Biology subjects

Zinder, D.

Publications and source records attributed to Zinder, D..

3 recordsLinked to original sources

bioRxiv2017

Selection and neutral mutations drive pervasive mutability losses in long-lived B cell lineages

High-affinity antibodies arise within weeks of infection from the evolution of B cell receptors under selection to improve antigen recognition. This rapid adaptation is enabled by the frequency and distribution of highly mutable \"hotspotx\" motifs in B cell receptor genes. High mutability in antigen binding regions (CDRs) creates variation in binding affinity, whereas low mutability in structurally important regions (FRs) may reduce the frequency of destabilizing mutations. During the response, the loss of mutational hotspots and changes in their distribution across CDRs and FRs are predicted to compromise the adaptability of B cell receptors, yet the contributions of different mechanisms to gains and losses of hotspots remain unclear. We reconstructed changes in anti-HIV B cell receptor sequences and show that mutability losses were about 60% more frequent than gains in both CDRs and FRs, with the higher relative mutability of CDRs maintained throughout the response. At least 34% of the mutability losses were caused by synonymous mutations. However, non-synonymous substitutions caused most of the mutability loss in CDRs. Because CDRs also show strong positive selection, this result suggests positive selection contributed to as much as 66% of the mutability loss in those regions. Although recurrent adaptation to the evolving virus could indirectly select for high mutation rates, we found no evidence of indirect selection to increase or retain hotspots. Our results suggest mutability losses are intrinsic to the neutral and adaptive evolution of B cell populations and might constrain their adaptation to rapidly evolving pathogens such as HIV and influenza.

evolutionary biology↗

bioRxiv2017

Role Of Competition In The Strain Structure Of Rotavirus Under Invasion And Reassortment

The role of competitive interactions in the formation and coexistence of viral strains remains unresolved. Neglected aspects of existing strain theory are that viral pathogens are repeatedly introduced from animal sources and readily exchange their genes. The combined effect of introduction and reassortment opposes strain structure, in particular the predicted stable coexistence of antigenically differentiated strains under strong frequency-dependent selection mediated by cross-immunity. Here we use a stochastic model motivated by rotavirus, the most common cause of childhood diarrheal mortality, to investigate serotype structure under these conditions. We describe a regime in which the transient coexistence of distinct strains emerges despite only weak cross-immunity, but is disturbed by invasions of new antigenic segments that reassort into existing backgrounds. We find support for this behavior in global rotavirus sequence data and present evidence for the displacement of new strains towards open antigenic niches. Our work extends previous work to bacterial and viral pathogens that share these rotavirus-like characteristics, with important implications for the effects of interventions such as vaccination on strain composition, and for the understanding of the factors promoting emergence of new subtypes.

evolutionary biology↗

bioRxiv2017

Conservation of single amino-acid polymorphisms in Plasmodium falciparum erythrocyte membrane protein 1 and association with severe pathophysiology

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a parasite protein encoded by a multigene family known as var. Expressed on the surface of infected red blood cells, PfEMP1 plays a central role in parasite virulence. The DBL domain of PfEMP1 contains short sequence motifs termed homology blocks. Variation within homology blocks, at the level of single amino-acid modifications, has not been considered before in association with severe disease. Here we identify a total of 2701 amino-acid polymorphisms within DBL homology blocks, the majority of which are shared between two geographically distant study populations in existing transcription data from Kenya and in a new genomic dataset sampled in Ghana. Parasitemia levels and the transcription levels of specific polymorphisms are as predictive of severe disease (AUC=0.83) and of the degree of rosetting (forecast skill SS=0.45) as the transcription of classic var groups. 11 newly categorized polymorphisms were strongly correlated with grpA var gene expression (SS=0.93) and a different set of 16 polymorphisms was associated with the H3 subset (SS=0.20). These associations provide the basis for a novel method of relating pathophysiology to parasite gene expression levels--one that, being site-specific, has more molecular detail than previous models based on var groups or homology blocks. This newly described variation influences disease outcome, and can help develop anti-malarial intervention strategies such as vaccines that target severe disease. Further replication of this analysis in geographically disparate populations and for larger sample sizes can help improve the identification of the molecular causes of severe disease.

genomics↗