Adaptive evolution of Plasmodium vivax in Duffy-negative hosts: insights from
East African genomes
#MMPMID41346480
Ford A
; Dieng CC
; Abagero BR
; Yan G
; Yewhalaw D
; Janies DA
; Lo E
bioRxiv
2025[Dec]; ? (?): ? PMID41346480
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Historically, Plasmodium vivax ( Pv ) malaria was rare in Africa due to the lack
of Duffy antigen receptor for chemokines (DARC) expression on host erythrocytes,
an essential receptor for Pv Duffy Binding Protein (PvDBP1)-mediated invasion.
However, increased reports of Pv cases across Africa and among Duffy-negative
individuals have led to the hypothesis that the parasites have evolved alternate
invasion mechanisms that are DARC-independent. To investigate potential genetic
adaptations underlying this phenomenon, we performed genome-wide single
nucleotide polymorphisms (SNPs) analyses of 110 Pv isolates collected from
Ethiopia, comprising 38 Duffy-negative and 72 Duffy-positive infections. Pv from
Duffy positives exhibited markedly higher genetic variation (477,561 SNPs) than
those from Duffy negatives (197,461 SNPs). Chromosomes 1, 2, 9, 10, and 12
harbored the highest SNPs densities, consistent across both host genotypes but
elevated in Duffy-positive infections. Among 43 erythrocyte-binding gene
candidates, tryptophan rich antigen 3 and 34 ( TRAg 3 and TRAg 34) and members of
the merozoite surface protein 3 ( MSP 3) family showed the greatest nucleotide
diversity per kilobase, highlighting these loci as potential mediators of
host-parasite interaction shifts. Signals of positive selection differed by host
Duffy genotypes. In Duffy-positive Pv , adaptive signatures were observed in
genes related to drug resistance (chloroquine resistance-associated protein CG 1
and 26S proteasome regulatory subunit RPN 2) and erythrocyte binding ( MAEBL );
whereas in Duffy negative Pv , positive selection was observed in genes linked to
organellar maintenance and vesicle trafficking (plastid replication repair enzyme
and the AP-5 complex subunit beta 1), implicating alternative metabolic or
trafficking adaptations. Amino acid substitutions in invasion ligands ( PvDBP 1,
PvEBP/DBP 2, and PvRBP 2b) were common in Duffy-positive Pv but largely absent in
Duffy-negative ones, with almost half of the mutations located in critical
binding domains. Overall, Pv isolates in Duffy-negative hosts displayed reduced
genomic diversity yet retained high conservation across the genome, suggesting
strong selective constraints and limited diversification. Phylogenetic comparison
revealed that Ethiopian Pv clustered closely with other East African isolates,
whereas Southeast Asian and South American Pv represented more distant lineages.
These findings indicate that Pv circulating in Duffy-negative populations
maintains a genetically conserved background, potentially reflecting stringent
evolutionary bottlenecks and/or specialized host-parasite interactions required
for invasion of Duffy-negative erythrocytes.
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