Ancestral clans of malaria parasites in each region of Africa share drug resistance genes, putting malaria elimination at risk

23 August 2019

Whole genome sequence analysis of malaria parasites and other pathogens could pave the way for improved understanding of infections and development of new intervention approaches for elimination.

In the first continent-wide genomic study of malaria parasites in Africa, a team of African scientists, in collaboration with the Wellcome Sanger Institute have uncovered distinct regional populations of the deadliest malaria parasite, Plasmodium falciparum. The genetic features of these regional blocs shed new light on the way that drug resistance is emerging in different locations and moving by various routes across Africa, putting previous success in controlling malaria at risk.

The research, published in science, led by scientists at the MRC Unit The Gambia at the London School of Hygiene & Tropical Medicine, brings together the first network of African scientists – the Plasmodium Diversity Network Africa (PDNA) – to work with genomic tools to study the diversity of malaria parasites across the continent. The researchers studied the genetic diversity of P. falciparum populations which is mainly responsible for malaria across several countries in sub-Saharan Africa.

Malaria remains a global problem, with the deadliest parasite species P. falciparum prevalent across sub-Saharan Africa. Between 2000 and 2015, an ongoing drive to eliminate the disease has seen worldwide malaria deaths halve from 864,000 to 429,000 per year. In 2015, 92 per cent of global malaria deaths were in Africa, with 74 per cent of these occurring in children under five years of age. But the findings of this new study suggest this progress may be at risk if new forms of treatment aren’t developed. Understanding the genomic features of the parasite populations could help measure the impact of key interventions like drugs and vaccines, especially to track the emergence and spread of drug-resistant strains, assisting efforts to eliminate malaria especially in Africa.

The researchers found that regional populations of the malaria parasite are sharing genetic material in all directions – including genes that can confer resistance to antimalarial drugs, with new types of drug resistance emerging in different parts of Africa. It is thought that human migration, including that resulting from colonial activity, has played a part in the evolution of P. falciparum in Africa.

Dr Alfred Amambua-Ngwa, first author of the study, Assistant Professor at the MRC Unit The Gambia at LSHTM and a Wellcome International Fellow at the Wellcome Sanger Institute said, “Whatever the historic factors affecting the flow of genes between the distinct P. falciparum populations, the multi-directional flow we’ve identified raises the prospect of continental spread of resistance to artemisinin-based combination therapies, which could arise from anywhere in Africa. Genomic surveillance, and on a large scale, is going to be vital to tracking the emergence and spread of resistance to combination therapies.”

The study included malaria samples from 15 African countries collected by the PDNA and their genomes were sequenced at the Wellcome Sanger Institute as part of the MalariaGEN data sharing network. The genetic data on these samples, along with other African data that have previously been generated and openly released by MalariaGEN, were analysed at the MRC Unit The Gambia at LSHTM. Boosted by the high performance computing facility at the Unit, researchers combined new sophisticated software and approaches to trace ancestral connectivity between the various parasite populations, increasing the resolution of African P. falciparum parasites into genetically distinct groups according to which region of Africa they are found.

The Director of MRC Unit The Gambia at LSHTM, Professor Umberto D’Alessandro, said, “Until recently, most large scale genomic data analyses could only be possible at our collaborating institutions in the North. Our Unit seeks to explore molecular data to promote deeper insight into pathogen dynamics and non-communicable diseases, to improve health and transform lives across the world. By this study, the local team led by Drs Amambua-Ngwa and Jeffries have demonstrated that it’s now possible to conduct sophisticated genomic analysis in Africa — turning big data into knowledge with support from our established experienced partners such as the Wellcome Sanger Institute.”

Researchers noted the fact that the Ethiopian parasite population is highly-differentiated from those in the rest of Africa, which suggested that the ancestry of malaria parasites may have been influenced by human migration. The human population in Ethiopia also has a distinct ancestry to others in Africa, suggesting that the lack of colonization of the country might explain its outlier status. By contrast, parasites from distant former French colonies share genetic material.

The results confirmed that populations of P. falciparum have shared genetic information over time, particularly genes associated with resistance to antimalarial drugs.

Senior author, Professor Abdoulaye Djimdé, Wellcome International Fellow at the Wellcome Sanger Institute and Chief of the Molecular Epidemiology and Drug Resistance Unit at the Malaria Research and Training Centre, University of Bamako, said, “Contrary to previous studies, we identified distinct Western, Central and Eastern populations of P. falciparum, as well as a highly-divergent Ethiopian population. Genetic material originating from all directions was shared by all populations, indicating that the flow of genes is multi-directional, as opposed to unidirectional from east to west as previously thought. This is crucial information for understanding how resistance to malaria drugs is developing in Africa.”

Going forward, the further strengthening of the collaboration between the MRC Unit The Gambia at LSHTM, PDNA and MalariaGEN teams is an important step in continuing to track the spread of drug-resistant malaria in Africa at a crucial time, when efforts to eliminate the disease are now stalling and the prospect of multi-drug resistant strains of P. falciparum in Africa on the horizon.

Professor Dominic Kwiatkowski, Head of the Parasites and Microbes Programme at the Wellcome Sanger Institute, and Director of the MRC Centre for Genomics and Global Health said, “Back in 2013, this impressive team of African scientists within the PDNA recognised the need to work together across the continent to monitor how this deadly malaria parasite is evolving. This has involved many practical and logistical challenges, and the team have done an amazing job in pulling together the most comprehensive genetic picture of the parasite population in different parts of Africa. It proves the feasibility of using modern genomic technologies to monitor malaria drug resistance in Africa, and it is now extremely important to ensure that the work is continued and used by policymakers and public health agencies to guide sustainable strategies for disease control.”