Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

<jats:title>Abstract</jats:title><jats:p>Malaria is transmitted through female Anopheline mosquitoes where gamete fusion and meiosis occurs, and humans where parasites proliferate asexually. We describe a powerful approach to identify the genetic determinants of parasite fitness across both invertebrate and vertebrate life-cycle stages in human malaria parasite<jats:italic>Plasmodium falciparum</jats:italic>using bulk segregant analysis (BSA). We combined experimental genetic crosses using humanized mice, with selective whole genome amplification and BSA at multiple developmental stages in both mosquito and vertebrate host to examine parasite competition and identify genomic regions under selection. We generated crosses between artemisinin resistant (ART-R,<jats:italic>kelch13</jats:italic>-C580Y) and ART-sensitive (ART-S,<jats:italic>kelch13</jats:italic>-WT) parasite clones recently isolated from Southeast Asian patients. We then quantified genome-wide changes in allele frequency in the parasite progeny population from infected midgut and salivary glands of<jats:italic>Anopheles stephensi</jats:italic>mosquitoes, infected livers, emerging merozoites and aliquots of<jats:italic>in vitro</jats:italic>cultured progeny parasites at intervals over 30 days. Three striking results emerge: we observed (i) a strong skew (&gt;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; (ii) highly repeatable skews in allele frequencies across the genome in blood stage parasites; (iii) 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.</jats:p>

Original publication

DOI

10.1101/570085

Type

Journal article

Publisher

Cold Spring Harbor Laboratory

Publication Date

07/03/2019