population expansion - senecio7の日記

Gazave E, Chang D, Clark AG & Keinan A 2013 Population growth inflates the per-individual number of deleterious mutations and reduces their mean effect. Genetics 195:969-978.

while population growth dramatically increases the number of deleterious segregating sites in the population, it only mildly increases the number carried by each individual
while each individual carries a larger number of deleterious alleles than expected in the absence of growth, the average selection coefficient of each segregating allele is less deleterious
the genetic risk of complex diseases in growing populations might be distributed across a larger number of more weakly deleterious rare variants

several theoretical predictions of natural selection in a population of varying size have been formulated
there is no adequate coverage of the situation where a population started growing only recently and is far from reaching a new mutation–selection–drift equilibrium
rapid growth of human populations may have led natural selection to be inefficient at removing deleterious mutations
an increase in N_e increases the efficacy of natural selection to raise the frequency of favorable mutations and reduce the frequency of deleterious mutations
with the current human N_e, even slightly deleterious mutations can be purged
the expected time until fixation (conditional upon fixation) increases with population size (Kimura and Ohta 1969; Muruyama [Maruyama] and Kimura 1974; Waxman 2012)
weakly deleterious mutations can segregate longer, and increase in their number of copies in the population

due to the limitations of theoretical results that assume equilibrium, we addressed these questions, using forward-in-time simulations that track the evolution of newly arisen mutations with known selective effects over time
using simulations allowed the comparison of models with and without recent growth, as well as with and without purifying selection, thereby revealing how population growth alone has altered the efficacy of purifying selection

we simulated genetic sequences of 5 kb with a mutation rate of 2 × 10^{− 8} per nucleotide
the value chosen for the mutation rate is higher than recent estimates
for computational efficiency, each individual 5-kb locus is in complete linkage, with no recombination

the ancestral population follows a demographic model of European history with two population bottlenecks, as described in Keinan et al. (2007)
one population (referred to as the "with growth" population) starts growing exponentially 400 generations before present (~10,000 years ago) at a rate of 1.74% per generation thereby reaching a final size of N_e = 10,000,000 at the end of the simulation (Keinan and Clark 2012)
in all models we considered a generation time of 25 years
for each deleterious mutation, s was obtained from the population-scaled selection coefficient, γ = 2Ns with γ following the opposite of a gamma distribution
we choose the shape parameter α = 0.206 and rate parameter β = 1/2740 from Boyko et al. (2008), after rescaling to an ancestral N_e of 10,000
the average s was −0.028
the fitness of each individual is the product of the fitness effect of the mutations it carries
1 + s in heterozygotes and (1 + s)² in homozygotes
the selection coefficient of alleles that reach fixation is reset to 1
we therefore ignored mutations that reach fixation
fixations are extremely rare (<0.3% of the mutations) during the 400 generations followed here
for computational efficiency, and since the extant effective population size following growth is very large (10,000,000), we scaled down both the effective population size and the time by a factor of 10

results are presented every 10 generations (corresponding to a single simulated generation) during the last 440 generations
trends with time in the models without growth are due to the preceding population bottlenecks

we estimated at each generation the percentage of segregating sites that are not observed in the next generation (%S_lost)
%S_lost becomes higher for the model with population growth, both for neutral and for deleterious loci
population growth increases not only the number of segregating sites, but also the rate at which they are lost

among all segregating sites that are lost in a given generation, singletons and doubletons make up >95% in both population models

mutations lost during population growth have on average more deleterious fitness effects than in a population that does not experience growth
this effect is attributable to the increased efficacy of purifying selection as the population size increases
derived alleles present in the growing population have on average a less deleterious effect when averaged per allelic copy
this result may seem at odds with recent sequencing studies that have shown that human populations carry a burden of recent mutations that tend to be more deleterious due to their recency (Fu et al. 2012 [2013]; Nelson et al. 2012; Tennessen et al. 2012)
recent mutations are expected to be more deleterious also in the absence of population growth
to understand how population growth has affected the selection coefficient of segregating mutations, the empirical comparison should be made to a human population that has not experienced recent growth
the selection coefficient of an allele copy picked at random in the extant human population is less deleterious than it would have been had the population not gone through an epoch of extreme growth
natural selection purges the most deleterious alleles more efficiently in the scenario with growth
each individual carries a larger number of deleterious alleles in a growing population
though only modestly so due to the recency of the growth in the human genealogical scale

applying Murayama's [Maruyama's] theory (Muruyama [Maruyama] 1974) to population growth, Maher et al. (2012) and Kiezun et al. (2013) showed that—conditioned on allele frequency—allele age can be powerful in predicting selective effect

importantly, a larger population size by itself (and the consequent higher efficiency of selection), without population growth, would also result in increased genetic heterogeneity