Ron Korstanje & Beverly Paigen
1. Using in silico Mapping to Evaluate Clustering of Quantitative Trait Loci
Previous work by Center faculty has established two critical properties of quantitative trait loci (QTL). First, they represent only a sub-set of the totality of genes functionally required for a complex trait such as the regulation of blood pressure or relative susceptibility to atherosclerosis. And second, the same sub-set of genes determine QTLs across mammalian species. QTLs for a given trait are often located at homologous chromosomal locations in human, mouse and rat. A probable explanation for these findings is that QTLs represent key regulatory functions whose role has been conserved over the course of mammalian evolution.
Given that the QTLs for various phenotypes are responsible for most of the population variation on which evolution can act and that the identity of these QTL is an ancient property of mammals, genome dynamics predicts that the QTLs for fundamental physiological properties are likely to be genetically linked to promote the co-inheritance of favorable allelic combinations. The hypothesis of this project is that functional domains are a general feature of mammalian chromosomal organization and will be revealed by the clustering of QTLs affecting a phenotype. Rigorously testing this hypothesis requires that we efficiently locate QTLs at a resolution of a few Mb or less across the diversity of Mus subspecies.
We are performing the following activities to test this hypothesis:
- Further developing in silico QTL mapping with the goals of improving its statistical validity, genetic resolution and efficiency.
- Characterizing the large number of strains collected for the Population Genetics project for a series of phenotypes that are quantitatively robust, and easy to collect.
- Determining in silico QTLs for the phenotypes using the SNPs genotyped in the Population Genetics project.
- Testing whether the QTLs for a trait cluster physically or belong to the same LD network.
2. Pathway Modeling Through Systems Genetics Approaches
The vast genetic resources at The Jackson Laboratory combined with the methods and tools developed by The Center for Genome Dynamics allow us to try a new approach to pathway modeling. In this systems genetics approach we focus on one pathway, perturb the pathway by changing the genetic and environmental background and measure as many parameters within the pathway as possible. Combining this systematically collected high-quality quantitative data with the Bayesian models build by Rachael Hageman result in quantitative models that can predict the effect of specific perturbations (e.g. drugs, genetic mutations) on the pathway. We are currently focusing on two pathways:
The involvement of the vitamin D pathway in the cardio-renal axis
The cardio-renal axis is the association between cardiac and renal function resulting in mutual pathologies, so patients with chronic renal function are likely to develop left ventricular hypertrophy (LVH), and those with LVH, chronic renal function. We are particularly interested in the role of vitamin D in this important syndrome. Mice from eight different inbred strains are being fed normal chow, vitamin D deficient, and vitamin D enriched diets and many parameters of the vitamin D pathway and renal and cardiac phenotypes are measured
Perturbing the HDL cholesterol pathway with ENU mutants
The Jackson Laboratory’s ENU mutagenesis program has identified an excellent collection of 19 mutant mice, all in the C57BL/6J background, that either have suppressed or elevated HDL. These are a great resource for understanding HDL regulation and for discovering novel genes. So far, the mutation in two of these lines has been identified (Scarb1 and Ldlr), while gene discovery in the other 17 lines is ongoing. We currently focus on the liver and look at the differential gene expression between the mutants and C57BL/6J. The expression profiles of the different mutant lines allow us to identify the genetic networks involved in the regulation of HDL cholesterol levels. In addition, the hepatocytes of the different lines can provide a model system that for each line has a different perturbation and therefore will have a different outcome when challenged. Therefore, primary cell cultures are being set up and used for quantitative studies on metabolic fluxes when being treated with HDL.
