Course Information. Computational Genetics Lecture 1. Course Prerequisites. Course Goals
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1 Course Informtion. Computtionl Genetics Lecture 1 ckground Redings: Chpter 2&3 of n introduction to Genetics, Griffiths et l. 2000, Seventh Edition (CS/Fishch/Other lirries). This clss hs een edited from severl sources. Primrily from Terry Speed s homepge t Stnford nd the Technion course Introduction to Genetics. Chnges mde y Dn Geiger. Meetings: Lecture, y Dn Geiger: Thursdys 14:30 16:30, Tu 4. Tutoril, y M yn Fishelson: Thursdys 16:30 17:30 Grde: 50% in five question sets. These questions sets re oligtory. Ech contins 4-6 theoreticl prolems. Sumit in pirs in two weeks time. 50% tke-home exm. (Few my e llowed to replce with seminr lecture). Informtion nd hndouts: rochure with zeroxed mteril (if needed) t Tu lirry. 2 Course Prerequisites Computer Science nd Proility ckground lgorithms 1 (cs234247) Proility (ny course) lgorithms in computtionl iology (or tke in prllel). Some iology ckground Formlly: None, to llow CS students to tke this course. Recommended: Introduction to Genetics (or in prllel). Course Gols Lerning out computtionl nd mthemticl methods for genetic nlysis. We will focus on Gene hunting finding genes for simple humn diseses. Methods covered in depth: linkge nlysis (using pedigree dt), ssocition nlysis (using rndom smples). nother gol is to lern more out yesin networks usge for genetic linkge nlysis. 3 4
2 Most humn cells contin 46 chromosomes: 2 sex chromosomes (X,Y): XY in mles. XX in femles. Humn Genome Genetic Informtion Gene sic unit of genetic informtion. They determine the inherited chrcters. Genome the collection of genetic informtion. Chromosomes storge units of genes. 22 pirs of chromosomes, nmed utosomes. 5 6 Sexul Reproduction The Doule Helix egg Meiosis gmetes sperm zygote 7 Source: lerts et l 8
3 Centrl Dogm Chromosome Logicl Structure Trnscription Trnsltion Mrker Genes, SNP, Tndem repets. Locus loction of mrkers. llele one vrint form of mrker. Gene mrn Protein cells express different suset of the genes In different tissues nd under different conditions Locus1 Possile lleles: 1,2 9 Locus2 Possile lleles: 1,2,3 10 lleles - the O locus exmple : Phenotype Genotype /, /O..,.1 O is recessive to. is dominnt over O. nd re codominnt. Multiple lleles:,,o. O /, /O / O/O (Homozygote) -.(Hetrozygote).,,(,,O).2.3 Trit = Chrcter = Phenotype 11 12
4 (X-linked) genotype phenotype Mendel s Work Modern genetics egn with Mendel s experiments on grden pes (lthough, the rmifiction of his work were not relized during his life time). He studied seven contrsting pirs of chrcters, including: The form of ripe seeds: round, wrinkled The color of the seed lumen: yellow, green The length of the stem: long, short -dominnt llele. Nmely, (,), (,w) is lck. w - recessive llele. Nmely, only (w,w) is White. This is n exmple of n X-linked ( ) trit/chrcter. For mles lone is lck nd w lone is white. There is no homolog gene ( ) on the Y chromose. 13 Mendel Gregor Experiments on Plnt Hyridiztion. Trnsctions of the rünn Nturl History Society. 14 P: X Mendel s first lw F1: Chrcters re controlled y pirs of genes which seprte during the formtion of the reproductive cells (meiosis) F1 X F1 X test cross X Gmetes: Gmetes: F2: 1 : 2 : 1 Phenotype ~ ~ Phenotype: ~ ~ 1 :
5 : Mendel's First low. Results of crosses in which prents differed for one chrcter Prentl Phenotype F1 F2 F2 rtio F2 : F1.1.3:1 1. Round X wrinkled seeds 2. Yellow X green seeds Round yellow 5474 round; 1850 wrinkled 6022 yellow; 2001 green 2.96:1 3.01:1. F1 :.2 1:1 3. Purple X white petls 4. Inflted X pinched pods 5. Green X yellow pods purple inflted green 705 purple; 224 white 882 inflted; 299 pinched 428 green; 152 yellow 3.15:1 2.95:1 2.82:1 6. xil X terminl flowers xil 651 xil; 207 terminl 3.14:1 7. Long X short stems long 787 lon; 277 short 2.84:1 Conclusion, First low: The two memers of gene pir segregte from ech other into the gmetes ( ) Polydctyly dominnt muttion 19 20
