Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
DNA – RNA – Protein transcription – translation Double stranded DNA Microarrays: An introduction to the biotechnology A B A Splitting into two single strands B mRNA Transcription from strand B A B E1 E2 E3 E4 Transcribed RNA RNA splicing results in an mRNA molecule E1 E2 E3 E4 mRNA is translated into protein Jan Komorowski Central dogma of molecular biology Gene expression patterns in physiology and pathophysiology normal resting normal stimulated gastric mucosa gastric mucosa Jan Komorowski gastric cancer type A type B Jan Komorowski 1 Sample Gene Expression Regulation • Physiological and pathophysiological responses are associated with specific changes in cellular gene expression • Insight into the specific patterns of gene expression associated with physiological and pathophysiological responses and conditions enable hypotheses about gene function and medical diagnosis a c c f f e b Why is gene expression worth studying? b d ¾ Physiology is the study of the body in a healthy state ¾ Pathophysiology is the study of disease states. u1 u5 u7 u8 u6 u2 u4 u3 Jan Komorowski Jan Komorowski Overview Pharmacogenomics • Genetic variability in drug response – Sensitivity of some individuals to debrisoquine: certain Cytochrome P450 gene mutations incapacitate the protein enzyme and cause poor drug metabolism, eventually leading to poisoning due to the extensive exposure to the drug. – Obtain a DNA test of the patient, make a decision based on his/her genetic make-up – Large DB’s of genetic and drug response data are commercially built for the discovery of geneticallybased rules of drug selection (e.g. Genometrix Inc.) And much more! Jan Komorowski Jan Komorowski 2 Hybridization Image after scanning Jan Komorowski Extracting Data Jan Komorowski Hierarchical Cluster Analysis Experiments Fluorescence ratios Samples 1 2 3 4 5 6 Gene 1 Red > green: up-regulated Gene 7 Red = green 200 10000 50.00 5.64 4800 4800 1.00 0.00 9000 300 0.03 -4.91 Cy3 Cy5 Genes Gene 6 Gene 8 Green > red : down-regulated Gene 3 Not available Cy5 log ( Cy5 ) Cy3 Cy3 Jan Komorowski Jan Komorowski 3 In a few words, microarrays are … Data analysis goals … devices for measuring relative gene expression levels of a large number of preselected genes What to study? • Classes of experiments; changes in expression levels in tissue samples with different e.g. diseases, treatments, environmental effects etc. • Classes of genes; expression profiles of genes with similar biological function • Both of the above Jan Komorowski Data analysis methods Jan Komorowski Example • Unsupervised learning (clustering, class discovery); used to “discover” natural groups of genes/experiments e.g. – discover subclasses of a form of cancer that is clinically homogenous • Supervised learning; used to “learn” a model of a set of predefined classes of genes/experiments e.g. – diagnosis of cancer/subclasses of cancer Jan Komorowski 96 normal and malignant lymphocyte samples Almost 20 000 cDNA clones Two sub-clusters of DLBCL were shown to include patients with significantly different expected survival time! Alizadeh et al., Distinct types of diffuse large Bcell lymphoma identified by gene expression profiling, Nature, 403:503-511, 2000. Jan Komorowski 4