Importance of var gene in the evolution of P. falciparum

Akash Singh, Banaras Hindu University

Malaria claimed the lives of an estimated 409,000 people worldwide in 2019. The most vulnerable population to malaria is children under the age of five. They were responsible for 67% of all malaria deaths globally in 2019. Caused by Plasmodium parasites, which are single-celled parasitic organisms that cannot survive outside of their hosts, malaria parasites develop and multiply in human liver cells initially, then in red blood cells exponentially. The Var gene codes for proteins involved in Plasmodium erythrocyte cytoadherence and antigenic variation. Researchers recently suggested that these var genes were important in transmission dynamics that selected for significant changes in the transcriptional regulatory systems that govern antigenic variation in the P. falciparum parasite lineage thus putting forward the importance of var genes in the evolution of P. falciparum.

P. falciparum in infection of Laverania:

Plasmodium eukaryotic parasites infect a wide range of vertebrate taxa, including birds, reptiles, and mammals. Five types of malaria infect humans and cause the disease malaria.  Malaria parasites go through a variety of morphological forms as they migrate from mosquito vectors to vertebrate hosts, but all symptoms are caused by asexual parasite reproduction in the infected person’s circulating red blood cells (RBCs). P. falciparum is the most virulent of the five parasite species that infect humans. The cyto-adhesive properties of infected RBCs, which result from the placement on the RBC surface of parasite encoded variable antigens such as RIFIN (repetitive interspersed family), STEVOR (sub-telomeric variant open reading frame), PfMC-2TM (P. falciparum Maurer’s left-2 transmembrane domain proteins), and PfEMP1 (P. falciparum Maurer’s left-2 trans (P. falciparum erythrocyte membrane protein 1).

Plasmodium falciparum is the only human-infective member of the Laverania subgenus of Plasmodium, which infects apes. The seven characterised Laverania species are unusual in that they express EMP1 on the surface of infected RBCs, unlike malaria species from other evolutionary lineages.

Importance of var genes:

The ability of the Laverania parasites to modify the expressed form of EMP1 throughout an infection is due to the growth of the genes encoding diverse forms of the protein into vast, multi-copy gene families known as var. Var gene families ranging in size from 28 to 105 copies have been uncovered in recent investigations, with the genes arranged into clusters found inside the sub-telomeric areas.

Parasites vary the form of EMP1 expressed on the infected cell surface and hence undergo antigenic variation by flipping the single var gene that is actively translated. The var gene family thus reflects a fundamental feature of the Laverania that has significantly contributed to its evolutionary success as well as P. falciparum‘s higher virulence as compared to other human-infective malaria parasites.

Role of var genes in the evolution of P. falciparum

The findings show that regulatory proteins involved in var gene transcription are found in the conserved intron of var genes prevalent throughout the Laverania subgenus, implying that many elements of var gene expression evolved in the parasites’ common ancestor. Unlike other Laverania members, the clade that gave origin to P. falciparum acquired separate subsets of var genes, which have been linked to different expression profiles and virulence features. Furthermore, two highly conserved var genes (var1csa and var2csa) have been postulated to play a role in coordinating transcriptional flipping. The evolution of var2csa and a second strain-transcendent var gene called var1csa, as well as the separation of var upstream regulatory regions into various subtypes connected to virulence, occurred relatively recently within the Laverania subgenus, within the clade that contains P. falciparum.

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Reference:

1. Gross, M.R., Hsu, R. & Deitsch, K.W. Evolution of transcriptional control of antigenic variation and virulence in human and ape malaria parasites. BMC Ecol Evo 21, 139 (2021). https://doi.org/10.1186/s12862-021-01872-z

Author info:

Akash Singh is a first year masters student of Biochemistry in Banaras Hindu University. He plans to pursue a PhD in future. He aims to pursue his career in research and teach the young minds of the country.

Social media links : LinkedIn : https://www.linkedin.com/in/akash-singh-82b5811a2/

Publications :

1. https://vidwaanforever.com/2021/06/a-new-period-invention-a-novel-thread-device-for-uti-detection/
2. https://vidwaanforever.com/2021/06/the-fall-of-insecta-apocalyptic-consequences-for-humanitys-survival/

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