Introduction to Genetics and Genomics

1. Genes and Inheritance

2016

ggibson.gt@gmail.comhttp://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

Thegenotypeofanorganismisthesequence ofit’sgenes.

Thephenotypeofanorganismthewayitappears.

Ingeneral, genesarenotdeterministic. Genotypicvariationamongorganismsspecifies theinformation that,incombinationwiththeenvironment,influences thephenotype.

Pleiotropy refers totheabilityofsinglegenestoinfluencemultiplephenotypes.

Penetrance istheproportionofindividualswithagenotypewhohave thephenotype/disease.

Expressivity isthedegree /severityofthephenotype inaffected individuals.

Mendelian Genetics

AA

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Aa

Aa

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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

Models of the Genetics of Complex Traits

Manolio etal(2009)Nature461:747-753

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

Dominance ratio

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Number of “b” alleles

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a = 18-10 = 8

d = 16-10 = 6

Expected mid-value = (18+2)/2 = 10

VP = VA + VD + VI + VGxE + VE

• LociaresaidtohaveAdditive effectsifthecontributionsofeachindividualallelecansimplybeaddedalgebraicallytoarriveatapredictionofaphenotypegivenagenotype.

• Dominance referstotheobservationthatheterozygotesresembleoneclassofhomozygotesmorethantheother.

• Epistasis referstoalocus-by-locusInteraction,suchaswhenallelesattwolociantagonizeorsynergizewithoneanother.

• VE istheenvironmental variance

Broad Sense Heritability

VG =VA +VD+VI +VG×E

NarrowsenseheritabilityisonlytheadditivecomponentwhereasBroadsenseheritabilityincludesdominance,interactionandgenotype-by-environmenteffects.

Additive Multiplicative

Recessive Epistatic

From Mendelian to Quantitative genetics

Estimating Heritability

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

Mendelian Pedigree Studies

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

Online Mendelian Inheritance in Man (OMIM)

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.

Multiplicative Rare Alleles of Major Effect

Assume thereare100mutations at1%frequency,eachofwhichincreases theriskofdisease 2.5-foldoverabaseline environmentalriskof1%.Whence0alleles haveariskof1%,1of2.5%,2of6%,3of15%,4of39%,5ormoreishighlypenetrant.

The Infinitesimal Model Triumphs – for now

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