Genetic mapping of fitness determinants across the malaria parasite Plasmodium falciparum life cycle

Autoři: Xue Li aff001;  Sudhir Kumar aff002;  Marina McDew-White aff001;  Meseret Haile aff002;  Ian H. Cheeseman aff001;  Scott Emrich aff003;  Katie Button-Simons aff003;  Francois Nosten aff005;  Stefan H. I. Kappe aff002;  Michael T. Ferdig aff003;  Tim J. C. Anderson aff001;  Ashley M. Vaughan aff002
Působiště autorů: Texas Biomedical Research Institute, San Antonio, Texas, United States of America aff001;  Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, Washington, United States of America aff002;  Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America aff003;  Electrical Engineering and Computer Science, University of Tennessee, Knoxville, Tennessee, United States of America aff004;  Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand aff005;  Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research building, University of Oxford Old Road campus, Oxford, United Kingdom aff006;  Department of Global Health, University of Washington, Seattle, Washington, United states of America aff007
Vyšlo v časopise: Genetic mapping of fitness determinants across the malaria parasite Plasmodium falciparum life cycle. PLoS Genet 15(10): e32767. doi:10.1371/journal.pgen.1008453
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008453


Determining the genetic basis of fitness is central to understanding evolution and transmission of microbial pathogens. In human malaria parasites (Plasmodium falciparum), most experimental work on fitness has focused on asexual blood stage parasites, because this stage can be easily cultured, although the transmission of malaria requires both female Anopheles mosquitoes and vertebrate hosts. We explore a powerful approach to identify the genetic determinants of parasite fitness across both invertebrate and vertebrate life-cycle stages of P. falciparum. This combines experimental genetic crosses using humanized mice, with selective whole genome amplification and pooled sequencing to determine genome-wide allele frequencies and identify genomic regions under selection across multiple lifecycle stages. We applied this approach to genetic crosses between artemisinin resistant (ART-R, kelch13-C580Y) and ART-sensitive (ART-S, kelch13-WT) parasites, recently isolated from Southeast Asian patients. Two striking results emerge: we observed (i) a strong genome-wide skew (>80%) towards alleles from the ART-R parent in the mosquito stage, that dropped to ~50% in the blood stage as selfed ART-R parasites were selected against; and (ii) repeatable allele specific skews in blood stage parasites with particularly strong selection (selection coefficient (s) ≤ 0.18/asexual cycle) against alleles from the ART-R parent at loci on chromosome 12 containing MRP2 and chromosome 14 containing ARPS10. This approach robustly identifies selected loci and has strong potential for identifying parasite genes that interact with the mosquito vector or compensatory loci involved in drug resistance.

Klíčová slova:

Blood – Malarial parasites – Mammalian genomics – Natural selection – Parasitic diseases – Parasitic life cycles – Plasmodium – Quantitative trait loci


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