Genetic diversity and evolution pattern of Plasmodium falciparum multidrug resistance 1 gene (Pfmdr1) in Indian and global populations.

Abstract

Background: Among the crucial molecular markers contributing to multidrug resistance, the Plasmodium falciparum multidrug resistance-1 gene (Pfmdr1) remains understudied as compared to other drug-resistant genes in terms of its genetic diversity and evolution pattern. This study presents a comprehensive analysis of Pfmdr1 gene's genetic diversity aiming to discern its dynamics, distribution and evolutionary trends especially in Indian and global populations.

Methods and results: The Pfmdr1 gene was amplified and sequenced from 256 Plasmodium falciparum mono-infected samples collected from 14 Indian states during the years 1993-2023. Analysis revealed six non-synonymous (N86Y, N86F, S137C, D144F, F157L and Y184F) and one synonymous mutation (G182G) in N-terminal fragment. Among these, N86F, S137C, D144F and F157L were novel findings. The most prevalent mutations were N86Y (18.91%), Y184F (64.71%) and G182G (GGT > GGG) (59.24%; exclusive to India), with Y184F showing increasing trend when compared to N86Y over time. The mutation GGT > GGG is experiencing a hitchhiking by Y184F mutation which is likely undergoing a selective sweep. High haplotype and nucleotide diversity were observed in most Indian states, particularly in Odisha and Delhi. However, a decrease in diversity was noted in samples from 2020 onwards throughout India. Globally Pfmdr1 showed tendency of negative selection, except for populations from Liberia, Nigeria, Sudan and Central African Republic. Notably, samples from Sudan depicted a distinct haplotype and population structure compared to other countries.

Conclusions: These findings contribute significantly to our understanding of the genetic structure and evolutionary trends of Pfmdr1, which can help to strengthen the current malaria control policies for emergence of drug resistance.