ARPS10

ARPS10 (PF3D7_1460900) is annotated as an apicoplast ribosomal protein S10, but the available corpus characterizes it not through any biochemical or ribosomal function but as a genetic modifier of artemisinin susceptibility in Plasmodium falciparum. A nonsynonymous polymorphism in ARPS10 shows strong genome-wide association with artemisinin resistance across Southeast Asia and marks a permissive genetic background on which kelch13 resistance mutations preferentially arise (PMID:25599401). This modifier role is causally demonstrated: introducing the ARPS10-V127M variant into a kelch13-C580Y parasite, but not into a wild-type kelch13 parasite, increases ring-stage survival in the RSA0–3h assay, establishing that ARPS10-V127M acts epistatically with the kelch13 resistance allele rather than conferring resistance on its own (PMID:36303209). The resistance-associated ARPS10 locus also carries a blood-stage fitness cost, as alleles inherited from an artemisinin-resistant parent are strongly selected against over successive asexual cycles in experimental crosses (PMID:31609965). Beyond this population-genetic and epistatic role, no direct biochemical, structural, or ribosome-associated function of the ARPS10 protein has been characterized in the available corpus.

1. 2015 Medium

   Before this work it was unknown what genetic features distinguished parasites prone to acquiring artemisinin resistance; associating an ARPS10 polymorphism with resistance established it as a marker of a predisposing genetic background.

   Evidence Genome-wide association study across 15 Southeast Asian sites with population structure analysis in P. falciparum

   PMID:25599401

   Open questions at the time

   • Association only; no causal or biochemical test of the ARPS10 variant
   • Does not establish whether ARPS10 affects the ribosome or a separate pathway
   • Does not distinguish ARPS10 causation from linkage to other chromosome 14 loci
2. 2019 Medium

   It was unknown whether resistance-associated ARPS10 alleles carry a fitness penalty; experimental crosses showed strong selection against the resistant-parent allele at this locus across asexual cycles, revealing a blood-stage fitness cost.

   Evidence Experimental genetic crosses in humanized mice with selective whole-genome amplification and pooled allele-frequency tracking in P. falciparum

   PMID:31609965

   Open questions at the time

   • Selection was measured at the locus, not attributed to the ARPS10 coding variant specifically
   • Mechanism of the fitness cost was not defined
   • No biochemical characterization of ARPS10 protein
3. 2022 High

   The GWAS association left open whether ARPS10-V127M is causally involved; allelic replacement showed it increases ring survival only in a kelch13-C580Y background, establishing it as an epistatic modifier rather than an independent resistance determinant.

   Evidence Allelic replacement mutagenesis in P. falciparum 3D7 combined with RSA0–3h ring survival assay and epistasis analysis

   PMID:36303209

   Open questions at the time

   • The variant was introduced together with FD-D193Y, leaving the independent contribution of ARPS10-V127M alone undefined
   • The molecular mechanism by which the variant modifies kelch13-mediated survival is unknown
   • Single-lab result

• The biochemical function of the ARPS10 protein and the mechanism linking its variant to artemisinin susceptibility remain unresolved.
• No experimental confirmation of apicoplast ribosome association for the ARPS10 protein in the corpus
• No mechanistic connection between ARPS10-V127M and kelch13 pathway function
• Independent effect of ARPS10-V127M separate from co-introduced variants not established