A Study Deciphers the Mechanisms Underlying Mutually Exclusive Gene Expression in the Malaria Parasite

A study led by Dr. Alfred Cortés, ICREA research professor at ISGlobal, reports for the first time the mechanisms regulating the expression of a group of genes in Plasmodium falciparum, the parasite responsible for the most severe form of human malaria. The results were published in Nucleic Acids Research, a high-impact journal in the field of gene regulation. 

P. falciparum  has a complex life cycle where progression through each stage is determined by differential gene expression. One of the mechanisms controlling the expression of these genes is the ‘epigenetic' modification of the DNA-binding proteins (histones) that "switch" gene transcription on or off. These non-genetic modifications- that are not on the DNA- can nevertheless be transmitted from one generation to the next. P. falciparum has been shown to express certain genes in a mutually exclusive manner (in other words, each parasite expresses only one of the gene variants because when one copy is active, the other variants are in a silenced state). One example of clonally variant genes are the clag3 genes that encode for a protein that regulates the transport of substances (including compounds with antimalarial activity) at the membrane of the infected erythrocyte.

By using transgenic parasites expressing additional copies of clag3 regulatory regions, the authors investigated the mechanisms leading to the mutually exclusive expression of these genes. They found that the additional copies were silenced by default but that, under strong selective pressure, parasites expressing more than one copy of the gene were observed. The group had previously demonstrated that other environmental conditions could lead to the selection of parasites where no copies of clag3 genes were expressed.

The authors propose that at the population level most of the parasites express only one of the gene variants but that a reduced number of individuals express none or both. Certain environmental conditions such as the presence of antimalarial compounds can confer a selective advantage to these parasites that can then become predominant. "Deciphering the mechanisms underlying clag3 gene expression is important because of the key role of such protein in parasite biology and also because it helps us understand how the parasite may adapt to environmental changes" says Dr. Cortés. "In addition, this study provides valuable insight into the principles that govern mutually exclusive gene expression, an enigmatic phenomenon that is frequently observed in evolution" explains the first author of the study, Núria Rovira-Graells.

Reference: Núria Rovira-Graells, Valerie M. Crowley, Cristina Bancells, Sofía Mira-Martínez, Lluís Ribas de Pouplana and Alfred Cortés. Deciphering the principles that govern mutually exclusive expression of Plasmodium falciparum clag3 genes. Nucl. Acids Res. 2015. July 21. doi: 10.1093/nar/gkv730