Models of Molecular Models of Molecular Evolution IIIEvolution III

Level 3 Molecular Evolution and Level 3 Molecular Evolution and BioinformaticsBioinformatics

Jim ProvanJim Provan

Page and Holmes: Sections 7.5 – 7.8Page and Holmes: Sections 7.5 – 7.8

The nearly neutral theoryThe nearly neutral theory

Variable rates ofnucleotide substitution

Variable rates ofnucleotide substitution

Variable mutation ratesVariable mutation rates(generation time, metabolic rate, DNA repair)(generation time, metabolic rate, DNA repair)

Nearly neutral mutationsNearly neutral mutations(population size and weak selection)(population size and weak selection)

Development of the nearly Development of the nearly neutral theoryneutral theory

By the early 1970s it was By the early 1970s it was becoming clear that:becoming clear that:

Some amino acid Some amino acid substitution rates were substitution rates were inconsistent with a Poisson inconsistent with a Poisson clockclockLevels of heterozygosity Levels of heterozygosity were not as high as were not as high as expected in natural expected in natural populationspopulations

Tomoko Ohta suggested Tomoko Ohta suggested that most non-that most non-synonymous changes synonymous changes were not perfectly neutralwere not perfectly neutral

DeleteriousDeleterious

AdvantageousAdvantageous

NeutralNeutral

Slightly deleteriousSlightly deleterious

Slightly advantageousSlightly advantageous

Development of the nearly Development of the nearly neutral theoryneutral theory

Nearly neutral mutations are those where the product Nearly neutral mutations are those where the product of the population size and the selection coefficient is of the population size and the selection coefficient is near zero i.e. near zero i.e. Ns Ns 0 0

These changes are subject to weak natural selection as well as These changes are subject to weak natural selection as well as genetic driftgenetic drift

Rate of substitution (per year) for nearly neutral mutations will Rate of substitution (per year) for nearly neutral mutations will depend on population size, selective coefficient and mutation depend on population size, selective coefficient and mutation rate, set to generation timerate, set to generation time

Mutations at non-coding and synonymous sites are still neutralMutations at non-coding and synonymous sites are still neutral

Relative importance of selection or genetic drift and Relative importance of selection or genetic drift and hence probability of fixation depends on population hence probability of fixation depends on population sizesize

The nearly neutral theory and The nearly neutral theory and real time molecular clocksreal time molecular clocks

Long generation timeLong generation time(lower mutation rate)(lower mutation rate)

Small population sizeSmall population size(higher probability of fixation)(higher probability of fixation)

++

Short generation timeShort generation time(higher mutation rate)(higher mutation rate)

Large population sizeLarge population size(lower probability of fixation)(lower probability of fixation)

++~ Real time

molecular clock~ Real time

molecular clock

The nearly neutral theory and The nearly neutral theory and real time molecular clocksreal time molecular clocks

A study of 20 mammalian genes showed that A study of 20 mammalian genes showed that R(t) R(t) values were generally well over 1.0, rejecting the values were generally well over 1.0, rejecting the Poisson clockPoisson clockAfter correcting for generation time and lineage After correcting for generation time and lineage effects:effects:

Average Average R(t) R(t) for synonymous sites dropped from 14.4 to 4.6for synonymous sites dropped from 14.4 to 4.6Average Average R(t) R(t) for non-synonymous sites only dropped from for non-synonymous sites only dropped from 8.26 to 6.958.26 to 6.95

Most variation in synonymous sites is due to lineage Most variation in synonymous sites is due to lineage effectseffectsNon-synonymous rates are less generation time Non-synonymous rates are less generation time dependent than synonymous sitesdependent than synonymous sites

Testing the neutral theory within Testing the neutral theory within speciesspecies

Neutral theory makes two very important Neutral theory makes two very important predictions about levels of genetic variation within predictions about levels of genetic variation within species:species:

Extent of polymorphism is a function only of the Extent of polymorphism is a function only of the population size (population size (NN) and the mutation rate () and the mutation rate ())Levels of polymorphism are correlated with amount of Levels of polymorphism are correlated with amount of variation between species i.e. genes that evolve slowly variation between species i.e. genes that evolve slowly between species also exhibit low variation within a between species also exhibit low variation within a speciesspecies

Original allozyme studies cast doubt on these Original allozyme studies cast doubt on these predictions:predictions:

