introduction to genetics and genomics 1. genes and …...carriers for multiple mendelian disease...
TRANSCRIPT
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Introduction to Genetics and Genomics
1. Genes and Inheritance
2016
[email protected]://www.cig.gatech.edu
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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)
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Genotype and Phenotype
Thegenotypeofanorganismisthesequence ofit’sgenes.
Thephenotypeofanorganismthewayitappears.
Ingeneral, genesarenotdeterministic. Genotypicvariationamongorganismsspecifies theinformation that,incombinationwiththeenvironment,influences thephenotype.
Pleiotropy refers totheabilityofsinglegenestoinfluencemultiplephenotypes.
Penetrance istheproportionofindividualswithagenotypewhohave thephenotype/disease.
Expressivity isthedegree /severityofthephenotype inaffected individuals.
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Mendelian Genetics
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F0: Purebreedingparents
F1: Heterozygousoffspring
F2: Mendelain proportions ofHomozygotes+Heterozygotes
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CDCV: Common Disease / Common VariantTheproposition thatmostdisease susceptibilitycanbeattributedto10to20loci,eachofwhichexplainaround5%ofdisease risk.
RAME: Rare alleles of Major EffectTheproposition thatdiseases arehighlyheterogeneous, withhundredsorthousandsofraremutationscausingindividualcasesofdisease.
Infinitesimal:Theproposition thatweallcarrythousandsofveryweaksusceptibilityalleles,andthoseunluckyenough tohavetoomanyareathighestrisk,where rarevariantsorenvironmental triggerspushusover theedge.
3 Models of Complex Disease
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Models of the Genetics of Complex Traits
Manolio etal(2009)Nature461:747-753
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h2 =VG/VP whereVP =VG +VE
Thephenotypesmaybediscrete,suchasdiseasestatus;categorical,suchasnumberofdigits;orcontinuous,suchasheightorabiochemicalmeasure.
1.Heritabilityisnotastatementaboutindividuals.Aheritability of50%fordiabetesdoesnotimplythathalfthereasonwhysomeoneisdiabetic isgenetic,theotherhalfenvironmental.Rather,itsuggeststhattherewouldbehalfasmuchdiabetesinthepopulationifeveryonewasgenetically identical.
2.Heritabilityisonlyastatementaboutasinglepopulation.Aheritability of80%forheightdoesnotimplythatmostoftheaveragedifferenceinheightbetweenpopulationsisduetogeneticdifferences.Heritability estimatesaloneshouldnotbeusedtodrawinferencesaboutgeneticdivergencebetweengroups.
3.Heritabilityisnotthesameasinheritance.Inheritance isthecorrespondencebetweenchildrenandtheirbiologicalparents.Itcanbeduetoenvironmental,includingcultural,factorsthataresharedbyfamilymembers,ortoeffects.Theonlywaytoconfidentlyinterpretheritability istoactuallymeasurethegenotypiccontribution.
4.Verylowheritabilitydoesnotimplyverylittlegeneticcontribution.Itmayeitherbeduetorelativelyhighenvironmentalvariance (hence,alargedemominator VP),ortoanabsenceofvariance inthegenesthatcontribute.Manyimportantgenes,includingdrugtargets,arenotpolymorphicandwillonlybediscoveredthroughothertypesofapproachincludingmodelorganismresearch.
HeritabilityHeritabilityistheproportionofvarianceinapopulationthatcanbeattributedtogenotypicdifferences
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Dominance ratio
BB
0 1 2
201816141210 8 6 4 2 0
a d
0
-a
Bbbb
Number of “b” alleles
Mea
n ph
enot
ype
a = 18-10 = 8
d = 16-10 = 6
Expected mid-value = (18+2)/2 = 10
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VP = VA + VD + VI + VGxE + VE
• LociaresaidtohaveAdditive effectsifthecontributionsofeachindividualallelecansimplybeaddedalgebraicallytoarriveatapredictionofaphenotypegivenagenotype.
• Dominance referstotheobservationthatheterozygotesresembleoneclassofhomozygotesmorethantheother.
• Epistasis referstoalocus-by-locusInteraction,suchaswhenallelesattwolociantagonizeorsynergizewithoneanother.
• VE istheenvironmental variance
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Broad Sense Heritability
VG =VA +VD+VI +VG×E
NarrowsenseheritabilityisonlytheadditivecomponentwhereasBroadsenseheritabilityincludesdominance,interactionandgenotype-by-environmenteffects.
Additive Multiplicative
Recessive Epistatic
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From Mendelian to Quantitative genetics
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Estimating Heritability
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Twin Studies
Identical/Maternal
Tiki andRonde Barber
Dizygotic/Fraternal
JennaandBarbaraBush
rmz =A+C rdz =½A+C
A=AdditiveGenetic component; C=CommonEnvironment(smaller ifrearedapart)E=uniqueenvironment =1– rmz
rdz shouldbegreaterthanrsib sinceCislargerwherethewomb/upbringing isshared
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Mendelian Pedigree Studies
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Monogenic Disorders
Approximately1in3,700AmericanshaveCysticFibrosisAssumingp2 =0.00027,thenp =0.016,themutantallelefrequency
Thatis,1in30peoplearecarriers(whichis120timesasmanypeopleashaveCF),thatis,3%ofCaucasiansarecarriers,andlessthan0.03%sufferers.ItisverylikelythatsomeoneinthisclassisacarrierofaCFmutation
ACFcarrierhasa1in30chanceofmarryinganothercarrierbychance, and1in4oftheirchildrenwillbeexpected tohaveCF,andonlyhalfofall2-childfamilieswillhaveanaffectedchild
Therearehundredsofsimilarconditions(rarerecessiveswithp~0.01),soweareallcarriersformultipleMendeliandiseasegenes.Collectively,asmanyas1in25couplesshouldexpecttobedualcarriersforarecessiveMendeliandisorder,correspondingtoanapproximate1%affectedrateinallchildren
Around1in400childrenhaveaninheritedInbornErrorofMetabolism,namelyanenzymedeficiencyaffectingaminoacid,lipidorotherorganicmoleculebiosynthesis.Forexample:
- Phenylketonuria 1/15,000 mentalretardationsyndrome- Galactosemia 1/40,000 liverdysfunctionandcataracts- Gaucher ’s Disease 1/60,000 facialdysmorphology,liverdisease- Zellweger Syndrome 1/50,000 seizures,lowmuscletone- Lesch-Nyhan Syndrome 1/380,000 self-inflictedinjury,gout/kidneydisease
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Online Mendelian Inheritance in Man (OMIM)
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MeanLineviability0.90.951.0
Frequency
G0G30G60
Mutation Accumulation
Halligan andKeightley (2009)AnnuRevEcol Evol Syst.40:151-172
Ineachgeneration,slightlydeleterious mutations add~0.1%ofthestandingenvironmentalvariancetotheheritability oftraits,alsoreducingviability.
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Multiplicative Rare Alleles of Major Effect
Assume thereare100mutations at1%frequency,eachofwhichincreases theriskofdisease 2.5-foldoverabaseline environmentalriskof1%.Whence0alleles haveariskof1%,1of2.5%,2of6%,3of15%,4of39%,5ormoreishighlypenetrant.
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The Infinitesimal Model Triumphs – for now
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The Complexity of Disease Risk
Themissingheritability problemisthatvariantsdiscoveredbyGWASonlyexplainaminorfractionoftheexpected 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