Research Report 2010 - MDC

Norbert HübnerStructure of the GroupGroup LeaderProf. Norbert HübnerScientistsDr. Anja BauerfeindDr. Claudia GöseleOliver HummelDr. Svetlana PaskasDr. Giannino PatoneDr. Carola RintischDr. Franz RüschendorfDr. Klaus RohdeDr. Kathrin SaarDr. Herbert SchulzMedical Genomics and Genetics ofComplex Cardiovascular DiseasesMy group is investigating the molecular genetic basis of common cardiovascular riskfactors and disorders in experimental rodent and human populations. We are workingwith inbred rat strains since they provide one of the most relevant models of commonmultifactorial cardiovascular human disease. It has been the major model for physiologicalinvestigation, providing a body of data on patho-physiology, including detailed mechanistic,biochemical and metabolic characterisation that cannot easily be replaced by other models.The work of our group focuses on the development of genomic tools and to utilize these forfunctional genetic and genomic approaches for complex disease gene identification.Additionally my group has an increasing interest in translating findings from modelorganisms to humans by comparative genome analysis.Establishment of functional genetic and genomicresources for the ratWe have developed a large number of genomicresources to facilitate functional genomic studies in therat. These efforts included long-range physical mapsand characterization of single nucleotide variationwithin the rat genome. We contributed to the annotationand assembly of the rat genome sequence. Therecent availability of the rat genome sequence andassociated genomic tools has raised the profile andpace of research into genetic analysis of rat traits anddramatically accelerated prospects for gene identification.Decades of exquisite phenotyping and detailedanalysis of crosses of inbred rats have resulted in initiallocalization of hundreds of loci involved in complex diseaseand quantitative phenotypes, but with very feweventual gene identifications to date. A clear understandingof the origin and structure of genetic variationin the rat will provide a key-missing piece of this puzzle.To fully realize the power of the recent rat genomesequence, we are currently initiating the completegenetic dissection of the ancestral segments makingup the most commonly used inbred lines.Haplotype mapping for genetic analysis in the ratGenetic variation in genomes is organized in haplotypeblocks and species-specific block structure is defined bydifferential contribution of population history effects incombination with mutation and recombination events.Haplotype maps characterize the common patterns oflinkage disequilibrium in populations and have importantapplications in the design and interpretation ofgenetic experiments. Although evolutionary processesare known to drive the selection of individual polymorphisms,their effect on haplotype block structuredynamics has not been shown.We have led an international consortium (STAR) andreported a survey of genetic variation based on almost3 million newly identified SNPs. We constructed highdensitygenetic maps, creating a large dataset of fullycharacterized SNPs for disease gene mapping. Our datacharacterize the population structure and illustrate thedegree of linkage disequilibrium. We provide a detailedSNP map and demonstrate its utility for mapping quantitativetrait loci. This community resource is openlyavailable and augments the genetic tools for studyingthis model of human disease.30 Cardiovascular and Metabolic Disease Research