Inferring Signatures of Positive Selection in Whole-Genome Sequencing Data: An Overview of Haplotype-Based Methods

Abstract

Signatures of positive selection in the genome are a characteristic mark of adaptation that can reveal an ongoing, recent, or ancient response to environmental change throughout the evolution of a population. New sources of food, climate conditions, and exposure to pathogens are only some of the possible sources of selective pressure, and the rise of advantageous genetic variants is a crucial determinant of survival and reproduction. In this context, the ability to detect these signatures of selection may pinpoint genetic variants that are responsible for a significant change in gene regulation, gene expression, or protein synthesis, structure, and function. This review focuses on statistical methods that take advantage of linkage disequilibrium and haplotype determination to reveal signatures of positive selection in whole-genome sequencing data, showing that they emerge from different descriptions of the same underlying event. Moreover, considerations are provided around the application of these statistics to different species, their suitability for ancient DNA, and the usefulness of discovering variants under selection for biomedicine and public health in an evolutionary medicine framework.

Keywords: haplotype; haplotype composition; haplotype frequency; haplotype homozygosity; haplotype-based methods; linkage; positive selection; selective sweep; statistics; whole-genome sequencing.

Figure 1

Effect of selection of standing and novel alleles. (A) A novel allele, in grey, appears after selection has begun its action and is immediately beneficial, so it will rapidly increase its frequency in the population over time; a standing allele, in orange, already exists in the population as a neutral allele with relatively low frequency, and it increases after becoming beneficial. (B) Representation of a hard and a soft sweep, relative to the conditions described for panel A. (C) Variation in the pattern of haplotype homozygosity in a region surrounding a central ancestral (orange) or derived (grey) allele under selection. (D) Variation in the pattern of haplotype composition in a region surrounding a central ancestral (orange) or derived (grey) allele under selection. (E) Decrease in the frequency of each most frequent haplotype, given an increasing number of haplotypes surrounding a standing (orange) or novel (grey) positively selected allele in the population.