02coct01d1

02coct01d1 - Intro 2: Last week's take home lessons...

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1 Intro 2: Last week's take home lessons Elements & Purification Systems Biology & Applications of Models Life Components & Interconnections Continuity of Life & Central Dogma Qualitative Models & Evidence Functional Genomics & Quantitative models Mutations & Selection Harvard-MIT Division of Health Sciences and Technology HST.508: Genomics and Computational Biology x= u c a g U xu F Y C S - - R - W C L H P R Q a N S I T K R M NH+ g D V A G E A uxc uxa T E uxg cxc cxa cxg axc C - S axa axg gxc O - gxa gxg H:D/
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DNA 1: Today's story, logic & g oals Binomial & exponential dx/dt = kx Types of mutants Mutation, drift, selection Association studies χ 2 statistic Linked and causative alleles Haplotypes Computing the first genome, the second . .. New technologies Random and systematic errors 2
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Connecting Genotype & Phenotype %DNA identity 100% Functional measures 99.9% S ingle N ucleotide P olymorphisms (SNPs) 70-98% Speciation 30% Sequence homology <25% Distant (detectable only in 3D structures) 3
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Types of phenotypic effects of mutations Null: PKU Dosage: Trisomy 21 Gain of function: HbS Altered ligand specificity Conditional (e.g. temperature or chemical) 4
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Types of mutations Single substitution: A to C, G or T, etc. Deletion: 1 bp . .. chromosomes (aneuploidy) Duplication: as above (often at tandem repeats) Inversion: ABCDEFG to AB edc FG Translocation: ABCD & WXYZ to AB YZ & WX CD Insertion: ABCD to AB ινσερτ CD Recombination: ABCDEFGH & AB c DE f GH to AB c DEFGH & ABCDE f GH 5
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Mutations & Polymorphisms Mutations become polymorphisms or “common alleles” when frequency > 1% in a population (arbitrary) All Single Nucleotide Polymorphisms (SNPs) (probably) exist in the human population: 3 billion x 4 (ACGT) at frequencies near 10 -5 . SNPs linked to a phenotype or causative. 6
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Haplotypes Representation of the DNA sequence of one chromsome (or smaller segments in cis). Indirect inference from pooled diploid data Direct observation from meiotic or mitotic segregation, cloned or physically separated chromsomes or segments 7
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Linkage & Association Family Triad: parents & child vs case-control vs. Case-control studies of association in structured or admixed populations. Pritchard &Donnelly, 2001. To appear in Theor. Pop. Biol. Program STRAT Null hypothesis: allele frequencies in a candidate locus do not depend on phenotype (within subpopulations) 8
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Pharmacogenomics Gene/Enzyme Drug Quantitative effect Examples of clinically relevant genetic polymorphisms influencing drug metabolism and effects. Additional data (http://www.sciencemag.or g/feature/data/1044449.shl) CYP2C9 Tolbutamide, warfarin, phenytoin, nonsteroidal anti- inflammatories Anticoagulant effect of warfarin Beta blockers, antidepressants, antipsychotics, Tardive dyskinesia from codeine, debrisoquin, dextromethorphan, encainide, antipsychotics; narcotic side CYP2D6 flecainide, guanoxan, methoxyamphetamine, N - effects, efficacy, and dependence; propylajmaline, perhexiline, phenacetin, phenformin, imipramine dose requirement; beta- propafenone, sparteine blocker effect Dihydropyrimidine dehydrogenase Fluorouracil Fluorouracil neurotoxicity
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02coct01d1 - Intro 2: Last week's take home lessons...

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