Jakhan Jahnvi, Hawadak Joseph, Narang Geetika, Tamang Suman, Chakraborti Soumyananda, Singh Vineeta
ICMR-National Institute of Malaria Research (NIMR), Dwarka, New Delhi, 110077, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
Mol Biol Rep. 2025 Mar 22;52(1):332. doi: 10.1007/s11033-025-10424-3.
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.
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.
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.
在导致多药耐药性的关键分子标记中，与其他耐药基因相比，恶性疟原虫多药耐药-1基因（Pfmdr1）在遗传多样性和进化模式方面的研究仍较少。本研究对Pfmdr1基因的遗传多样性进行了全面分析，旨在了解其动态变化、分布情况和进化趋势，特别是在印度和全球人群中的情况。
从1993年至2023年期间从印度14个邦收集的256份恶性疟原虫单感染样本中扩增并测序Pfmdr1基因。分析揭示了N端片段中的六个非同义突变（N86Y、N86F、S137C、D144F、F157L和Y184F）和一个同义突变（G182G）。其中，N86F、S137C、D144F和F157L是新发现。最常见的突变是N86Y（18.91%）、Y184F（64.71%）和G182G（GGT > GGG）（59.24%；仅在印度出现），与N86Y相比，Y184F随时间呈上升趋势。GGT > GGG突变正经历Y184F突变的搭便车效应，而Y184F突变可能正在经历选择性清除。在印度的大多数邦，尤其是奥里萨邦和德里，观察到高单倍型和核苷酸多样性。然而，从2020年起，印度各地的样本多样性有所下降。在全球范围内，除了来自利比里亚、尼日利亚、苏丹和中非共和国的人群外，Pfmdr1呈现出负选择趋势。值得注意的是，与其他国家相比，苏丹的样本呈现出独特的单倍型和种群结构。
这些发现对我们理解Pfmdr1的遗传结构和进化趋势有重要贡献，有助于加强当前针对耐药性出现的疟疾控制政策。
