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1Computing and Genomic MedicineIsaac S. Kohanehttp://www.chip.orgOverview The future is now Genomic vs genetic Heredity Resequencing of the diagnostic process Accelerating consumer activation Genomic database and AssignmentThe Long Path from Genotype to FunctionDNATranscriptionTrans-lationStructuralBiologySequencingandgenotypingTranscriptionalProfilingNathan Baker UCSDProteomics2Magnitude of the TaskMagnitude of the TaskMagnitude of the Task3StadiumMagnitude of the Task× 1000Myhrvold’s Madonna Complex4RNA/DNA expression detection chipsSchena M, et al. Proc Natl Acad Sci USA; 93: 10614 (1996).Entire issue. Nature Genetics, 21: supplement (Jan 1999).TissueRNATaggedwith fluorcDNA spotted on glass slide oroligonucleotides built on slideTissue underinfluenceorcDNAcopyThe Promise: The New DiagnosticsAlizadeh et al.Retreading the cancer chemotherapeuticprotocol Cancer and Leukemia Group B (CALGB) CALGB has grown into a national network of 29university medical centers, over 185 communityhospitals and more than almost 3000 physicians whocollaborate in clinical research studies aimed atreducing the morbidity and mortality from cancer Dozens of new protocols (breast cancer, prostate cancer,renal cancer) that use genome-wide Which genes best predict survival? Which adjuvant improves surgical outcome the best? Can we find expression measure proxies for Stage, Gradeand Cell Type5Changes in Use of “Every day” MedicationsSome perspectiveGrowth in Our Knowledge of VariantsPolymorphism Publications0100020003000400050006000700080001980 1985 1990 1995 2000 2005Year (1981-2001)Publications/year6One-pass genotyping•Chromosome 21: 21,676,868 bases (67%) of unique sequence were assayedfor variation with high-density oligonucleotide arrays•Synthesized 3.4 × 109 oligonucleotides on 160 wafers to scan 20 independentcopies of human chromosome 21 for DNA sequence variation.Patil, Science 2001Bioinformatics: 1998 Ambitions Find the functions of all30,000+genes using DNA sequence Genetics maps Physical maps Polymorphisms Structure information Existing biomedical literature Gene transcription patterns Protein translation/activity With growing databases containingdata, thisbecomes a problem in the realm ofbioinformaticsErmolaeva O, et al. Nature Genetics; 20: 19 (1998).A GrowingGapSystemsThe engineer exclaims, “Look! Scottish sheep are black!”The physicist yells, “No, no. Some Scottish sheep are black.”The computer scientist says, “Oh, no, a special case!”Finally, the statistician says, “It is not statistically significant!”The mathematician looks irritated and says, “There is at least onefield, containing at least one sheep, of which at least one side isblack.”An engineer, a physicist, a mathematician, a computer scientist, anda statistician are on a train heading north, and had just crossed theborder into Scotland. They look out the window and see a blacksheep for the first time.7Genomic vs geneticGenetic MedicineGenomic MedicineLow frequency of ~1000 of usuallyhigh penetrance genesThe genetic risk for common diseases willoften be due to disease-producing alleleswith relatively high frequencies (>1%). Allgenes may be disease causing.1000’s of relatively uncommondiseases (1/300 for mostcommon)Common disorders due to the interactions of multiplegenes and environmental factorsMostly assessed indirectly & focused On single genesDirect experimental access to the entire genomeComprehensiveBioinformaticsApproach:All Data Are GristReductionist methodsthat take into accountdata-typeparticularitiesInteractionsbetween all the“grist” is relevantto the healthstateTraditionalgenetics8Determining the aforementioned interaction is hard andruns counter to traditional biostatistical techniquesVariables (10,000 - 100,000)Cases (1000’s-1,000,000’s)Cases (10’s-100’s)High-dimensionality systems withinsufficient data areundeterdeterminedNot tractable by standardbiostatistical techniquesVariables (10’s-100’s)The New Pharmacology RNA expression in NCI 60 cell lines was determined usingAffymetrix HU6000 arrays 5,223 known genes 1,193 expressed sequence tags The RNA expression data set and Anti-cancersusceptibility data set were merged, using the 60 celllines the two tables had in commonRNA Expression Drug Susceptibility6,000 genes 5,000 anti-cancer agentsCommon 60Cell LinesGenes and Anti-Cancer Agents Threshold r^2 was0.8 202 networks 834 features outof 11,692 (7.1%) 1,222 links out of68,345,586(.0018%) Only one linkbetween a geneand anti-canceragent9Genes and Anti-Cancer Agents Elevated levels of J02923 (lymphocyte cytosolic protein-1, LCP1, L-plastin,pp65) is associated with increased sensitivity to 624044 Agent 624044 is 4-Thiazolidinecarboxylic acid, 3-[[6-[2-oxo-2-(phenylthio)ethyl]-3-cyclohexen-1-yl]acetyl]-2 thioxo-, methyl ester, [1R-[1a(R*),6a]]- (9CI)) LCP1 is an actin-binding proteininvolved in leukocyte adhesion A role for LCP1 in tumorogenicityhas been previously postulated Low level expression of LCP1 isthought to occur in most humancancer cell lines Other thiazolidine carboxylic acidderivatives are known to inhibittumor cell growthButte et al. PNAS 2000Overview The future is now Genomic vs genetic Heredity Resequencing of the diagnostic process Accelerating consumer activationHeritability: the way a population geneticistwould think of it. Heritability in the Broad Sense (H) This measure of heritability includes all geneticinfluences on the phenotype, whether due toadditive, dominance, or interactive effects. H2 = VG / VP, where VG = VA + VD + VI10Obesity Don’t some people just eat and not get fat? Isn’t it in their genes?HeritabilityAll those of you with… leave the roomOBESITY• National Center for Health Statistics:Over 50% of US adults have BMI > 25About 22% of US adults have BMI > 30• National Health & Nutrition Examination Survey III:20% of U.S. children overweight• Behavioral Risk Factor Surveillance System (CDC)Prevalence of obesity up by 50% from 1991 - 199811202530354045Percent1960 1970 1980 1990YearCalories from FatPrevalence of ObesityAfter: Allred JB. JADA 95:417, 1995Prevalence of Obesity Compared to PercentCalories from Fat Among US AdultsHeritability is defined with respect toenvironment How do we define environment? Diet Daily habits


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MIT 6 872 - Computing and Genomic Medicine

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