Identification of genetic determinants of IGF-1 levels and longevity among mouse inbred strains.
The IGF-1 signaling pathway plays an important role in regulating longevity. To identify the genetic loci and genes that regulate plasma IGF-1 levels, we intercrossed MRL/MpJ and SM/J, inbred mouse strains that differ in IGF-1 levels. Quantitative trait loci (QTL) analysis of IGF-1 levels of these F2 mice detected four QTL on chromosomes (Chrs) 9 (48 Mb), 10 (86 Mb), 15 (18 Mb), and 17 (85 Mb). Haplotype association mapping of IGF-1 levels in 28 domesticated inbred strains identified three suggestive loci in females on Chrs 2 (13 Mb), 10 (88 Mb), and 17 (28 Mb) and in four males on Chrs 1 (159 Mb), 3 (52 and 58 Mb), and 16 (74 Mb). Except for the QTL on Chr 9 and 16, all loci co-localized with IGF-1 QTL previously identified in other mouse crosses. The most significant locus was the QTL on Chr 10, which contains the Igf1 gene and which had a LOD score of 31.8. Haplotype analysis among 28 domesticated inbred strains revealed a major QTL on Chr 10 overlapping with the QTL identified in the F2 mice. This locus showed three major haplotypes; strains with haplotype 1 had significantly lower plasma IGF-1 and extended longevity (P < 0.05) than strains with haplotype 2 or 3. Bioinformatic analysis, combined with sequencing and expression studies, showed that Igf1 is the most likely QTL gene, but that other genes may also play a role in this strong QTL.
Leduc
Magalie S
MS
The Jackson laboratory, Bar Harbor, ME 04609, USA.
Hageman
Rachael S
RS
Meng
Qingying
Q
Verdugo
Ricardo A
RA
Tsaih
Shirng-Wern
SW
Churchill
Gary A
GA
Paigen
Beverly
B
Yuan
Rong
R
D000818:Animals; D004247:DNA / Q000235:genetics; D005260:Female; D005838:Genotype; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008136:Longevity / Q000235:genetics*; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D019463:Mice, Inbred MRL lpr; D020411:Oligonucleotide Array Sequence Analysis
C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D004247:DNA