Deleterious Passengers in Adapting Populations

Abstract

Most new mutations are deleterious and are eventually eliminated by natural selection. But in an adapting population, the rapid amplification of beneficial mutations can hinder the removal of deleterious variants in nearby regions of the genome, altering the patterns of sequence evolution. Here, we analyze the interactions between beneficial "driver" mutations and linked deleterious "passengers" during the course of adaptation. We derive analytical expressions for the substitution rate of a deleterious mutation as a function of its fitness cost, as well as the reduction in the beneficial substitution rate due to the genetic load of the passengers. We find that the fate of each deleterious mutation varies dramatically with the rate and spectrum of beneficial mutations and the deleterious substitution rate depends nonmonotonically on the population size and the rate of adaptation. By quantifying this dependence, our results allow us to estimate which deleterious mutations will be likely to fix and how many of these mutations must arise before the progress of adaptation is significantly reduced. RECENT years have witnessed an increased interest in the evolutionary dynamics of rapid adaptation. Once regarded as an obscure limit of population genetics, this regime has since been observed in a variety of empirical settings, from laboratory evolution experiments (Barrick et al. 2009;Lang et al. 2013) to natural populations of pathogenic viruses (Strelkowa and Lässig 2012), bacteria (Lieberman et al. 2014), and certain cancers (Nik-Zinal et al. 2012). In these populations, natural selection plays a central role in driving beneficial variants to fixation, and significant theoretical and empirical effort has been devoted to the study of these beneficial mutations and the dynamics by which they spread through the population (see Sniegowski and Gerrish 2010 for a review). Yet even in the most rapidly adapting populations, the vast majority of new mutations are neutral or deleterious, and much less is known about how these variants influence (or are influenced by) adaptation in nearby regions of the genome. As a result, even the most basic questions about this process remain unanswered. How deleterious must a mutation be before it is effectively purged by selection? Which deleterious mutations have the largest influence on the spread of the adaptive mutations? And how do the answers to these questions depend on the size of the population and the spectrum of beneficial mutations? These questions are the focus of the present study.In the absence of other mutations, the fate of a deleterious variant is determined by the interplay between natural selection and genetic drift. Selection purges harmful variants from the population on a timescale inversely proportional to the fitness cost, s d , of the deleterious mutation. Meanwhile, random fluctuations from genetic drift can drive these variants to fixation, which requires a time proportional to the effective population size, N e . Deleterious mutations with s d ) N 21 e ...

The Genetic Cost of Neanderthal Introgression

“…But it is likely that introgressed Neanderthal DNA has been subject to a selective tug-of-war, with selection favoring Neanderthal DNA in regions where humans carry recessive deleterious mutations and selection disfavoring Neanderthal alleles that have additive or dominant effects. In a sense, this is the opposite of the tug-of-war that may occur when a beneficial allele is linked to recessive deleterious alleles that impede the haplotype from sweeping to high frequencies (Good and Desai 2014;Assaf et al 2015).…”

Obstruction of adaptation in diploids by recessive, strongly deleterious alleles

“…An interesting extension would thus be to incorporate arbitrary rates of beneficial and deleterious mutations (similar to ref. 30), Table 1. Estimates of the the proportion of the genome in which the probability of fixation of the beneficial mutation is decreased for Drosophila melanogaster and humans Due to variation in functional density across genomes and organisms, we frame our estimates in terms of coding genes and their densities, using the Drosophila and human reference genomes (SI Text, section 3).…”

“…It is well established that in finite populations, the fate of a new adaptive mutation should be affected by its genetically linked neighbors. For example, the rate of fixation of beneficial mutations at a single site will be lower if there are additional sites subject to positive or negative selection along the chromosome (25)(26)(27)(28)(29)(30). This "Hill−Robertson" or "linkage" interference can be alleviated by recombination, allowing adaptive mutations to combine onto the same background or escape deleterious neighbors (31-35).…”

The population genetics of drug resistance evolution in natural populations of viral, bacterial and eukaryotic pathogens

“…In addition, it can unlink positively selected traits from deleterious passenger mutations and mitigate the effects of linked selection (Hill & Robertson 1966; Birky & Walsh 1988; Good & Desai 2014). In populations with no recombination, each mutation remains on the genetic background on which it originally occurred.…”