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Date of Award

Spring 5-15-2010

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

The analysis of "mutant" growth phenotypes with Mendelian properties has been successful at identifying key genetic and environmental contributors to bone development, but the molecular basis of "normal" bone length variation remains unknown. A quantitative genetics approach can identify genomic elements (quantitative trait loci; QTL) with complex genetic properties that play smaller, modulatory roles in development. Individuals from the F2-3, F9-10, and F34 generations (n ~ 5000) of the LG,SM advanced intercross were SNP-genotyped and QTL for humerus, ulna, femur, and tibia lengths were mapped using standard quantitative genetics techniques, resulting in the identification of ~40 pleiotropic QTL with complex genetic architectural elements, including epistasis as well as diet- and sex-specific QTL. Developmental differences between LG/J and SM/J parental strains were characterized by examining bone lengths and stained sections of the proximal tibia from just prior to birth through 6 weeks of age, revealing that bone length variation between LG/J and SM/J occurs postnatally and results from changes in the rate at which elongation slows as the mice age. Finally, QTL positional candidate genes were evaluated by assessing mRNA expression levels in the growth plate and analyzing coding region sequence differences between LG/J and SM/J. The presence of relatively few nonsynonymous changes in protein sequence and increased expression of some candidate genes suggests that more variation in bone length may be explained by mutations in genetic regulatory elements than mutations in coding regions. Future work will focus on understanding how individual mutations interact with other genomic elements and the environment to produce variation in adult bone lengths.

Language

English (en)

Chair and Committee

Guojun Bu

Committee Members

Stuart Kornfeld, David Piwnica-Worms

Comments

Permanent URL: https://doi.org/10.7936/K7NS0S2G

Available for download on Thursday, May 15, 2110

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