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2016 Introduction to Genetics and Genomics 1. Genes and Inheritance [email protected] http://www.cig.gatech.edu Course Outline 1. Genes and Inheritance (GG) 2. Molecular Biology of the Genome (JL) 3. Association Studies (GG) 4. Population and Evolutionary Genetics (JL) 5. Evolution and Disease Risk (JL) / Precision Medicine (GG) Genotype and Phenotype Thegenotype ofanorganismisthesequence ofit’sgenes. Thephenotype ofanorganism thewayitappears. Ingeneral, genes arenotdeterministic. Genotypicvariation amongorganisms specifies theinformation that,incombination withtheenvironment, influences thephenotype. Pleiotropy refers totheabilityofsingle genestoinfluence multiplephenotypes. Penetrance istheproportion ofindividualswithagenotype whohave the phenotype /disease. Expressivity isthedegree /severity ofthephenotype inaffected individuals. Mendelian Genetics A A x a a A A a x a A A ; A ; a a A ; a a F0: Purebreeding parents F1: Heterozygous offspring F2: Mendelain proportions of Homozygotes+Heterozygotes 3 Models of Complex Disease CDCV: Common Disease / Common Variant Theproposition thatmostdisease susceptibility canbeattributedto10 to20loci,eachofwhichexplainaround5%ofdisease risk. RAME: Rare alleles of Major Effect Theproposition thatdiseases arehighlyheterogeneous, withhundreds orthousands ofrare mutationscausingindividualcases ofdisease. Infinitesimal: Theproposition thatweallcarrythousands ofveryweaksusceptibility alleles, andthoseunluckyenough tohavetoomanyareathighestrisk, where rarevariants orenvironmental triggers pushusover theedge. Models of the Genetics of Complex Traits Manolio etal(2009)Nature461:747-753 Heritability Heritabilityistheproportionofvarianceinapopulationthatcanbeattributedtogenotypicdifferences h2 =VG/VP where VP =VG +VE Thephenotypesmaybediscrete,suchasdiseasestatus;categorical,suchasnumberofdigits;or continuous,suchasheightorabiochemicalmeasure. 1.Heritabilityisnotastatementaboutindividuals. Aheritability of50%fordiabetesdoesnotimplythathalfthereasonwhysomeoneisdiabetic isgenetic,the otherhalfenvironmental.Rather,itsuggeststhatthere wouldbehalfasmuchdiabetesinthepopulationif everyonewasgenetically identical. 2.Heritabilityisonlyastatementaboutasinglepopulation. Aheritability of80%forheightdoesnotimplythatmostoftheaveragedifferenceinheightbetween populationsisduetogenetic differences.Heritability estimatesalone shouldnotbeusedtodrawinferences aboutgenetic divergence betweengroups. 3.Heritabilityisnotthesameasinheritance. Inheritance isthecorrespondence betweenchildren andtheir biological parents.Itcanbedueto environmental,including cultural,factorsthataresharedbyfamilymembers,ortoeffects.Theonlywayto confidentlyinterpretheritability istoactually measurethegenotypiccontribution. 4.Verylowheritabilitydoesnotimplyverylittlegeneticcontribution. Itmayeither beduetorelatively highenvironmentalvariance (hence,alargedemominator V P),ortoan absenceofvariance inthegenesthatcontribute.Manyimportantgenes,including drugtargets,arenot polymorphicandwill onlybediscoveredthroughothertypesofapproachincludingmodelorganismresearch. Mean phenotype Dominance ratio 20 18 16 14 12 10 8 6 4 2 0 bb Bb a d d = 16-10 = 6 a = 18-10 = 8 0 Expected mid-value = (18+2)/2 = 10 BB -a 0 1 Number of “b” alleles 2 VP = VA + VD + VI + VGxE + VE • LociaresaidtohaveAdditive effectsifthecontributionsof eachindividualallelecansimplybeaddedalgebraicallyto arriveatapredictionofaphenotypegivenagenotype. • Dominance referstotheobservationthatheterozygotes resembleoneclassofhomozygotes morethantheother. • Epistasis referstoalocus-by-locusInteraction,suchas whenallelesattwolociantagonizeorsynergizewithone another. • VE istheenvironmental variance Broad Sense Heritability VG =VA +VD+VI +VG×E NarrowsenseheritabilityisonlytheadditivecomponentwhereasBroadsenseheritability includesdominance,interactionandgenotype-by-environmenteffects. Additive Multiplicative Recessive Epistatic From Mendelian to Quantitative genetics Estimating Heritability Twin Studies Identical/Maternal Dizygotic/Fraternal Tiki andRonde Barber JennaandBarbaraBush rmz =A+C rdz =½A+C A=AdditiveGenetic component;C=CommonEnvironment(smaller ifrearedapart) E=uniqueenvironment=1– rmz rdz shouldbegreaterthanrsib sinceCislargerwherethewomb/upbringing isshared Mendelian Pedigree Studies Monogenic Disorders Approximately1in3,700AmericanshaveCysticFibrosis Assumingp2 =0.00027,thenp =0.016,themutantallelefrequency Thatis,1in30peoplearecarriers(whichis120timesasmanypeopleashaveCF), thatis,3%ofCaucasiansarecarriers,andlessthan0.03%sufferers. ItisverylikelythatsomeoneinthisclassisacarrierofaCFmutation ACFcarrierhasa1in30chanceofmarryinganothercarrierbychance, and 1in4oftheirchildrenwillbeexpected tohaveCF,andonlyhalfofall2-child familieswillhaveanaffectedchild Therearehundredsofsimilarconditions(rarerecessiveswithp~0.01),soweareall carriersformultipleMendeliandiseasegenes.Collectively,asmanyas1in25 couplesshouldexpecttobedualcarriersforarecessiveMendeliandisorder, correspondingtoanapproximate1%affectedrateinallchildren Around1in400childrenhaveaninheritedInbornErrorofMetabolism,namelyanenzyme deficiencyaffectingaminoacid,lipidorotherorganicmoleculebiosynthesis.Forexample: - Phenylketonuria Galactosemia Gaucher ’s Disease Zellweger Syndrome Lesch-Nyhan Syndrome 1/15,000 1/40,000 1/60,000 1/50,000 1/380,000 mentalretardationsyndrome liverdysfunctionandcataracts facialdysmorphology,liverdisease seizures,lowmuscletone self-inflictedinjury,gout/kidneydisease Online Mendelian Inheritance in Man (OMIM) Mutation Accumulation Frequency G60 G30 G0 0.90.951.0 MeanLineviability Ineachgeneration,slightlydeleterious mutations add~0.1%ofthestanding environmentalvariancetotheheritability oftraits,alsoreducingviability. Halligan andKeightley (2009)Annu RevEcol Evol Syst.40:151-172 Multiplicative Rare Alleles of Major Effect Assume thereare100mutations at1%frequency,eachofwhichincreases the riskofdisease 2.5-foldoverabaseline environmentalriskof1%. Whence 0alleles haveariskof1%,1of2.5%,2of6%,3of15%,4of39%,5ormoreishighlypenetrant. The Infinitesimal Model Triumphs – for now The Complexity of Disease Risk Themissingheritability problemisthatvariantsdiscoveredbyGWASonlyexplaina minorfractionoftheexpected heritability. Thismaybebecause: - Theeffectsizesaremuchsmaller thanpreviouslythought(GRR1.1ratherthan2) Narrowsense heritability hasbeenover-estimated inpedigree studies Itisrare,notcommon,variants,thatcontributemostofthevariation Epigenetic inheritance accountsformuchoftheresemblance amongrelatives Broadsense heritability isprevalent,buthardtodetect Genotypingchipsdonottagcausalvariantseffectivelyenough