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Pharmacogenomics Ch 9 pg 232 Pharmacology + Genomics How genome affects body response to disease, drugs People inherit/exhibit differences in drug : Absorption Metabolism and degradation of the drug Transport of drug to the target molecule Excretion of the degradation products 1 Goals of pharmacogenomics Use drugs better and use better drugs Patient Outcomes by Year 1 AERS = Adverse Events Reporting System. This system managed by the U.S. Food and Drug Administration (FDA) contains over four million reports of adverse events and reflects data from 1969 to the present. 2 Year 2004 2005 2006 2007 2008 2009 2010 Total 2006-2010 % Chg Death 34,928 40,238 37,465 36,834 49,958 63,846 82,724 Serious 199,510 257,604 265,130 273,276 319,741 373,535 471,291 270,827 +66.7% 1,702,973 +77.5% GOALS Dosage and drug specific to individual Get it right first time Create individual metabolic profile Screen 3 presymptomatic carriers preimplantation, prenatal, newborn disease susceptibility Barriers Complexity – there are millions of SNPs Which genes affect drug response? Disincentive for companies $$ for small population Educating physicians in genetics 4 Will be commonplace in the doctors office Genetic ID cards? Certain diseases have gene expression “signatures” 5 SNPs Chapter 8 pg 192 6 DNA polymorphisms People differ in nucleotide sequence Coding sequences Non-coding sequences (most) Used as DNA markers Evolution To identify individuals To diagnose disease To diagnose genetic predisposition Potential of individual to develop disease based on hereditary factors 7 Can assist in The study of how non-genetic factors interplay with genetic 8 SNPs = Single nucleotide polymorphisms (handout and CH 8 pg 270) DNA sequence variations due to a single nucleotide in the genome Occur ~1/300 bases in human genome ~ 90% of all human genetic variation Effort underway to map all human SNPs (~3 million) What is the size of the human genome in base pairs? SNPs Albuterol and SNPs Utah 10 Many SNPs have no effect on cell function Others could: cause disease predispose influence disease progression influence response to a drug 11 SNP Read the gel results 12 Tumor gene Find the SNP HapMap project Haplotype SNPs that tend to be inherited together. Association studies 14 DNA Microarrays pg. 239 Microarrays =small, glass slide spotted with short ssDNA sequences from ~20,000 different genes at fixed locations oligonucleotides ~20 bases single stranded 15 Skin cancer microarray animation 1. Obtain samples blood, tissue, tumor etc. 16 What is the difference in gene expression in normal versus cancerous tissue? 2,3. Isolate mRNA Expressed genes only Quantitative 4. Reverse transcribe mRNA to cDNA cDNA more stable than mRNA Fluorescently labeled nucleotides used 17 5. Coat microarray chip with tagged cDNAs Hybridization - Immobilized target oligos found by probe DNA (the cDNAs) and nucleotides hybridize Transcriptic microarray (vs. genomic) You tube phg foundation plants 6. Scan for fluorescence 19 20 GREEN =Control DNA, cDNA derived from normal tissue hybridized to oligo DNA. RED = Sample DNA, cDNA iderived from diseased tissue hybridized YELLOW = combination of Control and Sample DNA, both hybridized equally to target DNA. BLACK =neither Control nor Sample DNA hybridized . . 21 Yeast flash animation Case study microarray 76 patients with acute myeloid leukemia DNA microarrays of 23,040 genes used to study gene expression . Identified 63 overexpressed genes and 373 suppressed genes 22 Among the over- and underexpressed genes, 28 were found to have different expression levels between patients who responded to chemotherapy and those who did not respond. (!) 40 of 44 patients with a certain expression pattern underwent remission. Compared 3of 20 patients in the other group. Similar investigations are being undertaken in many other diseases, with the common goal of being able to predict therapeutic response prospectively through genomic methods, thereby allowing physicians to create far more specific and personalized treatment plans. http://radiology.rsna.org/content/231/3/613.full 2011 Microarrays and molecular markers for tumor classification Brian Z Ring and Douglas T Ross Human cancers have been classified according to tissue of origin, histological characteristics and, to some extent, molecular markers. Clinical studies have associated different tumor classes with differences in prognosis and in response to therapy. Measurement of the expression of thousands of genes in hundreds of cancer specimens has begun to reveal novel molecularly defined subclasses of tumor; some of these classes appear to predict clinical behavior, while others may define tumor types that are ripe for directed development of therapeutics. 23 The future (and present) Transcriptome Collection of all RNA transcripts (m, t, rRNA) Tissue specific gene expression Which genes are on/off Varies with cell type, environment, disease, etc.. Use microarrays 24 The transcriptome includes transcribed: coding sequences non-coding sequences 25 <5% of human genome is transcribed Metabolome All the small molecules involved in metabolic pathways 3000 common metabolites in body tissues and biofluids Dynamic! 26 Proteome All proteins in the cell Larger than the genome Alternative splicing Post translational modification Different proteins are found in different cells Why proteins Catalyze chemical reactions Mount an immunological response to infection chemical messengers to regulate growth, development, reproductive function, and metabolism. 27 Microbiome Human gut and how it changes with disease 10X more bacteria in/on human body than human cells 28 600 species in oral cavity (most uncultivated, unnamed!) Over 1000 species in human gut Influence development, breakdown and absorption of nutrients , immunity, physiology Study microbes as community 29 Recent articles Gut bacteria in Japanese people borrowed sushi-digesting genes from ocean 30 bacteria The bacterial zoo in your bowel Gut bacteria – fat or thin, family or friends, shared or unique Human gut bacteria linked to obesity Divided by language, united by gut bacteria – people have three common gut types Gut bacteria recap the evolution of apes Gut bacteria change the sexual preferences of fruit flies You are what you eat – how your diet defines you in trillions of ways Baby’s first bacteria depend on route of delivery The Effects of Circumcision on the Penis Microbiome Characterization of the Oral Fungal Microbiome (Mycobiome) in Healthy Individuals Gnotobiotic mouse models born, removed from the mother by C-section in sterile environment Can be “humanized” 31 Our colons harbor trillions of microbes including a prominent archaea, Methanobrevibacter smithii. To examine the contributions of Archaea to digestive health, we colonized germ-free mice with Bacteroides thetaiotaomicron, an adaptive bacterial forager of the carbohydrates that we consume, with or without M. smithii 32