Sequencing sheds new light on malaria parasites

13 November 2012

NIMR scientists have collaborated in a major genomic survey of malaria parasites. The research is published in PLOS Genetics.

Evolutionary and population genetic analyses of pathogens can help to reveal mechanisms of pathogenesis, immune evasion and drug resistance. Researchers are applying these approaches to malaria parasites to try and identify targets of immunity as potential vaccine candidates, and to understand and monitor the continuous evolution and emergence of drug resistance. New sequencing methods make it easier to detect signatures of natural selection from patterns of genetic variation. Plasmodium falciparum causes more human disease than any other eukaryotic pathogen, and contains ~5560 annotated genes in a compact genome of ~23 megabase pairs.

Tony Holder (pictured) and Ellen Knűpfer, in the Division of Parasitology, have collaborated with colleagues in the UK and The Gambia in a comprehensive screen to discover targets of immunity in the major human malaria parasite Plasmodium falciparum. They undertook a genome-wide survey of polymorphism in coding sequences of P. falciparum in an endemic population sample of 65 Gambian clinical isolates. This is the largest sample of parasite genomes from a single location reported to date. They identified genes having polymorphic site frequency spectra consistent with effects of balancing selection, forming a prime catalogue of candidates for studies of immune mechanisms and potential vaccine development.

The product of the gene with the strongest statistical signature was studied, revealing an unexpected pattern of variation in expression among different isolates and within individual parasite clones, suggesting that selection for phase variation may operate alongside selection for amino acid polymorphisms.

The search for antigens to form the basis of a vaccine against blood stage malaria and to prevent the disease has proved difficult. This genetic approach identifies those proteins that are most variable and potentially under strong selection from host immunity. The next challenge will be to show a direct role of these proteins in a process such as invasion of red blood cells and the ability of specific antibodies to inhibit this process.

Tony Holder

Original article

Alfred Amambua-Ngwa, Kevin K. A. Tetteh, Magnus Manske, Natalia Gomez-Escobar, Lindsay B. Stewart, M. Elizabeth Deerhake, Ian H. Cheeseman, Christopher I. Newbold, Anthony A. Holder, Ellen Knuepfer, Omar Janha, Muminatou Jallow, Susana Campino, Bronwyn MacInnis, Dominic P. Kwiatkowski, David J. Conway (2012)

Population Genomic Scan for Candidate Signatures of Balancing Selection to Guide Antigen Characterization in Malaria Parasites.

PLOS Genetics 8(11): e1002992. Full-text

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