Abstract
Var genes encode the major surface antigen (PfEMP1) of the blood stages of the human malaria parasite Plasmodium falciparum. Differential expression of up to 60 diverse var genes in each parasite genome underlies immune evasion. We compared the diversity of the DBLα domain of var genes sampled from 30 parasite isolates from a malaria endemic area of Papua New Guinea (PNG) and 59 from widespread geographic origins (global). Overall, we obtained over 8,000 quality-controlled DBLα sequences. Within our sampling frame, the global population had a total of 895 distinct DBLα “types” and negligible overlap among repertoires. This indicated that var gene diversity on a global scale is so immense that many genomes would need to be sequenced to capture its true extent. In contrast, we found a much lower diversity in PNG of 185 DBLα types, with an average of approximately 7% overlap among repertoires. While we identify marked geographic structuring, nearly 40% of types identified in PNG were also found in samples from different countries showing a cosmopolitan distribution for much of the diversity. We also present evidence to suggest that recombination plays a key role in maintaining the unprecedented levels of polymorphism found in these immune evasion genes. This population genomic framework provides a cost effective molecular epidemiological tool to rapidly explore the geographic diversity of var genes.
Highlights
Quantifying the diversity of major surface antigens underlying immune evasion of HIV 1 and 2 and Influenza A has been central to characterizing the transmission dynamics of these important human pathogens
Malaria parasites live in red blood cells of the human host for part of the life cycle, during which a family of diverse antigens known as Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) are placed on the surface
We completed the first systematic sampling of var genes from parasite genomes obtained from the same (Papua New Guinea [PNG]) and different populations
Summary
Quantifying the diversity of major surface antigens underlying immune evasion of HIV 1 and 2 and Influenza A has been central to characterizing the transmission dynamics of these important human pathogens. In-depth molecular epidemiological sampling and population genomic analyses of the var genes encoding the major blood stage surface antigen of the malaria parasite, Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), has not been done. This is largely due to the inherent difficulties in the population genomic analysis of highly diverse multigene families. Variant specific anti-PfEMP1 antibodies are believed to contribute to the regulation of parasite density in a manner that decreases the incidence of clinical disease [9,10,11,12,13] This immunity may reduce the duration of infection in a variant-specific manner to drive the dynamics of multiple infections in semi-immune children [14] and induced infections in humans [15]. Diversity of PfEMP1 or var genes is able to promote transmission success by immune evasion
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