Many inherited traits in the mouse, including important models for human diseases, result from the combined action of many genes. Several powerful approaches are currently being used to map and identify the polygenes that control these traits. However, these approaches are time-consuming and expensive, requiring extensive genotyping of large crosses, typically followed by many generations of breeding to construct congenic strains before fine-structure mapping and gene cloning and can be undertaken. We propose making specialized genetic resources, called chromosome substitution strains (CSSs), that greatly enhance the study of polygenic traits. The advantages of CSSs include polygene mapping without linkage testing crosses or genotyping, fewer mice that need to be phenotyped, and weaker phenotypes that can be detected. The choice of progenitor strains for these CSS panels was based on differences in important biological traits and disease models, including cancers, metabolic diseases, susceptibility to infections, drug addiction, skin diseases, learning, birth defects, hearing loss, bone mass, life span, and many others. Three of the panels are also useful for detecting and characterizing background genes that modulate the phenotype of mice with engineered mutations. We propose four Specific Aims:
Specific Aim 1. Construct a A.B6 panel to complement the soon to be completed B6.A panel.
Specific Aim 2. Construct complementary panels with progenitor strains C57BL/6J and 129/SvJ.
Specific Aim 3. Test feasibility of making a CSS panel with an inbred, wild-derived progenitor CAST/Ei.
Specific Aim 4. Test feasibility of using single nucleotide polymorphisms for making CSSs more efficiently. With the prospect of a complete sequence of the mouse genome in the not-too-distant future, increasing emphasis should be placed on ways to capture in a tractable form phenotypic variation in the mouse. Large-scale mutagenesis programs are being launched to collect new alleles having strong phenotypic effects. Similarly, new types of strains, such as CSS panels, should be constructed to facilitate the genetic dissection of important physiological processes.
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