Allele ages provide limited information about the strength of negative selection

Abstract

For many problems in population genetics, it is useful to characterize the distribution of fitness effects (DFE) of de novo mutations among a certain class of sites. A DFE is typically estimated by fitting an observed site frequency spectrum (SFS) to an expected SFS given a hypothesized distribution of selection coefficients and demographic history. The development of tools to infer gene trees from haplotype alignments, along with ancient DNA resources, provides us with additional information about the frequency trajectories of segregating mutations. Here, we ask how useful this additional information is for learning about the DFE, using the joint distribution on allele frequency and age to summarize information about the trajectory. To this end, we introduce an accurate and efficient numerical method for computing the density on the age of a segregating variant found at a given sample frequency, given the strength of selection and an arbitrarily complex population size history. We then use this framework to show that the unconditional age distribution of negatively selected alleles is very closely approximated by re-weighting the neutral age distribution in terms of the negatively selected SFS, suggesting that allele ages provide very little information about the DFE beyond that already contained in the present day frequency. To confirm this prediction, we extended the standard Poisson Random Field (PRF) method to incorporate the joint distribution of frequency and age in estimating selection coefficients, and test its performance using simulations. We find that when the full SFS is observed and the true allele ages are known, including ages in the estimation provides only small increases in the accuracy of estimated selection coefficients. However, if only sites with frequencies above a certain threshold are observed, then the true ages can provide substantial information about the selection coefficients, especially when the selection coefficient is large. When ages are estimated from haplotype data using state-of-the-art tools, uncertainty about the age abrogates most of the additional information in the fully observed SFS case, while the neutral prior assumed in these tools when estimating ages induces a downward bias in the case of the thresholded SFS.