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Submitted on March 3, 2006
Accepted on April 24, 2006
The Jackson Laboratory, Bar Harbor Maine; The University of Connecticut Medical Center, Farmington Connecticut; The University of Texas Health Sciences Center at San Antonio, San Antonio, Texas
* To whom correspondence should be addressed. E-mail: rofe{at}aol.com.
We identified quantitative trait loci (QTL) that determined the genetic variance in serum IGF-I through genome-wide scanning of mice derived from C57BL/6J(B6) x C3H/HeJ(C3H) inter-crosses. One QTL (Igf1s2), on mouse Chromosome 10 (Chr10), produces a 15% increase in serum IGF-I in B6C3 F2 mice carrying c3 alleles at that position. We constructed a congenic mouse, B6.C3H-10 (10T), by backcrossing c3 alleles from this 57 megabase(Mb) region into B6 for 10 generations. 10T mice have higher serum and skeletal IGF-I, greater trabecular bone volume fraction (BV/TV), more trabeculae, and a higher number of osteoclasts at 16 weeks compared with B6 (P < 0.05). Nested congenic sublines generated from further backcrossing of 10T allowed for recombination and produced 4 smaller sublines with significantly increased serum IGF-I at 16 weeks (i.e. 10-4, 10-7, 10-10, and 10-13)compared with B6, P < 0.0003, and three smaller sublines which showed no differences in IGF-I vs. age and gender matched B6 mice. Like 10T, the 10-4 nested sublines at 16 weeks had higher femoral mineral (P < 0.0001), and greater trabecular connectivity density with significantly more trabeculae than B6(P < 0.01). Thus, by comprehensive phenotyping, we were able to narrow the QTL to an 18.3Mb region containing approximately 148 genes, including Igf1, and Elk-3(ETS domain protein). Allelic differences in the Igf1s2 QTL produce a phenotype characterized by increased serum IGF-I and greater peak bone density. Congenic mice establish ‘proof of concept’ of shared genetic determinants for both circulating IGF-I and bone acquisition.
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