In this project we examine the developmental and genetic bases for variation in long bone growth. Advances in developmental biology over the last decades have greatly enhanced our knowledge of vertebrate limb development. However, it is often not clear which developmental processes are responsible for normal and pathological variation in limb length. Is such variation primarily due to the developmental patterning genes active during limb outgrowth, such as the Tbox and Hox genes, or is it primarily due to genes affecting the size of the original mesenchymal condensations from which the limb bones form, such as Msx1 and Sox9, or even genes affecting later growth processes localized to the growth plates of the limb bones, such as Fgfr3 and Ihh? We will approach these questions using both quantitative genetic and quantitative trait locus (QTL) mapping procedures to identify genes and genomic regions affecting long bone growth from limb formation in the fetus through the adult. Longitudinal studies of the cellular and molecular bases for variation in limb growth are hampered by the need for terminal sampling to obtain phenotypic measures, even in model organisms. By using mice from Recombinant Inbred (RI) strains as a model system, we will be able to perform “longitudinal” growth studies for individual genotypes. Comparison of growth rates and patterns across strains of a RI set allows us to identify genomic regions, and eventually genes, responsible for variation in skeletal growth.

Collaborators

Dr. Linda Sandell, Washington University
Dr. Nelly Farnum, Cornell University
Dr. David Ornitz, Washington University
Dr. Thomas Sanger, Loyola University

Grant Funding

Supported by NIAMS grant AR053224

Publications on the Topic

Pavlicev, M., G. P. Wagner, J. P. Noonan, B. Hallgrimsson, and J. M. Cheverud. 2013. Genomic correlates of relationship-QTL involved in fore- vs. hind limb divergence in mice. Genome Biology and Evolution, 5:1926-1936.

Pavlicev, M., E. A. Norgard, G. L. Fawcett and J. M. Cheverud. 2011. Evolution of pleiotropy: Epistatic interaction pattern supports a mechanistic model underlying variation in genotype-phenotype map. Journal of Experimental Zoology (Molecular and Developmental Evolution), 316: 371-385.

Norgard, E. A., H. A. Lawson, L. S. Pletscher, B. Wang, V. R. Brooks, J. B. Wolf and J. M. Cheverud. 2011. Complex factors and diet affect long bone length in the F₃₄ LG,SM advanced intercross. Mammalian Genome 22: 178-196.

Sanger, T. J., E. A. Norgard, L. S. Pletscher, M. Bevilacqua, V. R. Brooks, L. M. Sandell, and J. M. Cheverud. 2011. Developmental and genetic origins of murine long bone length variation. Journal of Experimental Zoology (Molecular and Developmental Evolution), 316: 146-161.

Norgard, E. A., J. P. Jarvis, C. C. Roseman, T. J. Maxwell, J. P. Kenney-Hunt, K. E. Samocha, L. S. Pletscher, B. Wang, G. L. Fawcett, C. J. Leatherwood, J. B. Wolf and J. M. Cheverud. 2009. Replication of long bone length QTL in the F₉ – F₁₀ LG,SM advanced intercross. Mammalian Genome 20:224-235.

Norgard, E, Roseman, C, L Fawcett, G, Pavličev, M, D Morgan, C, Pletscher, L, Wang, B & Cheverud, J. (2008) 'Identification of quantitative trait loci affecting murine long bone length in a two-generation intercross of LG/J and SM/J mice', Journal of Bone and Mineral Research, vol. 23, no. 6, pp. 887-895. doi:10.1359/jbmr.080210 [pdf] [Supplement]

Kenney-Hunt, J, Vaughn, T, Pletscher, L, Peripato, A, Routman, E, Cothran, K, Durand, D, Norgard, E, Perel, C, & Cheverud, J. (2006) 'Quantitative trait loci for body size components in mice', Mammalian Genome, vol. 17, pp. 526-537. doi:10.1007/s00335-005-0160-6 [pdf]