In populations of finite size, sampling of gametes from the gene pool can cause evolution. Incorporating Genetic Drift

Probability of Maintaining the Same Initial Allele Frequency

The Ultimate Fate of Random Genetic Drift

The Effects of Drift are More Pronounced in Smaller Populations

8 pops The frequency of heterozygotes decreases under drift. H g+1 = H g [1-1/2N]

N e = 4N m N f / (N m + N f ) N=16 Effective population size N=16N=9 107 pops

Rate of Evolution by Genetic Drift Rate of evolution equals rate that an allele is fixed at a locus. K = 2N  x 1/2N =  Depends upon: (2Nu) number of mutations arising at locus per generation, and initial frequency of new allele (1/2N) rate of allele substitution = rate of mutation!

Neutralist view: allele substitution and polymorphism are determined by the same evolutionary process. Mutation provides a continual supply of new alleles. Because many alleles are neutral or effectively neutral, alleles becomes fixed or lost from a population as a result of genetic drift. Polymorphism is simply a snapshot of a continuous process of mutational input and subsequent random extinction or fixation of alleles.

Mootoo Kimura’s concept of neutralism is illustrated in the following diagram from his original paper.

Selectionist view: allele substitution and polymorphism are determined by different, selective processes. Mutation yields advantageous alleles that are driven to fixation by positive natural selection. Two or more alleles are maintained at a locus in a population by over-dominance.

Evolution by Genetic Drift : Main Points 1.Allele frequencies fluctuate at random within a population; eventually, one or another allele becomes fixed. 2. Genetic variation at a locus declines and is eventually lost; the rate of decline in heterozygosity is used to estimate the strength of drift: frequency of heterozygotes (H) = 2p(1-p). 3. At any time, the probability of allele fixation ~equals its frequency at that time. 4. Evolution by genetic drift proceeds faster in smaller populations; the average time to fixation is 4Ne. 5. Populations with the same initial allele frequency diverge; the same or different allele maybe fixed but the average allele frequency remains the same. The frequency of heterozygotes declines.

V 0 = v T f o Rate of Neutral Mutation Total Mutation Rate per Unit Time Fraction of Selectively Neutral Mutations Functional constraint: Range of alternative nucleotides that is acceptable at a site without negatively affecting the function or structure of a protein. Neutral Theory Predicts k = V 0 : k = v T f o Rate of Substitution (allele) So,

Highest Rate of Substitution is Expected in Sequence That Does Not Have A Function k = v T f o So, rate of substitution will be greatest when f o is 1.0 i.e. Pseudogenes!

Expect an inverse relationship between the intensity of the functional constraint and the rate of neutral evolution Got to be careful here!

Also, expect higher rates of substitution for synonymous vs nonsynonymous sites. (1) Mutations that result in amino acid replacements have a higher probability of causing a deleterious effect on the structure/function of the protein. (2) Accordingly, the majority of nonsynonomous mutations will be eliminated from the population by purifying selection. (3) As a result, there will be a reduction in the rate of nonsynonymous substitution vs synonymous substitution. Given this relationship: Logic:

Why is the rate of substitution at 4-fold sites lower than the rate within pseudogenes? Synonymous substitutions are not selectively neutral! Codon Usage is non-random: species-specific, and patterns may vary among genes within a genome.

Testing the Neutral Mutation Hypothesis dN dS <1 When replacements are deleterious dN dS =1 When replacements are neutral dN dS >1 When replacements are advantageous

Testing the Neutral Mutation Hypothesis The neutral theory predicts that polymorphism within species is correlated positively with fixed differences between species Genes that exhibit many interspecific differences will also have high levels of intraspecific polymorphism. i.e.

Nonsynonymous Synonymous Fixed Differences Polymorphisms % % nonsynonymous fixed synonymous fixed nonsynonymous polymorphism synonymous polymorphism = McDonald-Krietman Test G6PDH from D. melanogaster and D. simulans. Eanes et al Neutral Prediction: % nonsynonymous

Frequency If most nonsynonymous substitutions are adaptive, then they will increase in frequency and be fixed more rapidly than neutral alleles. Time As a result, they spend less time in a polymorphic state, therefore contribute less to within species polymorphism. neutral allele advantageous allele

Nonsynonymous Synonymous Fixed Differences Polymorphisms % % Adh from D. melanogaster, D. simulans, and D. Yakuba MacDonald and Kreitman 1991 % nonsynonymous Another example (N = 6-12 alleles per species for the coding region).

Is the CFTR allele maintained by mutation/selection balance? In some populations: Freq of Cystic Fibrosis Alleles: 2% Under mutation/selection balance, need:  = 4 x However the actual rate is 6.7 x too low!

Cultured mouse cells with CFTR genotypes The fitness cost of dF508 / dF508 with respect to Pseudomonas is balanced by the fitness advantage of dF508 / + with respect to Salmonella

Continent Island Incorporating Migration Geneflow Migration is a homogenizing force; it prevents divergence of populations Migration can alter allele and genotype frequencies.

Lake Erie Water Snakes Banded vs Unbanded

BandedUnbanded Natural Selection for Unbanded Forms on Islands

Continent Island Incorporating Migration Banded alleles Opposed by Natural Selection It is possible to calculate the change in frequency of the banded allele (q) as a function of q.

Change in frequency of the unbanded allele (q) as a function of q for island populations. Equilibrium points a)Strong selection for q, little migration.