A new gene that protects against malaria has been discovered

Ancient Nuragic warriors face Plasmodium falciparum: the long evolutionary battle between our species and the malarial parasite

A genetic variant capable of hindering the growth of the malaria parasite was discovered by a group of researchers from the Institute of Genetic and Biomedical Research of the National Research Council (Cnr-Irgb) of Cagliari and the University of Sassari. The work entitled " Reduced cyclin D3 expression in erythroid cells protects against malaria ”, published in the magazine  Nature , also clarifies the biological mechanism of protection and indicates a possible path for new drugs. 
An article was also dedicated to the article editorial of the magazine .

Malaria still causes over 600,000 deaths per year, especially in tropical countries. However, not all infected people become ill in the same way: some individuals develop very severe forms, others show milder symptoms. Understanding why this happens is one of medicine's most important challenges.

A clue in the DNA of the Sardinians

The discovery arises from an observation carried out starting from genomic analyzes on approximately 7,000 volunteers of the Sardinian population study SardiNIA in Ogliastra, a large population genetics project that analyzes how the genetic heritage of the island's inhabitants influences thousands of variables relevant to health. Researchers had identified a DNA variant associated with particular characteristics of red blood cells, the blood cells in which the malaria parasite lives.

What happens inside red blood cells

The scientists then reconstructed step by step the biological mechanism underlying the genetic observations. "The variant reduces the activity of the CCND3 gene which regulates the development of red blood cell precursors, producing larger circulating red blood cells with particular characteristics. With experiments lasting several years we have explained in detail the molecular and biological mechanisms underlying these observations" explains Maria Giuseppina Marini, first author of the study together with Maura Mingoia and Maristella Steri of the Cnr-Irgb.

“Human genetics preserves traces of past diseases” - explains Francesco Cucca, geneticist from the University of Sassari and the Cnr-Irgb, coordinator of the study. - This allows us to identify biological adaptations selected by evolution."

Evolutionary analyzes have in fact shown that the variant became frequent in Sardinia because it offered a survival advantage. “We therefore hypothesized that malaria, historically endemic in Sardinia, could be the evolutionary pressure that favored the spread of the variant,” adds Cucca.

And when red blood cells from individuals with that variant were infected in the laboratory with the  Plasmodium falciparum  — the main agent of malaria — the parasite is unable to proliferate normally.

“We observed a strong inhibition of the growth of the parasite until its death” – explains Antonella Pantaleo of the University of Sassari, who coordinated the infection experiments in the laboratory. - The phenomenon is linked to an increase in oxidative stress in red blood cells, a mechanism similar to that which protects people with G6PD deficiency as it creates an inhospitable environment for the parasite in these cells."

From evolution to medicine

The variant is now frequent in Sardinia but absent in regions of the world where malaria is still widespread. It probably appeared in Europe after the exit of Homo sapiens from Africa.

For researchers, however, this very "natural experiment" offers a new therapeutic opportunity.

“Nature has shown us an effective way to block malaria,” concludes Cucca. “The challenge now is to transform this biological mechanism into a therapy: to pharmacologically reproduce the protective effect of the variant to protect the populations that currently live with the disease”.

The study thus provides a concrete scientific basis for developing new targeted drugs, directly inspired by human evolution.

For information:
Francesco Cucca
University of Sassari and Cnr-Irgb
 

Head of Press Office Unit:
Emanuele Guerrini
emanuele. guerrini@cnr. it
ufficiostampa@cnr. it