Download Genetics Session 1_2016

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