Population Genomics of the Immune Evasion (var) Genes of Plasmodium falciparum

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. 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 PfEMP1 are placed on the surface. PfEMP1 variants switch by sequential expression of up to 60 var genes. This allows the parasite to evade immune detection within an individual host, enhancing its chances to be transmitted to the mosquito vector in situations where mosquitoes are seasonally available. Methods to rapidly assess var gene diversity in parasite populations are needed to measure antigenic diversity and define relationships with malaria transmission. Using a specialized framework, we completed the first systematic sampling of var genes from parasite genomes obtained from the same (Papua New Guinea [PNG]) and different (global) populations. Globally, there was no limit to the number of var genes because parasites rarely shared var genes. In PNG, var gene numbers were restricted due to high levels of sharing, and most were only found in that population. Recombination was important to the evolution of var genes in PNG. The data suggest there are distinct var genes in different populations, which may have consequences for the spread of malarial disease from one geographic area to another.