Homology blocks of Plasmodium falciparum var genes and clinically distinct forms of severe malaria in a local population

Abstract Background The primary target of the human immune response to the malaria parasite Plasmodium falciparum, P. falciparum erythrocyte membrane protein 1 (PfEMP1), is encoded by the members of the hyper-diverse var gene family. The parasite exhibits antigenic variation via mutually exclusive expression (switching) of the ~60 var genes within its genome. It is thought that different variants exhibit different host endothelial binding preferences that in turn result in different manifestations of disease. Results Var sequences comprise ancient sequence fragments, termed homology blocks (HBs), that recombine at exceedingly high rates. We use HBs to define distinct var types within a local population. We then reanalyze a dataset that contains clinical and var expression data to investigate whether the HBs allow for a description of sequence diversity corresponding to biological function, such that it improves our ability to predict disease phenotype from parasite genetics. We find that even a generic set of HBs, which are defined for a small number of non-local parasites: capture the majority of local sequence diversity; improve our ability to predict disease severity from parasite genetics; and reveal a previously hypothesized yet previously unobserved parasite genetic basis for two forms of severe disease. We find that the expression rates of some HBs correlate more strongly with severe disease phenotypes than the expression rates of classic var DBLα tag types, and principal components of HB expression rate profiles further improve genotype-phenotype models. More specifically, within the large Kenyan dataset that is the focus of this study, we observe that HB expression differs significantly for severe versus mild disease, and for rosetting versus impaired consciousness associated severe disease. The analysis of a second much smaller dataset from Mali suggests that these HB-phenotype associations are consistent across geographically distant populations, since we find evidence suggesting that the same HB-phenotype associations characterize this population as well. Conclusions The distinction between rosetting versus impaired consciousness associated var genes has not been described previously, and it could have important implications for monitoring, intervention and diagnosis. Moreover, our results have the potential to illuminate the molecular mechanisms underlying the complex spectrum of severe disease phenotypes associated with malaria—an important objective given that only about 1% of P. falciparum infections result in severe disease.http://deepblue.lib.umich.edu/bitstream/2027.42/112650/1/12866_2013_Article_2116.pd

Protein Structural Modularity and Robustness Are Associated with Evolvability

Theory suggests that biological modularity and robustness allow for maintenance of fitness under mutational change, and when this change is adaptive, for evolvability. Empirical demonstrations that these traits promote evolvability in nature remain scant however. This is in part because modularity, robustness, and evolvability are difficult to define and measure in real biological systems. Here, we address whether structural modularity and/or robustness confer evolvability at the level of proteins by looking for associations between indices of protein structural modularity, structural robustness, and evolvability. We propose a novel index for protein structural modularity: the number of regular secondary structure elements (helices and strands) divided by the number of residues in the structure. We index protein evolvability as the proportion of sites with evidence of being under positive selection multiplied by the average rate of adaptive evolution at these sites, and we measure this as an average over a phylogeny of 25 mammalian species. We use contact density as an index of protein designability, and thus, structural robustness. We find that protein evolvability is positively associated with structural modularity as well as structural robustness and that the effect of structural modularity on evolvability is independent of the structural robustness index. We interpret these associations to be the result of reduced constraints on amino acid substitutions in highly modular and robust protein structures, which results in faster adaptation through natural selection

Identifying functional groups among the diverse, recombining antigenic <i>var</i> genes of the malaria parasite <i>Plasmodium falciparum</i> from a local community in Ghana

