1. Develop an efficient, low cost SNP genotyping system for experimental murine intercrosses. - A database for computational selection of genotyping primers will be established. Assays for 200 SNPs, with a known chromosomal location will be produced, and alleles in 10 inbred murine strains and two different mouse species will be characterized. - Two experimental murine intercross populations will be genotyped by this method. 2. Demonstrate that this method can accurately determine allele frequencies in pooled murine DNA samples, which will greatly accelerate complex train analysis in murine genetic models of human disease. DNA samples from phenotypically extreme F2 progeny (top or bottom 10%) will be pooled to form two groups, and genotyped to rapidly identify chromosomal regions regulating susceptibility to emphysema and polycystic kidney disease. 3. The accuracy and reproducibility of this method for pooled human DNA samples will be determined. To identify cardiovascular disease susceptibility genes, DNA samples from 1000 probands and 1000 case controls have been individually genotyped at 35 SNPs in 16 genes. The samples will be pooled into disease affected and control groups and allele frequencies in the pooled samples will be measured and compared to the results from genotyping individual samples. - The statistical significance of the measured differences, and the sensitivity of screening studies of this type to detect disease-associated polymorphisms will be assessed.
| Klein, Robert F; Allard, John; Avnur, Zafrira et al. (2004) Regulation of bone mass in mice by the lipoxygenase gene Alox15. Science 303:229-32 |
| Liao, Guochun; Wang, Jianmei; Guo, Jingshu et al. (2004) In silico genetics: identification of a functional element regulating H2-Ealpha gene expression. Science 306:690-5 |
| Grupe, A; Germer, S; Usuka, J et al. (2001) In silico mapping of complex disease-related traits in mice. Science 292:1915-8 |
