Physiological Genomics from Rats to Human,Monika Stoll, Ph.DDirector, Genetic Epidemiology of vascular disorders Leibniz-Institute for Arteriosclerosis Research, Mnster,Genetic Variation influences - disease susceptibility- disease progression- therapeutic response- unwanted drug effects,The use of genetic variation for diagnostic purposes and targeted treatment,Genome-oriented Medicine,“Heterogeneity “ of complex diseases,complex phenotype,“polygenic with genetic Heterogeneity”,“Environmental factors”,Salt intake,Psychosocial Stress,Diet,others,Gene+,Gene +,Gene -,Gene+,Gene+,Gene -,Epistasis,Gene-environment interactions and CVD,Genetic factors,Diet, Smoking, Stress,Hypertension, Diabetes, Obesity, Age, Lipids, Genetic Background,Atherosclerosis,Myocardial infarction,Stroke,Peripheral vascular disease,Environment,Risk factors,Trait,Phenotype,Complex Diseases do not have a clear phenotype but may or may not share some features,Example: metabolic syndrome (syndrome X),hypertension,hyperglycemia,dislipidemia,obesity,athero-sclerosis,Insulin resistance,vascular disease,Polygenic: modest effects of single genesIncomplete penetrance Age-of-onset Environmental component Genetic Heterogeneity,High Complexity,Difficulties,Disease Etiology,Family studies/ Sib-Pair Analysis: large number of patients (2,500 sibpairs) Modest resolutionMultiple Genes: Interaction, Epistasis,Lack of Power,Difficulties,Human Linkage Analysis,Genetics of Multifactorial Diseases,Solutions,Reduction of complexity,Solutions,Association studies,Comparative Maps,Positional candidate loci for high density genotyping,Genetics of Multifactorial Diseases,Comparative Genomics with Biology,Human,Mouse Rat,Genes, Physiology and Pharmacology relevant to human disease,Genes and Genetic Manipulation relevant to human disease,Ability to avoid many biological barriers unique to one species,Why Comparative Genomics?Take advantage of the wealth of genome information from the various Genome Projects Genomic regions are evolutionary conserved between mammalian species (Synteny)Sequence is highly conserved between species (Homology)The genomic sequence of human, rat and mouse genomes are availableQTLs/Genes identified in rodent models are predictive for human lociRodent models can help to elucidate the function of novel disease genes e.g. implicated by human linkage studies or expression profiling,Strategies for comparative genomics,Map novel genes identified e.g. in expression profiling and anchor on existing comparative maps (www.rgd.edu/VCMap)Sequence positional candidate genes in mouse, rat and human to identify conserved mutations and/or regulatory elementsPredict potential target regions for human linkage studies based on model organismsCharacterize candidate genes from human studies in representative experimental model (inbred strains, congenics, transgenics, conditional knock-outs),Experimentelles Modell,Monogene Erkrankung,Geschwisterpaar-Untersuchungen: Besttigung Kandidatengen-Locus,Assoziationsstudien: Identifizierung von Kandidatengen-Polymorphismen,(polygene) komplexe Erkrankung,Cross design,SHR-SP,SHR or WKY,F1,Backcross,F2,F2,x,SHR-SP,SHR or WKY,F1,Human Chromosome Regions Implicated in Hypertension via a Cross-Species Comparison,Blood Pressure Phenotypes,Rat Models for Genetic Hypertension,SHR x WKY SHR x DNY SHR x BN,GH x BN,SS x BN,LH x LN,Spontaneously Hypertensive Rat (SHR) High blood pressure Cardiovascular disease,Genetically Hypertensive Rat (GH) Hypertension, cardiac hypertrophy Vascular disease, not salt-sensitive,Dahl Salt-Sensitive Rat (SS) Salt-sensitive hypertension Hyperlipidemia, insulin resistance,Lyon Hypertensive Rat (LH) Mild hypertension, hyperlipidemia,Fawn-hooded Hypertensive Rat (FHH) Systolic hypertension Renal failure,FHH x ACI,Linkage Analysis for Blood Pressure QTLs,Independent total genome scans in 7 intercrosses representing a model for genetic hypertension,200-300 SSLP markers 10-20 cM spacing 57- 390 animals,Linkage analysis using MAPMAKER/QTL computer package,LOD score 2.8 suggestive LOD score 4.3 significant,Integration of QTLs on integrated map based on genotyping information from crosses used for linkage analysis,QTL #1,QTL #2,QTL #3,QTL cluster,Drop of 1.6 LOD units = 95% confidence interval,Analysis of QTL Clustering,Establishment of Syntenic Regions in Human Genome,Identification of syntenic regions and evolutionary breakpoints using comparative maps between rat, mouse and human,Definition of positional candidate regions in human genome based on QTLs identified in rat models of hypertension,Designation of first priority and second priority regions,first priority regionbased on QTLs from multiple rat crosses,second priority regionbased on QTLs from single rat cross,