Predicting Carriers of Ongoing Selective Sweeps Without Knowledge of the Favored Allele

Abstract

Methods for detecting the genomic signatures of natural selection have been heavily studied, and they have been successful in identifying many selective sweeps. For most of these sweeps, the favored allele remains unknown, making it difficult to distinguish carriers of the sweep from non-carriers. In an ongoing selective sweep, carriers of the favored allele are likely to contain a future most recent common ancestor. Therefore, identifying them may prove useful in predicting the evolutionary trajectory -- for example, in contexts involving drug-resistant pathogen strains or cancer subclones. The main contribution of this paper is the development and analysis of a new statistic, the Haplotype Allele Frequency (HAF) score. The HAF score, assigned to individual haplotypes in a sample, naturally captures many of the properties shared by haplotypes carrying a favored allele. We provide a theoretical framework for computing expected HAF scores under different evolutionary scenarios, and we validate the theoretical predictions with simulations. As an application of HAF score computations, we develop an algorithm (PreCIOSS: Predicting Carriers of Ongoing Selective Sweeps) to identify carriers of the favored allele in selective sweeps, and we demonstrate its power on simulations of both hard and soft sweeps, as well as on data from well-known sweeps in human populations.\n\nAuthor summaryMethods for detecting the genomic signatures of natural selection have been heavily studied, and they have been successful in identifying genomic regions under positive selection. However, methods that detect positive selective sweeps do not typically identify the favored allele, or even the haplotypes carrying the favored allele. The main contribution of this paper is the development and analysis of a new statistic (the HAF score), assigned to individual haplotypes. Using both theoretical analyses and simulations, we describe how the HAF scores differ for carriers and non-carriers of the favored allele, and how they change dynamically during a selective sweep. We also develop an algorithm, PreCIOSS, for separating carriers and non-carriers. Our tool has broad applicability as carriers of the favored allele are likely to contain a future most recent common ancestor. Therefore, identifying them may prove useful in predicting the evolutionary trajectory -- for example, in contexts involving drug-resistant pathogen strains or cancer subclones.