@article{draghi_epistasis_2011,
Author = {Draghi, Jeremy A. and Parsons, Todd L. and Plotkin,
Joshua B.},
Title = {Epistasis increases the rate of conditionally neutral
substitution in an adapting population},
Journal = {Genetics},
Volume = {187},
Number = {4},
Pages = {1139--1152},
abstract = {Kimura observed that the rate of neutral substitution
should equal the neutral mutation rate. This classic
result is central to our understanding of molecular
evolution, and it continues to influence phylogenetics,
genomics, and the interpretation of evolution
experiments. By demonstrating that neutral mutations
substitute at a rate independent of population size and
selection at linked sites, Kimura provided an
influential justification for the idea of a molecular
clock and emphasized the importance of genetic drift in
shaping molecular evolution. But when epistasis among
sites is common, as numerous empirical studies suggest,
do neutral mutations substitute according to Kimura's
expectation? Here we study simulated, asexual
populations of RNA molecules, and we observe that
conditionally neutral mutations--i.e., mutations that
do not alter the fitness of the individual in which
they arise, but that may alter the fitness effects of
subsequent mutations--substitute much more often than
expected while a population is adapting. We quantify
these effects using a simple population-genetic model
that elucidates how the substitution rate at
conditionally neutral sites depends on the population
size, mutation rate, strength of selection, and
prevalence of epistasis. We discuss the implications of
these results for our understanding of the molecular
clock, and for the interpretation of molecular
variation in laboratory and natural populations.},
doi = {10.1534/genetics.110.125997},
issn = {1943-2631},
language = {eng},
month = apr,
pmcid = {PMC3070522},
pmid = {21288876},
year = 2011
}