Research
Medical Genomics and Genetics,Gene Mapping Center
Determining the molecular basis of natural phenotypic variation, including inter-individual susceptibility to common diseases, is a central challenge of post-genome genetics. Our group is investigating the molecular genetic basis of common cardiovascular risk factors and disorders in experimental rodent and human populations. Within the Gene Mapping Center (GMC) we are providing state-of-the art platforms for high throughput genotyping of single nucleotide polymorphisms (SNPs) and microsatellite markers for linkage and association mapping as well as genome wide expression profiling.
Genome approaches to dissecting cardiovascular and metabolic disease
Heritable differences in gene expression have been proposed to play critical roles in biomedical phenotype and evolution including inter-individual susceptibility to common diseases. The spontaneously hypertensive rat (SHR) is a widely studied model of human hypertension and also has many features of the metabolic syndrome. SHR and Brown Norway (BN) are founder strains for the BXH/HXB recombinant inbred (RI) strains, one of the largest rodent RI panels for analysis of cardiovascular and metabolic phenotypes. The reference BN genome sequence, together with availability of tens of thousands of rat SNPs, a dense genetic map and the previous mapping of over 70 physiological and pathophysiological phenotypes in this RI panel, make SHR an excellent model for dissection of complex cardiovascular and metabolic traits. We applied integrated gene expression profiling and linkage analysis to the regulation of gene expression in fat, kidney, and adrenal tissue in the BXH/HXB panel of rat RI strains. About 15% of the eQTLs detected independently in the three tissues investigated were commonly regulated, with the majority acting in cis. This suggests that the preponderance of trans-acting eQTLs observed in the three separate tissues belong to tissue-specific networks for control of gene regulation. To investigate the overall effect of polymorphisms on gene expression levels, we compared the SNP frequency across the genome with the SNP frequency in eQTL genes. We found a highly significant enrichment of SNPs in the cis-regulated eQTL genes compared with either the trans-regulated eQTL genes or the observed rate across the genome. Cis-acting eQTLs are of particular interest as positional candidate genes for QTLs. We applied a comparative mapping strategy to explore the applicability of the detected cis-acting eQTLs to human hypertension. By forming a robust dataset of cis-acting eQTL genes with a false discovery rate <5% that were contained within rat blood pressure related QTLs, we identified the human orthologs and compared them with the location of previously mapped human blood pressure QTLs. This analysis defined a set of 73 attractive candidate genes for testing in human hypertension data sets. By identifying several of robustly mapped cis- and transacting expression QTLs in a model with large number of existing physiological QTLs, we generated a permanent resource to test the hypothesis that genetic variation in gene expression has a key role in the molecular evolution of complex physiological and pathophysiological phenotypes that may be seen in similar disorders in humans.
Gene Mapping Center (GMC)
The GMC serves as a core facility to MDC investigators. Moreover, it is open to any scientific collaboration that requires access to high throughput genotyping and expression technologies and assistance in the analysis of these datasets. These efforts are partially supported by the national genome research initiative, NGFN 2. Within NGFN 2, we are currently supporting a number of studies that encompass high throughput microsatellite marker and SNP genotyping projects for linkage analysis. In addition, we are providing genotyping, technical, and analytical support for a large-scale family based association study that aims to perform a genome wide association scan using half a million SNP genotypes per individual.