Punnettsquares

impactof

Luria-Delbruck

types of mutations

P=G+E,Mendelian

v quantstochastic,

deterministic

random

associationtests

evolutionarymechanisms

expectationsunderHWE

memorizing equations

selection/fitness

driftand

pop size

homology

units ofinheritance

independentcontrasts

degrees of freedom

and thepicture wasAlfred Russell Wallace

mechanisms of evolution

mutation

selection

drift

non-random mating

migration

•different take on how many genes lead to normal distribution of trait

•just count “big” alleles, assume additive contribution

•more loci leads to more potential variation

phenotypic variance is caused by genotypic variance AND variance caused by environment

Var(P)=Var(G)+Var(E)

heritability•proportion of total phenotypic variance

caused by genotypic variance

•H2 = Var(G)/Var(P) = Var(G)/(Var(G)+Var(E))

•broad-sense heritability, all forms of genotypic variance are included

•but not all genotypic variance contributes to phenotype of next generation equally

additive v dominance, again...•when alleles make an additive contribution to

phenotype, a single allele makes same contribution regardless of other allele

• aa: white flower; Aa: some red pigment made, PINK flower; AA: more red made, RED flower

•when alleles are not additive (dominant/recessive), their contribution depends on the other allele in genotype

• a / a: white flower; a / A: red pigment made, RED flower; A / A: red made, RED flower

•that context disappears each generation with sexual recombination; alleles are heritable, the genotype isn’t

•slows effects of selection: recessive alleles ‘hide’ in heterozygotes (no effect) so requires drift to increase in frequency enough to make homozygotes (if good effect), or difficult to purge if negative

“dominance” and “recessiveness” is a variable traite.g. if selection coefficient is s

we can score relative fitness as 1-hs h is the level of dominance of that allele

0.5 is additivebut h can vary from 0 to 1 (in this plot, it is 100% dominance/recessive)

maintaining diversity

•standing variation: created by mutation

•stochastically changing in frequency via drift

•even with selection, dominance can maintain some allelic variation

•at level of an entire gene, there is a balance between mutation (µ) and selection (s)

•diversity ITSELF can be selected for!

selection and polymorphism

• flowers and pollinators: typical reward is nectar

• not all orchids produce nectar, must deceive

• elderflowers do this with color polymorphism

frequency-dependentyellowyellow flowers actually have higher relative

fitness, but when they get too common it

disappears and bees favor purple

actu

al fr

eq

uen

cy ~

70

%

mhc

• MHC molecules “show” processed proteins on cell surface

• immune system responds (usually to your benefit)

• extreme diversity at this locus: why?

molecule with benefits

• diversity allows presentation/recognition of diverse pathogen/foreign material (helps immune system clear body of disease)

• greater diversity, better presumed immune response

• (heterosis, overdominance: two forms of increased fitness with heterozygosity)

• so life (vertebrates) might act to increase diversity somehow?

old shirts andmate choice

• Wedekind study: MHC dissimilar mates preferred?

• T-shirts worn by guys, presented to women - all genotyped at MHC loci

• greatest mismatch at genotype (different alleles) = greatest “attraction”

being unusual and mating

Incongruity of primate species tree and DQA1 promoter region gene tree.

Loisel D A et al. PNAS 2006;103:16331-16336

©2006 by National Academy of Sciences

MHC- related gene

many forms of variance

•remember we are asking about causes for phenotypic variance in some trait, Var(P)

•environmental variance, Var(E) contributes: amount of sun, amount of nutrient, altitude, etc.

•genetic variation Var(G) now includes additive Var(A), dominance Var (D), epistasis (gene-gene interactions, Var(I)), and even gene x environment interactions

•selection acts on additive variance Var(A)

h2 is narrow-senseheritability (only involves

additive variance)

why do we care about heritability?

QuickTime™ and a decompressor

are needed to see this picture.

breeders equation

R = h2S•if the environment selects on a heritable trait, how will the population respond?

•quantitative trait loci: where are the genes contributing to such traits?

•generally requires at least F2 display of traits and dense genotype “mapping”

Small or Large?• Question with phylogenetic variation is

how labile is the trait? How conserved?

• Are flower colors and shapes controlled by many mutations of small effect, or can some individual mutations have major effect?

