Biology subjects

Corredor, V.

Publications and source records attributed to Corredor, V..

4 recordsLinked to original sources

bioRxiv2026

South American Plasmodium falciparum isolates reveal new insights into the role of PfAAT1 in mediating resistance to Chloroquine

Antimalarial drug resistance remains one of the most significant challenges to global malaria control. The emergence of resistance to chloroquine, the first truly globally distributed antimalarial, has been extensively studied but is still not fully understood. While mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) primarily drive resistance, the phenotype is complex and multigenic, with mutations in the putative amino acid transporter PfAAT1 recently confirmed to play a modulatory role. To date studies have focused on PfAAT1 mutations found in African and Southeast Asian P. falciparum lineages, but chloroquine resistance emerged independently in South America, where there may be novel PfAAT1 polymorphisms that are functionally important. We used AlphaFold modelling to reveal high homology between PfAAT1 and the human lysosomal arginine transporter SLC38A9, which allows prediction of membrane orientation and identifies a partially open channel accessible from the cytoplasm. Several PfAAT1 mutations found only in South American isolates sit near the entrance of this pore, most notably V231 where mutation to aspartate is predicted to alter channel conformation and influence transport, while nearby P446A (which is always found in combination with V231D) and I248T are predicted to impact pore flexibility and local structural stability. To functionally validate these insights, we employed CRISPR/Cas9 gene editing across parasite strains with diverse geographic origins. Reverting the regional V231D mutation in the South American 7G8 strain significantly reduced CQ resistance, providing the first functional evidence that this residue modulates drug susceptibility. Furthermore, introducing the apparently Colombia-specific I248T mutation significantly enhanced parasite multiplication rates in 7G8, demonstrating complex fitness and sensitivity trade-offs. Our findings reinforce the distinct evolutionary trajectory for South American CQ resistance and highlight the necessity of including additional pfaat1 mutations in global molecular surveillance strategies. Author SummaryAntimalarial drug resistance is a major threat to global public health. Chloroquine was used widely in the 1950s-60s as part of a global malaria eradication campaign, but resistance emerged in multiple places independently and chloroquine resistant parasites directly led to the death of millions of children. Chloroquine resistance is primarily driven by mutations in the transporter PfCRT which are thought to increase export of chloroquine from the digestive vacuole, where chloroquine acts to prevent the ability of the parasite to digest haemoglobin as a source of energy. However, it is becoming increasingly clear that additional vacuolar transporters can also modulate chloroquine resistance. In this study we focused on mutations in the putative amino acid transporter 1 (PfAAT1) which are specific to South America, where chloroquine resistance emerged independently from Southeast Asia. By integrating AlphaFold structural predictions with CRISPR/Cas9 gene editing across geographically diverse parasite backgrounds we provide the first functional evidence that the region-specific V231D mutation significantly diminishes chloroquine resistance. These findings emphasise that chloroquine resistance in South America followed a unique trajectory and that PfAAT1 is involved in complex fitness and sensitivity trade-offs. This work emphasises the benefits of integrating diverse experimental and modelling approaches with global molecular surveillance.

microbiology↗

bioRxiv2026

The shape of evolution: persistent homology of genetic-distancedata as an observable of reticulate processes in pathogen andplant genomes