6 rchydctyly dominnt muttion Mximum Likelihood Principle Wht is the proility of dt for this pedigree, ssuming recessive muttion? Wht is the proility of dt for this pedigree, ssuming dominnt muttion? Mximum likelihood principle: Choose the model tht mximizes the proility of the dt One locus: founder proilities Founders re individuls whose prents re not in the pedigree. They my of my not e typed (nmely, their genotype mesured). Either wy, we need to ssign proilities to their ctul or possile genotypes. This is usully done y ssuming Hrdy-Weinerg equilirium (H-W). If the frequency of D is.01, then H-W sys: pr(dd ) = 2x.01x.99 Genotypes of founder couples re (usully) treted s independent. 1 1 dd pr(pop Dd, mom dd ) = (2x.01x.99)x(.99) 2 2 One locus: trnsmission proilities Children get their genes from their prents genes, independently, ccording to Mendel s lws; lso independently for different children. 1 2 d d pr(kid 3 dd pop 1 Dd & mom 2 Dd ) = 1/2 x 1/
7 One locus: trnsmission proilities - II d d D D pr(3 dd & 4 Dd & 5 DD 1 Dd & 2 Dd ) = (1/2 x 1/2)x(2 x 1/2 x 1/2) x (1/2 x 1/2). The fctor 2 comes from summing over the two mutully exclusive nd equiprole wys 4 cn get D nd d. One locus: penetrnce proilities Pedigree nlyses usully suppose tht, given the genotype t ll loci, nd in some cses ge nd sex, the chnce of hving prticulr phenotype depends only on genotype t one locus, nd is independent of ll other fctors: genotypes t other loci, environment, genotypes nd phenotypes of reltives, etc. Complete penetrnce: DD pr(ffected DD ) = 1 Incomplete penetrnce ( ) : DD pr(ffected DD ) = One locus: penetrnce - II : ge nd sex-dependent penetrnce (liility clsses) D D (45) pr( ffected DD, mle, 45 y.o. ) =
8 One locus: putting it ll together 3 d d D D ssume penetrnces pr(ffected dd ) =.1, pr(ffected Dd ) =.3 pr(ffected DD ) =.8, nd tht llele D hs frequency.01. The proility of dt for this pedigree ssuming penetrnces of 1 =0.1 nd 2 =0.3 is the product: (2 x.01 x.99 x.7) x (2 x.01 x.99 x.3) x (1/2 x 1/2 x.9) x (2 x 1/2 x 1/2 x.7) x (1/2 x 1/2 x.8) This is function of the penetrnces. y the mximum likelihood principle, the vlues for 1 nd 1 tht mximize this proility re the ML estimtes. 29 Mendel s second lw When two or more pirs of genes segregte simultneously, they do so independently. ; P = P P P =P P P =P P P =P P 30 Mendel's second low. dihyrid cross for color nd shpe of pe seeds P wrinkled nd yellow X round nd green rryy RRyy F1 round yellow Rr Yy X Rr Yy F2 round yellow 315 round green 108 wrinkled yellow 101 wrinkled green Check segregtion pttern for ech llele in F2: 416 yellow : 140 green (2.97:1) 423 round : 133 wrinkled (3.18:1) Conclusion: oth trits ehve s single genes, ech crrying two different lleles
9 Question: Is there independent ssortment of lleles of the different genes? Proility to get yellow is 3/4; proility to get round is 3/4; proility to get yellow round is 3/4 X 3/4, nmely 9/16 Proility to get yellow is 3/4; proility to get wrinkled is 1/4; proility to get yellow wrinkledis 3/4 X 1/4, nmely 3/16 Proility to get green is 3/4; proility to get round is 3/4; proility to get green round is X 3/4, nmely 3/16 1/4 Proility to get green is 1/4; proility to get wrinkled is 1/4; proility to get green wrinkled is 1/4 X 1/4, nmely 1 /16. stndrd presenttion in terms of counts expected expected oserved yellow round yellow wrinkled green round green wrinkled Totl Conclusion, second lw: Different gene pirs ssort independently in gmete formtion Exceptions to Mendel s Second Lw Morgn s fruit fly dt (1909): 2,839 flies Morgn s explntion Eye color : red : purple Wing length : norml : vestigil x x F1: Expected Oserved 1, ,195 The pir stick together more thn expected Crossover hs tken plce from Mendel s lw F2:
10 Prentl types: Recominnts:,, Recomintion Phenomenon (Hppens during Meiosis) The proportion of recominnts etween the two genes (or chrcters) is clled the recomintion frction etween these two genes. Recomintion Hplotype Mle or femle It is usully denoted y r or. For Morgn s trits: r = ( )/2839 = If r < 1/2: two genes re sid to e linked. If r = 1/2: independent segregtion (Mendel s second lw). :, / 1 Exmple: O, K1 on Chromosome O 2 / 2 O O 2 2 Phse inferred O 3 4 O / 2 2 / Recominnt O O 1 2 O 1 / Recomintion frction is 12/100 in mles nd 20/100 in femles. One centi-morgn mens one recomintion every 100 meiosis. One centi-morgn corresponds to pprox 1M nucleotides (with lrge vrince) depending on loction nd sex. 40
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