Inherited differences in DNA sequence contribute to phenotypic variation, influencing an individual's risk of disease and response to the environment. A central goal of genetics is to pinpoint the DNA variants that contribute most significantly to variation in each trait. The rat is an important model organism for systems biology, provides the most relevant models of common multifactorial human disease, and it is by far the leading model species in pharmacology and toxicology. It has been the major model for physiological investigation, providing a body of data on patho-physiology, including detailed mechanistic, biochemical and metabolic characterisation that cannot be replaced by other models. Decades of exquisite phenotyping and detailed analysis of crosses of inbred rats have resulted in initial localization of hundreds of loci involved in complex disease and quantitative phenotypes, but with very few eventual gene identifications to date. A clear understanding of the origin and structure of genetic variation in the rat will provide a key missing piece of this puzzle. To fully realize the power of the recent rat genome sequence, we propose to initiate the complete genetic dissection of the ancestral segments making up the most commonly used inbred lines. The proposed SNP based haplotype map provides a valuable tool for functional genomics, specifically by focussing positional cloning of QTLs through:
i) the reduction of regions obtained through linkage analysis via identification of segments shared by the strains used for the cross;
ii) the selection of ideal strain combinations for further reduction of critical regions through simple intercross/backcross experiments;
iii) the use of correlation between phenotype and ancestral sequence origin across many inbred strains to identify very short genomic regions most likely to harbor responsible genes.
Field of science
- /natural sciences/biological sciences/genetics and heredity/dna
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