A challenge in studying diverse multi-copy gene families is deciphering distinct functional types within immense sequence variation. Functional changes can in some cases be tracked through the evolutionary history of a gene family; however phylogenetic approaches are not possible in cases where gene families diversify primarily by recombination. We take a network theoretical approach to functionally classify the highly recombining var antigenic gene family of the malaria parasite Plasmodium falciparum. We sample var DBLα sequence types from a local population in Ghana, and classify 9,276 of these variants into just 48 functional types. Our approach is to first decompose each sequence type into its constituent, recombining parts; we then use a stochastic block model to identify functional groups among the parts; finally, we classify the sequence types based on which functional groups they contain. This method for functional classification does not rely on an inferred phylogenetic history, nor does it rely on inferring function based on conserved sequence features. Instead, it infers functional similarity among recombining parts based on the sharing of similar co-occurrence interactions with other parts. This method can therefore group sequences that have undetectable sequence homology or even distinct origination. Describing these 48 var functional types allows us to simplify the antigenic diversity within our dataset by over two orders of magnitude. We consider how the var functional types are distributed in isolates, and find a nonrandom pattern reflecting that common var functional types are non-randomly distinct from one another in terms of their functional composition. The coarse-graining of var gene diversity into biologically meaningful functional groups has important implications for understanding the disease ecology and evolution of this system, as well as for designing effective epidemiological monitoring and intervention

Population structuring of multi-copy, antigen-encoding genes in Plasmodium falciparum

The coexistence of multiple independently circulating strains in pathogen populations that undergo sexual recombination is a central question of epidemiology with profound implications for control. An agent-based model is developed that extends earlier ‘strain theory’ by addressing the var gene family of Plasmodium falciparum. The model explicitly considers the extensive diversity of multicopy genes that undergo antigenic variation via sequential, mutually exclusive expression. It tracks the dynamics of all unique var repertoires in a population of hosts, and shows that even under high levels of sexual recombination, strain competition mediated through cross-immunity structures the parasite population into a subset of coexisting dominant repertoires of var genes whose degree of antigenic overlap depends on transmission intensity. Empirical comparison of patterns of genetic variation at antigenic and neutral sites supports this role for immune selection in structuring parasite diversity

Variations on a theme? Polyp and medusa development in Podocoryna carnea

The life cycles of many cnidarian species are notable for including two stages with very different morphologies - sessile polyp and swimming medusa. Cnidarians thus provide an opportunity to study the developmental bases of differences in body organization without the need to compare organisms of different taxa. Information about the two life cycle stages suggests the following questions about differences in their development. (1) Are the mouth and tentacle-bearing region (bell margin) specified using any of the same molecular mechanisms as in the polyp? (2) Has the oral-aboral axis of the medusa been truncated relative to that of the polyp by elimination of molecular processes specifying aboral tissue identity? (3) Is the elongated region between the hydrozoan medusa mouth and tentacle ring (the manubrium) patterned using processes that pattern the entire oral-aboral axis in the polyp? We describe how data on their expression of FoxA, NK-2, and Emx genes during polyp and medusa development, together with reagents targeting specific signaling pathways, could be used to address these questions. We have isolated portions of a FoxA2 homologue, an NK-2 gene, and two Emx genes from Podocoryna carnea Sars, an experimentally tractable hydrozoan with both polyp and medusa stages. Phylogenetic analyses indicate that the two P. carnea Emx genes are the result of a gene duplication

Identifying functional groups among the diverse, recombining antigenic <i>var</i> genes of the malaria parasite <i>Plasmodium falciparum</i> from a local community in Ghana - Fig 1

<p>Among the 11,385 DBLα sequence tags, which correspond to unique <i>var</i> types: <b>(A)</b> The distribution of total HB counts per sequence tag. <b>(B)</b> The frequency of each HB in the entire dataset.</p

The relationship between the <i>var</i> homology block recombination network, cys-2 <i>var</i> genes, and the <i>var</i> genes containing each homology block functional group.

<p>All panels show the recombination network, as defined in Materials and methods. Panel titles indicate which nodes are shown in blue. Remaining nodes are shown in red.</p

The sequences and locations of the HBs for each of the HB functional groups.

<p>The sequences are depicted with Logos in the top portion of each panel. The location(s) of the HBs within each of the sequence tags are depicted in the lower portion of each panel, with first and last positions in distinct colors.</p