cis-trans compensation

Carter AJR & Wagner GP 2002 Evolution of functionally conserved enhancers can be accelerated in large populations: a population-genetic model. Proc R Soc Lond B 269:953-960.

  • the rate of evolution by pairs of compensatory mutations increases dramatically for population sizes above several thousand individuals
  • to the point of greatly exceeding the neutral rate
  • the conservation of expression patterns need not be accompanied by preservation of the corresponding cis-regulatory elements
  • the model is based on the assumption that the evolution of functional cis-enhancer elements is due to pairs of deleterious mutations that, in combination, compensate for their individual deleterious effects
  • Ludwig et al. (2000) explain the aforementioned observations of sequence divergence in Eve 2 stripe enhancer sequences in closely related fixation of a series of slightly deleterious mutations by random drift, and subsequent selection for compensatory mutations
  • this suggestion can account for enhancer sequence divergence while maintaining conserved function
  • but also predicts that the rate of sequence evolution should decrease with increasing population size
  • in the second, less commonly considered pathway the compensatory mutation occurs while the population is still segregating a number of copies of the initial deleterious allele
  • although this pathway may also be expected to be slower in larger populations, due to selection being more efficient against the individuals carrying the deleterious allele (larger Ns again), we show that this is often not the case
  • we concern ourselves exclusively with the case in which the mutations are tightly linked, as is the case in cis-regulatory elements, the intermediate alleles are completely recessive and the final compensatory allele is slightly advantageous and dominant to the other alleles
  • we further simplify the formula by making the reasonable assumption that the second pathway only occurs for large population sizes
  • a change in population size of only 100-fold corresponds to a change in the evolutionary rate of ca. 1000-fold
  • estimates of effective population sizes (Kondrashov 1995; Nei & Graur 1984) of many vertebrates species are ca. 104−105
  • while invertebrates are estimated to have effective population sizes of ca. 106−107
  • values that would lead this model to predict 1000-fold differences, or more, in the rate of fixation of pairs of compensatory mutations
  • invertebrate species with up to 100-fold larger populations also tend to have generation times that are significantly shorter than vertebrates
  • (easily 10−100 times smaller)
  • amplifying this rate difference when measured in units of physical time