Population genetic and biophysical evidences reveal that purifying selection shapes the genetic landscape of Plasmodium falciparum RH ligands in Chhattisgarh and West Bengal, India
Autor: | Pramita Chowdhury, Mitashree Mitra, Sanghamitra Sengupta, Sanhita Ray, Sharmistha Ghoshal, Anjan Kr. Dasgupta, Srikanta Sen, Sumana Datta Kanjilal |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Nonsynonymous substitution lcsh:Arctic medicine. Tropical medicine lcsh:RC955-962 030231 tropical medicine Population Plasmodium falciparum Protozoan Proteins India Biology Ligands lcsh:Infectious and parasitic diseases Evolution Molecular 03 medical and health sciences Negative selection 0302 clinical medicine lcsh:RC109-216 Allele Selection Genetic Polymorphism education Selection Genetics education.field_of_study Natural selection PfRH Research Genetic Variation biology.organism_classification Malaria 030104 developmental biology Infectious Diseases Basigin Parasitology Selective sweep Vaccine |
Zdroj: | Malaria Journal Malaria Journal, Vol 19, Iss 1, Pp 1-14 (2020) |
ISSN: | 1475-2875 |
Popis: | Background Reticulocyte binding protein-like homologs (RHs) are currently being evaluated as anti-erythrocytic stage vaccine targets against Plasmodium falciparum malaria. Present study explores the possible evolutionary drivers shaping the genetic organization of Pfrhs in Indian parasite population. It simultaneously evaluates a putative gain-of-function variant of PfRH5, a keystone member of PfRH family. Methods Receptor binding regions of Pfrh1, Pfrh2a/b, Pfrh4 and whole Pfrh5 were amplified using blood samples of P. falciparum malaria patients from Chhattisgarh and West Bengal and sequenced. Assembled sequences were analysed using MEGA7 and DnaSPv6. Binding affinities of recombinant PfRH5 proteins with basigin (BSG) were compared using in silico (CHARMM and AUTODOCK) and in vitro (Circular dichroism, fluorescence spectroscopy and isothermal titration calorimetry) methods. Results Pfrh1 (0.5), Pfrh2a/b (0.875), Pfrh4 (0.667) and Pfrh5 (0.778) sequence changes corresponded to low frequency (Pfrh loci corroborated with the model of demographic expansion, a possible role of natural selection formulating Pfrh sequence diversity was investigated. Among the 5 members, Pfrh5 displayed very high dN/dS (5.7) ratio. Nevertheless, the model of selective sweep due to presence of any advantageous substitutions could not be invoked as polymorphic nonsynonymous sites (17/18) for Pfrh5 exceeded significantly over the divergent (62/86) ones (p = 0.0436). The majority of extant PfRH5 sequences (52/83) differed from the reference Pf3D7 allele by a single amino acid mismatch (C203Y). This non-conservative alteration was predicted to lower the total interaction energy of that PfRH5variant with BSG, compared to PfRH53D7. Biophysical evidences validated the proposition that PfRH5variant formed a more stable complex with BSG. Thermodynamic association constant for interaction of BSG with PfRH5variant was also found to be higher (Kavariant = 3.63E6 ± 2.02E6 M−1 and Ka3D7 = 1.31E6 ± 1.21E6 M−1). Conclusions Together, the study indicates that the genetic architecture of Pfrhs is principally shaped by purifying selection. The most abundant and ubiquitous PfRH5 variant harbouring 203Y, exhibits a greater affinity for BSG compared to PfRH53D7 possessing 203C allele. The study underscores the importance of selecting the functional allele that best represents circulating strains in natural parasite populations as vaccine targets. |
Databáze: | OpenAIRE |
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