Abstract
Natural selection is a significant force that shapes the architecture of the human genome and introduces diversity across global populations. The question of whether advantageous mutations have arisen in the human genome as a result of single or multiple mutation events remains unanswered except for the fact that there exist a handful of genes such as those that confer lactase persistence, affect skin pigmentation, or cause sickle cell anemia. We have developed a long-range-haplotype method for identifying genomic signatures of positive selection to complement existing methods, such as the integrated haplotype score (iHS) or cross-population extended haplotype homozygosity (XP-EHH), for locating signals across the entire allele frequency spectrum. Our method also locates the founder haplotypes that carry the advantageous variants and infers their corresponding population frequencies. This presents an opportunity to systematically interrogate the whole human genome whether a selection signal shared across different populations is the consequence of a single mutation process followed subsequently by gene flow between populations or of convergent evolution due to the occurrence of multiple independent mutation events either at the same variant or within the same gene. The application of our method to data from 14 populations across the world revealed that positive-selection events tend to cluster in populations of the same ancestry. Comparing the founder haplotypes for events that are present across different populations revealed that convergent evolution is a rare occurrence and that the majority of shared signals stem from the same evolutionary event.
Highlights
The process of positive natural selection leaves informative imprints in the human genome
Except in a handful of genes, it remains unanswered whether advantageous alleles that are shared across several populations (1) have arisen in the human genome as a result of a single mutation event subsequently followed by gene flow between these populations or (2) present evidence of convergent evolution where multiple independent mutation events, either at the same location or at different locations in the same gene, have occurred in these populations as a result of exposure to the same adaptive pressure
Power Comparison with integrated haplotype score (iHS) and XP-extended haplotype homozygosity (EHH) We benchmarked the performance of haploPS against iHS and XP-EHH via a series of simulations to evaluate the sensitivity of all three methods
Summary
The process of positive natural selection leaves informative imprints in the human genome. Bioinformatics strategies designed to discover evidence of local adaption predominantly focus on identifying the following two genomic features that accompany the introduction of an evolutionarily advantageous allele: (1) the presence of a long-range haplotype (LRH) on which the selected allele resides, given that this variant increases in frequency very rapidly and brings along neighboring variants (on the same haplotype) that recombination does not have sufficient time to break down; (2) stretches in the human genome that are highly differentiated between populations as a result of positive selection’s exerting a stronger force on the genetic backgrounds associated with the beneficial alleles to dominate above neutrally evolving regions. Another well-known example of convergent evolution is the lactase-encoding gene that confers lactase persistence in northern European populations[5] and certain nomadic African tribes,[6] in which different functional variants have arisen in the same gene to enable lactase persistence in the different populations
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