• Need to answer experimentally, but first need candidate loci: the QTLs

• linkage group may refer to a chromosome or region of the genome that are physically linked, and thus diversity at nearby genes is linked - not entirely independent

• recombination unlinks these regions, but frequency of recombination depends on proximity of genes

• linkage may be between known genes, or maybe just anonymous marker and a gene

linkage, haplotype

• haplotype - the multilocus description of a chromosome or gamete, or other physically linked set of loci (mitochondrion)

• genotype - the multilocus description of an individual, composed of haploid contributions from parental gametes

• an AaBBCc individual genotype could be generated by gametes ABC+aBc, or aBC+ABc, or ABc+aBC...

linkage disequilibrium

• loci are in linkage equilibrium when the genotype of one locus is independent entirely from the genotype at another locus (knowing one does not predict the other)

• disequilibrium when there is a nonrandom association

• 3 conditions (for 2 loci) must all be met for equilibrium:

• frequency of B on haplotypes with A is equal to B on haplotypes with a

• frequency of any haplotype obtained by mutliplying frequency of alleles

• for frequency g: gABgab - gAbgaB = D (coefficient of linkage disequilibrium) = 0

back to hardy-weinberg

• extend Hardy-Weinberg analysis to 2 loci: same conditions (selection, migration, mutation, nonrandom mating, drift)

• follow frequencies of multilocus genotypes created by possible haplotypes

• linkage disequilibrium can happen via selection, drift, and population admixture (pooling 2 genotypically distinct populations)

gamete/chromosome/haplotype frequencies will stay constant in

HWE

2 ways to make ABAb genotype, so frequency

is 2gABgAb

recombination

• adults of genotype AB/AB, AB/Ab, AB/aB will always produce some AB gametes (chromosomes) for next generation

• adults of genotype AB/ab will produce AB gametes only when meiosis involves no crossing-over (recombination, rate r)

• adults of genotype Ab/aB CAN produce AB gametes as long as there IS recombination (r > 0)

SNP, microsat, whatever

estimating linkage

• given some trait P that an F2 individual can be homozygous or heterozygous for at single locus (PP, Pp, pp; determined by phenotype)...

• and some marker M that an F2 can be scored at (MM, Mm, mm)...

• calculate probability of observed F2, e.g. trait suggests PP, and genotype is MM

• under LD with recombination rate r=0.1, an MP/mp F1 generates gametes MP (45%), mp (45%), Mp (5%), mP (5%)

• so MP/MP homozygote frequency 0.45x0.45 = 0.2025

• with r=0.5 all 2-locus gametes equally likely, 0.25 x 0.25 =0.0625

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Log of Odds: 10x=ratio of oddsso103=1000 times more likely0.2025/0.0625 = 3.24LOD 0.511cases where odds ratio is < 1 produce negative LOD scoresum LOD scores from many individuals to see result for given hypothesis test

find your QTLs

• find quantitative trait loci, and then use experiments to confirm what some of these loci do

• for example, clear relationship between pollinator and phenotype (bees like big flowers with less yellow pigment; hummingbirds deep, purple ones)

• experiment: breed M. lewisii but with the QTL for YUP locus (adds yellow) 4

7

adding YUP allele to M. lewisii made them much more preferred by hummingbirds, less so by beesshows that some mutations/alleles can have LARGE effect, can be quickly selected on

QuickTime™ and a decompressor

are needed to see this picture.

“sensitive stigma” in Mimulus guttatusstigma NOT sensitive in closely related self-fertilizing species

novel quantitative trait, continuous variation in F2with ≥4 QTLs contributing to sensitivity

•genes interacting with other genes is termed epistasis. in Hoekstra’s mice, the Agouti and Mc1r loci are in epistasis.

QTLs are themselves hypotheses

•if region seems to be involved in trait, now use genetic crosses/manipulation to directly test marker and how it affects trait

phenotypic plasticity

•how does the phenotype, as determined by genotype, respond to the environment?

•traits that are plastic - able to be molded

•reaction norm: pattern of phenotypic expression of a single genotype across a range of environments

•VP = VA + VD + VI + VE +VGxE

1.single genotype in different environments

2.multiple genotypes, but with little variation for trait

3.multiple genotypes, with genetic variation for trait

4.multiple genotypes, genetic variation for trait and variation in how genotype responds to environment

C. elegans (Nematoda)

•some traits have little GxE effect, others have a very strong GxE effect

plasticity

• remember ‘move, adapt, acclimate, or die’?

• one adaptive mechanism is to allocate resources only when necessary

• trade-offs between (for example) growth or reproduction and defense mechanisms

• reaction norm: how the phenotype of a genotype changes in a different environment

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phenotypic variation among 10 clonesreaction norms; genotype x environment

Lots of fish...

...or none

potential for adaptive response

• is there genotypic and phenotypic variation?

• some genotypes alter their behavior more than others in presence/absence of fish

• variation in phenotypic plasticity is a genotype-by-environment interaction

• when many fish present, greater plasticity (steeper slopes of reaction norm): plasticity has evolved!

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