Molecular Evolution and Variation (The neutral theory of molecular…
Molecular Evolution and Variation
The neutral theory of molecular evolution
Discovery of abundant electrophoretic variation in the 1960s
Discovery of the molecular clock by Zuckerkandl and Pauling (1962) - the approximate constancy of the molecular evolutionary rate among taxa.
Kimura (1968): molecular clock can be explained by a combination of mutation and genetic drift.
Neutral Theory: fate of most mutations contributing to molecular evolution and variation is determined by drift rather than selection; contributing mutations are either neutral or sufficiently weakly selected that they behave like neutral variants.
Advantageous mutations play a minor role in molecular evolution
Useful null model against which departures from neutrality can be tested.
The molecular clock
Genomic regions whose sequences are essentially functionless evolve at mutation rate higher than functionally significantly regions.
Functional regions subject to selective constraints, where selection is expected to eliminate deleterious mutations
Synonymous sites are believed to evolve largely free from selection
Ka (nonsynonymous) /Ks (synonymous) = estimate of the average fraction of nonsynonymous mutations eliminated by natural selection
To estimate the times of divergence
Ks >> Ka implies that most amino acid-changing mutations are deleterious
Consider: positive selection fixes some amino acid-changing mutations in selectively constrained regions (overestimate Ka)
Rare case: Ka > Ks implies strong positive selection
Variability within populations and the coalescent process
Tests of departure from neutrality
Measuring the rate of molecular evolution
Estimating rate of sequence evolution
The estimated divergence is subject to substantial sampling error because the actual number of differences is drawn from a Poisson distribution
K can be equated to \mu per site per generation if the number of generations per year is known
Divergence between sequences = number of differences x total comparison
Rate of substitution per (generation/year) = divergence / 2T
Probability new mutant goes to fixation is equal to initial frequency
Any allele must eventually become fixed or lost.
Rate of substitution does not depend on population size
The number of mutations that become fixed per generation = \mu
In the absence of selection, the chance of any one gene copy taking over the entire population = 1/2N