Strong positive selection biases identity-by-descent-based inferences of recent demography and population structure in Plasmodium falciparum

Abstract

Funding Information: We would like to thank the participants in studies contributing clinical samples from which the parasite WGS data were generated, as well as the clinical investigators at the Armed Forces Research Institute of Medical Sciences who conducted the studies contributing parasite isolates to our in-house data set. This publication uses data from the MalariaGEN Consortium and Plasmodium falciparum Community Project as described in “An open data set of Plasmodium falciparum genome variation in 7000 worldwide samples. MalariaGEN et al., Wellcome Open Research 2021642 DOI: 10.12688/wellcomeopenres.16168.1.” This work was supported by NIH 1R01AI145852 granted to ST-H and TDO by the U.S. National Institutes of Health. Publisher Copyright: © The Author(s) 2024.Malaria genomic surveillance often estimates parasite genetic relatedness using metrics such as Identity-By-Decent (IBD), yet strong positive selection stemming from antimalarial drug resistance or other interventions may bias IBD-based estimates. In this study, we use simulations, a true IBD inference algorithm, and empirical data sets from different malaria transmission settings to investigate the extent of this bias and explore potential correction strategies. We analyze whole genome sequence data generated from 640 new and 3089 publicly available Plasmodium falciparum clinical isolates. We demonstrate that positive selection distorts IBD distributions, leading to underestimated effective population size and blurred population structure. Additionally, we discover that the removal of IBD peak regions partially restores the accuracy of IBD-based inferences, with this effect contingent on the population’s background genetic relatedness and extent of inbreeding. Consequently, we advocate for selection correction for parasite populations undergoing strong, recent positive selection, particularly in high malaria transmission settings.publishersversionpublishe