Levels of heterozygosity were found to be too lowLevels of heterozygosity were found to be too lowDifficult to draw firm conclusions, since Difficult to draw firm conclusions, since N N and and are hard are hard to quantify, and allozymes underestimate diversity levelsto quantify, and allozymes underestimate diversity levels

Best to test theories at the DNA levelBest to test theories at the DNA level

Testing the neutral theory within Testing the neutral theory within speciesspecies

Important assessment of the neutral theory is to test Important assessment of the neutral theory is to test proposed correlation between levels of within species proposed correlation between levels of within species polymorphism and between species divergence:polymorphism and between species divergence:

If synonymous and non-synonymous substitutions are If synonymous and non-synonymous substitutions are neutral then ratio of both types of change will be the same neutral then ratio of both types of change will be the same within and between species because they result from the within and between species because they result from the same neutral mutation processsame neutral mutation process

Positive natural selection would alter this ratio because an Positive natural selection would alter this ratio because an advantageous non-synonymous mutation would be fixed advantageous non-synonymous mutation would be fixed quicker by natural selection i.e. be a polymorphism for less quicker by natural selection i.e. be a polymorphism for less time, leading to less within-species non-synonymous time, leading to less within-species non-synonymous variation than expected given levels detected between variation than expected given levels detected between speciesspecies

Patterns of substitution at the Patterns of substitution at the AdhAdh locus in locus in DrosophilaDrosophila

D. melanogasterD. melanogaster D. simulansD. simulans D. yakubaD. yakuba

2/142/14 0/110/11 0/170/17

1/21/2 1/01/0 5/155/15

SynonymousSynonymousNon-synonymousNon-synonymous

FixedFixed171777

PolymorphicPolymorphic424222

GG = 7.43 = 7.43 PP = 0.006 = 0.006

Recombination and DNA Recombination and DNA polymorphism in polymorphism in DrosophilaDrosophila

Most dramatic example of incompatibility Most dramatic example of incompatibility between levels of variation between and within between levels of variation between and within a species occurs in regions of the a species occurs in regions of the DrosophilaDrosophila genome where recombination rates are low:genome where recombination rates are low:

Distal tip of the X chromosomeDistal tip of the X chromosomeSmall chromosome IVSmall chromosome IV

Neutralist explanation is that these regions Neutralist explanation is that these regions have either lower mutation rates or are under have either lower mutation rates or are under selective constraintselective constraintIf this is the case, these regions should also If this is the case, these regions should also show reduced levels of variation between show reduced levels of variation between speciesspecies

Recombination and DNA Recombination and DNA polymorphism in polymorphism in DrosophilaDrosophila

The The yellow-achaeteyellow-achaete ( (y, acy, ac) region on the X ) region on the X chromosome of chromosome of D. melanogasterD. melanogaster has a reduced has a reduced level of polymorphismlevel of polymorphism

Extent of divergence in this region between Extent of divergence in this region between D. D. melanogastermelanogaster and and D. simulansD. simulans (5.4%) is similar to (5.4%) is similar to that observed in other genes (average 4.7%) – that observed in other genes (average 4.7%) – this contradicts the neutral theorythis contradicts the neutral theory

Natural selection can explain this discrepancy Natural selection can explain this discrepancy through the dual action of through the dual action of selective sweepsselective sweeps and and genetic hitchhikinggenetic hitchhiking

Hitchhiking and selective Hitchhiking and selective sweepssweeps

TimeTime

tt11 tt22 tt33 tt44

Can we resolve the neutralist-Can we resolve the neutralist-selectionist debate?selectionist debate?

Most support for neutral theory has come from Most support for neutral theory has come from comparisons of genes across distantly related speciescomparisons of genes across distantly related speciesNatural selection is more apparent over shorter time Natural selection is more apparent over shorter time scalesscales

As time proceeds, fixation due to selection may be obscured by As time proceeds, fixation due to selection may be obscured by neutral mutationsneutral mutationsMajority of original selection events in adaptive radiations e.g. Majority of original selection events in adaptive radiations e.g. mammalsmammals

Overall, it seems reasonable to conclude that both Overall, it seems reasonable to conclude that both selection and drift shape evolutionary fate of mutations:selection and drift shape evolutionary fate of mutations:

Majority of substitutions do not affect fitness (neutralist)Majority of substitutions do not affect fitness (neutralist)The “footprints” of natural selection are still evident in more The “footprints” of natural selection are still evident in more recently evolved levels, particularly at non-synonymous sitesrecently evolved levels, particularly at non-synonymous sites