Evolutionary biology has long theorized processes--recombination, lineage divergence, drug-resistance sweeps, introgression, refugial persistence--whose signatures in genomic data are incompatible with tree structure. We argue that the shape of genetic-distance data, formalized through simplicial complexes and quantified through persistent homology, is a direct observable of these processes. The Vietoris--Rips filtration of a genetic-distance matrix yields the Betti numbers {beta}0 (connected components), {beta}1 (loops), and {beta}2 (cavities); we read {beta}1 not as a literal count of recombination events but as a quantity that is monotone in effective recombination above a sampling-dependent geometric baseline, and we organise the resulting shapes into a four-letter alphabet of topological primitives (K1 clonal, K2 divergence, K3 reticulation, K4 higher-order reticulation). Coalescent and Wright--Fisher simulations establish the two load-bearing claims: {beta}1 rises monotonically with the recombination rate over six orders of magnitude, and persistent-homology features separate reticulate from non-reticulate histories with 98--100% recall (the residual confusion falls entirely within the non-reticulate K1/K2 pair, which {beta}1 does not distinguish). We then apply the pipeline to four empirical systems. (i) On the MalariaGEN Pf7 Plasmodium falciparum dataset (n = 20,864, 33 countries), per-population {beta}1 spans two orders of magnitude and diverges significantly from a label--shuffle null (median 20.5, range 8-32); the ordering runs opposite to recombination rate-freely-recombining African populations sit lowest and clonal/swept Southeast Asian and Papuan populations highest--because at the population scale {beta}1 is dominated by demographic structure rather than recombination rate, a point we reconcile explicitly with the controlled dose-response. (ii) Colombian Cauca SP-resistant samples carry {beta}1 = 12 against a near-clonal SP-sensitive baseline of {beta}1 = 5 (and two orders of magnitude more total persistence), the high-{beta}1, multi-origin band of K3 consistent with resistance carried on several genomic backgrounds. (iii) The Cambodia artemisinin sweep (2008-2018) traces a K3 [->] K1 trajectory, {beta}1 rising to a mid-sweep peak of 45 and collapsing to 13 at fixation--to our knowledge the first direct observation of a selective-sweep transient in topological coordinates, with the caveat that the per-bin values are medians of three subsamples with wide bars. (iv) On Arabidopsis thaliana 1001 Genomes data, Iberian relict populations (Spain, {beta}1/n = 0.64) exceed post-glacial-expansion populations (Sweden 0.54; United Kingdom 0), generalising the framework beyond pathogens. A P. falciparum mitochondrial negative control recovers {beta}1 = 0 across all subsamples, establishing pipeline specificity. Moving above the 1-skeleton, {beta}2 is zero at the clonal/expansion limits and positive across the reticulate systems; a controlled two-vs-three-way admixture simulation confirms that {beta}2 separates regimes that share a {beta}1 profile, while the further suggestion that the ratio = {beta}2/{beta}1 separates microevolutionary from macroevolutionary timescales is presented, given the small number of systems and the absence of a {beta}2 null, as a hypothesis for future testing. Together these results demonstrate that the topology of genetic-distance data is an evolutionary observable, with immediate implications for drug-resistance surveillance in P. falciparum. Author summaryBiologists usually picture the history of life as a tree, in which lineages split and never rejoin. Many of the most consequential evolutionary events break that picture: malaria parasites recombine in the mosquito gut, drug-resistant strains arise repeatedly on different genetic backgrounds, and plant populations that survived the Ice Age in southern refuges carry tangled ancestry that no tree can represent. We ask a different question of genetic data--not "what tree fits?" but "what shape does the data make?" --and answer it with topological data analysis, which measures shape through three counts (the Betti numbers) of clusters, loops, and higher-order cavities. Loops appear when lineages recombine and rejoin. We show, in simulations and in real Plasmodium falciparum and Arabidopsis thaliana genomes, that the loop count rises with recombination above a baseline set by finite sampling, cleanly separates recombining from clonal histories, and tracks a real artemisinin-resistance sweep in Cambodia as it rises and collapses over a decade. A non-recombining mitochondrial control correctly shows no loops. The shape of genetic data is thus a direct, tree-free readout of evolutionary process, with immediate value for drug-resistance surveillance.

evolutionary biology↗

bioRxiv2026

From low to high transmission: Diversity-dependent responses of Plasmodium falciparum population structure to transmission intensity

Genetic surveillance is increasingly used to track malaria transmission, yet genomic metrics can respond nonlinearly to changes in transmission intensity and depend on the diversity already present in the parasite population. Here, we present a stochastic agent-based model of hu-man-mosquito transmission that integrates SEIS-like epidemiological dynamics with within-host Plasmodium falciparum haplotype dynamics. By varying the maximum mosquito biting rate and the initial parasite diversity, we examine how transmission intensity and standing diversity jointly shape mixed infections, recombination, and long-term population structure across a continuous transmission gradient. Our study revealed a sequential pattern in which increasing biting intensity first increases infection prevalence and multiplicity of infection, then expands opportunities for outcrossing, and only thereafter increases effective recombination and recombinant haplotype generation. These responses are strongest in low- to intermediate transmission and tend to plateau at higher transmission levels. Initial population diversity constrains the amount of diversity that can be maintained and the magnitude of recombination output, while temporal trajectories show that haplotype evenness can pass through transient non-equilibrium phases before stabilizing. Together, these results show that the structure of the parasite population is shaped not by trans-mission intensity alone but by its interaction with standing genetic diversity. Furthermore, this study works to clarify when and how genomic metrics reliably reflect transmission conditions across heterogeneous malaria settings.

genetics↗

bioRxiv2022

Resolving drug selection and migration in an inbred South American Plasmodium falciparum population with identity-by-descent analysis

The human malaria parasite Plasmodium falciparum is globally widespread, but its prevalence varies significantly between and even within countries. Most population genetic studies in P. falciparum focus on regions of high transmission where parasite populations are large and genetically diverse, such as sub-Saharan Africa. Understanding population dynamics in low transmission settings, however, is of particular importance as these are often where drug resistance first evolves. Here, we use the Pacific Coast of Colombia and Ecuador as a model for understanding the population structure and evolution of Plasmodium parasites in small populations harboring low genetic diversity. The combination of low transmission and a high proportion of monoclonal infections means there are few outcrossing events and clonal lineages persist for long periods of time. Yet despite this, the population is evolutionarily labile and has successfully adapted to multiple drug regimes. Using 166 newly sequenced whole genomes, we measure relatedness between parasites, calculated as identity by descent (IBD), and find 17 distinct but highly related clonal lineages, six of which have persisted in the region for at least a decade. This inbred population structure is captured in more detail with IBD than with other common population structure analyses like PCA, ADMIXTURE, and distance-based trees. We additionally use patterns of intra-chromosomal IBD and an analysis of haplotypic variation to explore the role of recombination in spreading drug resistance mutations throughout the region. Two genes associated with chloroquine resistance, crt and aat1, show evidence of hard selective sweeps, while selection appears soft and/or incomplete at three other key resistance loci (dhps, mdr1, and dhfr). Overall, this work highlights the strength of IBD analyses for studying parasite population structure and resistance evolution in regions of low transmission, and emphasizes that drug resistance can evolve and spread in extremely small populations, as will occur in any region nearing malaria elimination.

evolutionary biology↗