Background: The primary target of the human immune response to the malaria parasite Plasmodium falciparum,\r\nP. falciparum erythrocyte membrane protein 1 (PfEMP1), is encoded by the members of the hyper-diverse var gene\r\nfamily. The parasite exhibits antigenic variation via mutually exclusive expression (switching) of the ~60 var genes\r\nwithin its genome. It is thought that different variants exhibit different host endothelial binding preferences that in\r\nturn result in different manifestations of disease.\r\nResults: Var sequences comprise ancient sequence fragments, termed homology blocks (HBs), that recombine at\r\nexceedingly high rates. We use HBs to define distinct var types within a local population. We then reanalyze a\r\ndataset that contains clinical and var expression data to investigate whether the HBs allow for a description of\r\nsequence diversity corresponding to biological function, such that it improves our ability to predict disease\r\nphenotype from parasite genetics. We find that even a generic set of HBs, which are defined for a small number of\r\nnon-local parasites: capture the majority of local sequence diversity; improve our ability to predict disease severity\r\nfrom parasite genetics; and reveal a previously hypothesized yet previously unobserved parasite genetic basis for\r\ntwo forms of severe disease. We find that the expression rates of some HBs correlate more strongly with severe\r\ndisease phenotypes than the expression rates of classic var DBLa tag types, and principal components of HB\r\nexpression rate profiles further improve genotype-phenotype models. More specifically, within the large Kenyan\r\ndataset that is the focus of this study, we observe that HB expression differs significantly for severe versus mild\r\ndisease, and for rosetting versus impaired consciousness associated severe disease. The analysis of a second much\r\nsmaller dataset from Mali suggests that these HB-phenotype associations are consistent across geographically\r\ndistant populations, since we find evidence suggesting that the same HB-phenotype associations characterize this\r\npopulation as well.\r\nConclusions: The distinction between rosetting versus impaired consciousness associated var genes has not been\r\ndescribed previously, and it could have important implications for monitoring, intervention and diagnosis.\r\nMoreover, our results have the potential to illuminate the molecular mechanisms underlying the complex spectrum\r\nof severe disease phenotypes associated with malariaââ?¬â?an important objective given that only about 1% of\r\nP. falciparum infections result in severe disease.
Loading....