Identity-by-descent analyses for measuring population dynamics and selection in recombining pathogens

Abstract

Identification of genomic regions that are identical by descent (IBD) has proven useful for human genetic studies where analyses have led to the discovery of familial relatedness and fine-mapping of disease critical regions. Unfortunately however, IBD analyses have been underutilized in analysis of other organisms, including human pathogens. This is in part due to the lack of statistical methodologies for non-diploid genomes in addition to the added complexity of multiclonal infections. As such, we have developed an IBD methodology, called isoRelate, for analysis of haploid recombining microorganisms in the presence of multiclonal infections. Using the inferred IBD status at genomic locations, we have also developed a novel statistic for identifying loci under positive selection and propose relatedness networks as a means of exploring shared haplotypes within populations. We evaluate the performance of our methodologies for detecting IBD and selection, including comparisons with existing tools, then perform an exploratory analysis of whole genome sequencing data from a global Plasmodium falciparum dataset of more than 2500 genomes. This analysis identifies Southeast Asia as having many highly related isolates, possibly as a result of both reduced transmission from intensified control efforts and population bottlenecks following the emergence of antimalarial drug resistance. Many signals of selection are also identified, most of which overlap genes that are known to be associated with drug resistance, in addition to two novel signals observed in multiple countries that have yet to be explored in detail. Additionally, we investigate relatedness networks over the selected loci and determine that one of these sweeps has spread between continents while the other has arisen independently in different countries. IBD analysis of microorganisms using isoRelate can be used for exploring population structure, positive selection and haplotype distributions, and will be a valuable tool for monitoring disease control and elimination efforts of many diseases.

Population genomics reveals the expansion of highly inbred Plasmodium vivax lineages in the main malaria hotspot of Brazil

“…vivax persist nearly unchanged over time remains open to speculation and evolutionary forces that actively restrain recombination have been hypothesized [ 43 ]. Population bottlenecks following the emergence of antimalarial drug resistance could be an explanation, as they contribute to increased parasite relatedness and can shape the regional population structure of malaria parasites [ 5 , 12 , 35 ]. However, we argue that drug-associated selective sweeps are very unlikely to have played a major role in the Juruá Valley hotspot, where resistance to chloroquine, the first-line antimalarial drug used to treat P .…”

“…vivax . Two key parameters were predefined: (a) we set to 25 the maximum number of outcrossed meioses since the most recent common ancestor (“number of generations”) to capture relatively recent gene flow [ 35 ], and (b) we set to 0.5 the minimal IBD fraction value used to define highly related parasite pairs that are connected in the network [ 11 ]. The 0.5 threshold is approximately equal to the mean relatedness between progeny derived from experimental P .…”

Resolving within-host malaria parasite diversity using single-cell sequencing

“…For 10/15 of the infections there was at least one block of IBD shared in all pairwise comparisons. As our filtering of IBD blocks was limited to >2.5cM we are limited to inference of relatedness over the last 25 generations (~6 years) 29 .…”

“…Recent studies have highlighted the power of IBD networks to capture the structure of a parasite population 29 . We built a network of pairwise shared IBD, creating links between parasites with >15% of their genomes shared IBD (Fig.…”

Strengthening Surveillance Systems for Malaria Elimination by Integrating Molecular and Genomic Data

“…Indeed, sequencing costs are decreasing, and novel techniques have been established to improve and standardize sequencing quality, even from dried blood spots (DBS), facilitating the use of the technique in epidemiological and surveillance studies [21][22][23]. Moreover, new analytical methods have also been developed to facilitate the analysis and provide meaningful results [24][25][26]. The integration of epidemiological, molecular, and genomic data could substantially improve malaria surveillance in elimination settings [27][28][29].…”