Abstract
BackgroundEndemic human pathogens are subject to strong immune selection, and interrogation of pathogen genome variation for signatures of balancing selection can identify important target antigens. Several major antigen genes in the malaria parasite Plasmodium falciparum have shown such signatures in polymorphism-versus-divergence indices (comparing with the chimpanzee parasite P. reichenowi), and in allele frequency based indices.Methodology/Principal FindingsTo compare methods for prospective identification of genes under balancing selection, 26 additional genes known or predicted to encode surface-exposed proteins of the invasive blood stage merozoite were first sequenced from a panel of 14 independent P. falciparum cultured lines and P. reichenowi. Six genes at the positive extremes of one or both of the Hudson-Kreitman-Aguade (HKA) and McDonald-Kreitman (MK) indices were identified. Allele frequency based analysis was then performed on a Gambian P. falciparum population sample for these six genes and three others as controls. Tajima's D (TjD) index was most highly positive for the msp3/6-like PF10_0348 (TjD = 1.96) as well as the positive control ama1 antigen gene (TjD = 1.22). Across the genes there was a strong correlation between population TjD values and the relative HKA indices (whether derived from the population or the panel of cultured laboratory isolates), but no correlation with the MK indices.Conclusions/SignificanceAlthough few individual parasite genes show significant evidence of balancing selection, analysis of population genomic and comparative sequence data with the HKA and TjD indices should discriminate those that do, and thereby identify likely targets of immunity.
Highlights
Dynamic interactions between hosts and pathogens result in positive selection on molecules responsible for pathogen invasion, host resistance, and pathogen evasion of host resistance [1,2,3]
The present study investigates a prospective panel of twenty six additional merozoite protein-coding genes, by sequencing from diverse laboratory cultured P. falciparum isolates and P. reichenowi to enable polymorphism-versus-divergence tests
Alleles of each of the genes were sequenced from 14 cultured lines of P. falciparum, representing species-wide polymorphism, along with the P. reichenowi orthologue of each gene (Accession numbers are listed in Supplementary Table S1)
Summary
Dynamic interactions between hosts and pathogens result in positive selection on molecules responsible for pathogen invasion, host resistance, and pathogen evasion of host resistance [1,2,3]. The ,23 Mb P. falciparum genome that encodes ,5300 proteins presents a challenge for identifying targets of immunity, but scans of currently available genome sequence data from different isolates can already identify loci with unusually high levels of polymorphism [5,6,7]. With available data, such scans do not discriminate loci under transient directional selection (such as drug resistance genes) [5], from those under balancing selection [6]. Several major antigen genes in the malaria parasite Plasmodium falciparum have shown such signatures in polymorphism-versus-divergence indices (comparing with the chimpanzee parasite P. reichenowi), and in allele frequency based indices
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
