13 December 2021

Genetic variants in malaria parasites that occur more frequently in people carrying the sickle haemoglobin gene have been found for the first time.

The new research suggests the parasites have adapted to overcome the protection offered by this well-known haemoglobin mutation in humans.

The research was a collaboration between the Wellcome Sanger Institute, the University of Oxford, the KEMRI-Wellcome Trust Research Programme and the MRC Unit The Gambia at the London School of Hygiene & Tropical Medicine (LSHTM).

The study, published in Nature, identified three genetic variants in the parasite genome that are found in infections of individuals who carry at least one copy of the sickle haemoglobin gene.

Sickle haemoglobin (HbS), which causes sickle-cell anaemia when inherited in two copies, is commonly found in individuals from sub-Saharan Africa because one copy provides protection against malaria.

Researchers sequenced the parasite genomes from more than 3,000 infections in children from The Gambia and Kenya, all of whom had severe symptoms of malaria, and compared their host and parasite genomes.

They found that infections of individuals with sickle haemoglobin tend to have particular mutations in three regions of the parasite genome, all of them in genes whose function is currently unknown.

The researchers suggest that sickle haemoglobin may have acted as a selective pressure on the parasite, driving it to adapt and leading to a malaria parasite that can now infect people with sickle haemoglobin as well as those with normal haemoglobin.

However, these sickle-associated parasites are not fully dominant across the African continent, which implies there may also be other factors impacting spread.

First author Dr Gavin Band, statistician at the Wellcome Centre for Human Genetics, University of Oxford, said: “We have known for years that human genetic variants such as sickle haemoglobin can provide protection against malaria, but we wanted to understand if malaria parasites have evolved to overcome this.

“In our study, large scale genome sequencing allowed us to compare thousands of human and parasite genomes. For the first time, we were able to highlight a correlation between the human sickle haemoglobin mutation and three regions of the parasite genome, suggesting that the human genome is a selective pressure in the evolution of the parasite.”

Study author Professor David Conway, from the London School of Tropical Medicine (LSHTM), added: “Making the connection between the genetic variants of the parasite and its ability to infect those with sickle haemoglobin paves the way for research to dive deeper into the biological mechanisms behind this.

“Greater clarity on the ways that P. falciparum evades the human body’s defences could lead to new opportunities for protecting against malaria and treating those living in the most affected areas.”

Source:

Band G, Leffler EM, Jallow M, Sisay-Joof F, Ndila CM, Macharia AW, Hubbart C, Jeffreys AE, Rowlands K, Nguyen T, Gonçalves S, Ariani CV, Stalker J, Pearson RD, Amato R, Drury E, Sirugo G, d'Alessandro U, Bojang KA, Marsh K, Peshu N, Saelens JW, Diakité M, Taylor SM, Conway DJ, Williams TN, Rockett KA, Kwiatkowski DP. (2021) “Malaria protection due to sickle haemoglobin depends on parasite genotype.” Nature, doi: 10.1038/s41586-021-04288-3

Link: https://www.nature.com/articles/s41586-021-04288-3

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