There are a wide range of human clinical disorders in limb growth. Some are due to single genes while others are complex, due to many genes and their interactions with each other and the environment. Longitudinal studies of the cellular and molecular bases for variation in limb growth are hampered by the need for destructive or terminal sampling to obtain phenotypic measures, even in model organisms. We propose to measure genetic variation in long bone growth, associated histomorphological features, and gene expression in mice in order to identify the genetic and physiological processes underlying limb growth variations. These studies will be carried out with animals from the LGXSM Recombinant Inbred (Rl) strains. Previous mapping studies in the F2 intercross of these strains uncovered 17 genomic locations affecting adult long bone length. However, these earlier studies do not identify which developmental periods or physiological processes are responsible for variations in limb length. We will map limb growth QTLs in the Rl strains because this allows the collection of detailed phenotypes requiring terminal preparations at a series of consecutive ages on animals of identical genotype. Thus, we will be able to obtain """"""""longitudinal"""""""" data for limb growth traits for specific genotypes. Mapping limb growth QTLs in the Rl strains will identify genomic regions affecting long bone growth and its associated physiological and molecular processes to 15 cM regions of the genome. We will fine-map these QTLs in the Advanced Intercross (Al) line formed by repeatedly intercrossing LG/J and SM/J strains to the F32 generation. At this point they will have accumulated 16x the recombination generated in the original F2 intercross allowing for 16x the genomic mapping resolution (sub-cM scale). Positional candidate genes will be identified within the sub-cM QTL support regions and evaluated for sequence and expression differences between the parental lines. The outcome of these experiments will be a better understanding of the genetic, molecular, and cellular processes responsible for variation in limb growth with consequences for our understanding of pathologies of growth. ? ? ?
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