects of particular QTLs on specific fat depots. The QTL lod scores for gonadal and inguinal fat pad percentages on Chromosome 2 are 7.9 and 0.5, respectively, while the corresponding lod scores on Chromosome 17 are 3.5 and 8.8. (A lod score of 4.3 is considered statistically significant.) The NZO strain contributes the fat promoting allele at one prominent AI QTL (lod=8.7) mapped to Chromosome 6 in the vicinity of the neuropeptide Y (Npy) gene. NPY is an abundant neuropeptide, whose hypothalamic expression is thought to stimulate feeding and lower metabolism. Mice deficient for both NPY and leptin are substantially less fat than mice lacking only leptin. NZO and SM were found to differ with respect to a previously reported microsatellite polymorphism within intron 2 of the Npy gene. Typing our cross placed Npy 1.6 cM proximal to the QTL peak, well within the 1-lod support interval. Amplification and sequencing of Npy exon 4 revealed a one nucleotide deletion in the 3' untranslated region (3' UTR) of the NZO allele (CTTTTCC CTTTCC). The SM heptanucleotide sequence (CTTTTCC) is conserved in mice, rats, and human NPY genes (GENBANK), and is located 26 bp downstream of the TGA stop codon in each case. Since 3' UTR sequences can affect message turnover and translation, we hypothesize that this deletion might disrupt normal regulation of the NZO Npy gene, resulting in overexpression. Further sequencing revealed that the heptanucleotide sequence is also conserved in Mus spretus, Mus caroli, and the Syrian hampster, Mesocricetus auratus. Thus, Npy remains an attractive candidate gene for an adiposity QTL.


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