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Register a new userQuantifying evolutionary constraints on B cell affinity maturation
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Added by
Frederick Matsen IV
Publication date
2014
fields
Biology
and research's language is
English
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The antibody repertoire of each individual is continuously updated by the evolutionary process of B cell receptor mutation and selection. It has recently become possible to gain detailed information concerning this process through high-throughput sequencing. Here, we develop modern statistical molecular evolution methods for the analysis of B cell sequence data, and then apply them to a very deep short-read data set of B cell receptors. We find that the substitution process is conserved across individuals but varies significantly across gene segments. We investigate selection on B cell receptors using a novel method that side-steps the difficulties encountered by previous work in differentiating between selection and motif-driven mutation; this is done through stochastic mapping and empirical Bayes estimators that compare the evolution of in-frame and out-of-frame rearrangements. We use this new method to derive a per-residue map of selection, which provides a more nuanced view of the constraints on framework and variable regions.
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We are frequently faced with a large collection of antibodies, and want to select those with highest affinity for their cognate antigen. When developing a first-line therapeutic for a novel pathogen, for instance, we might look for such antibodies in patients that have recovered. There exist effective experimental methods of accomplishing this, such as cell sorting and baiting; however they are time consuming and expensive. Next generation sequencing of B cell receptor (BCR) repertoires offers an additional source of sequences that could be tapped if we had a reliable method of selecting those coding for the best antibodies. In this paper we introduce a method that uses evolutionary information from the family of related sequences that share a naive ancestor to predict the affinity of each resulting antibody for its antigen. When combined with information on the identity of the antigen, this method should provide a source of effective new antibodies. We also introduce a method for a related task: given an antibody of interest and its inferred ancestral lineage, which branches in the tree are likely to harbor key affinity-increasing mutations? These methods are implemented as part of continuing development of the partis BCR inference package, available at https://github.com/psathyrella/partis.
The affinity of antibodies (Abs) produced in vivo for their target antigens (Ags) is typically well below the maximum affinity possible. Nearly 25 years ago, Foote and Eisen explained how an affinity ceiling could arise from constraints associated with the acquisition of soluble antigen by B cells. However, recent studies have shown that B cells in germinal centers (where Ab affinity maturation occurs) acquire Ag not in soluble form but presented as receptor-bound immune complexes on follicular dendritic cells (FDCs). How the affinity ceiling arises in such a scenario is unclear. Here, we argue that the ceiling arises from the weakest link of the chain of protein complexes that bridges B cells and FDCs and is broken during Ag acquisition. This hypothesis explains the affinity ceiling realized in vivo and suggests that strengthening the weakest link could raise the ceiling and improve Ab responses.
Population structure induced by both spatial embedding and more general networks of interaction, such as model social networks, have been shown to have a fundamental effect on the dynamics and outcome of evolutionary games. These effects have, however, proved to be sensitive to the details of the underlying topology and dynamics. Here we introduce a minimal population structure that is described by two distinct hierarchical levels of interaction. We believe this model is able to identify effects of spatial structure that do not depend on the details of the topology. We derive the dynamics governing the evolution of a system starting from fundamental individual level stochastic processes through two successive meanfield approximations. In our model of population structure the topology of interactions is described by only two parameters: the effective population size at the local scale and the relative strength of local dynamics to global mixing. We demonstrate, for example, the existence of a continuous transition leading to the dominance of cooperation in populations with hierarchical levels of unstructured mixing as the benefit to cost ratio becomes smaller then the local population size. Applying our model of spatial structure to the repeated prisoners dilemma we uncover a novel and counterintuitive mechanism by which the constant influx of defectors sustains cooperation. Further exploring the phase space of the repeated prisoners dilemma and also of the rock-paper-scissor game we find indications of rich structure and are able to reproduce several effects observed in other models with explicit spatial embedding, such as the maintenance of biodiversity and the emergence of global oscillations.
A cell-molecular based evolutionary model of tumor development driven by a stochastic Moran birth-death process is developed, where each cell carries molecular information represented by a four-digit binary string, used to differentiate cells into 16 molecular types. The binary string value determines cell fitness, with lower fit cells (e.g. 0000) defined as healthy phenotypes, and higher fit cells (e.g. 1111) defined as malignant phenotypes. At each step of the birth-death process, the two phenotypic sub-populations compete in a prisoners dilemma evolutionary game with healthy cells (cooperators) competing with cancer cells (defectors). Fitness and birth-death rates are defined via the prisoners dilemma payoff matrix. Cells are able undergo two types of stochastic point mutations passed to the daughter cells binary string during birth: passenger mutations (conferring no fitness advantage) and driver mutations (increasing cell fitness). Dynamic phylogenetic trees show clonal expansions of cancer cell sub-populations from an initial malignant cell. The tumor growth equation states that the growth rate is proportional to the logarithm of cellular heterogeneity, here measured using the Shannon entropy of the distribution of binary sequences in the tumor cell population. Nonconstant tumor growth rates, (exponential growth during sub-clinical range of the tumor and subsequent slowed growth during tumor saturation) are associated with a Gompertzian growth curve, an emergent feature of the model explained here using simple statistical mechanics principles related to the degree of functional coupling of the cell states. Dosing strategies at early stage development, mid-stage (clinical stage), and late stage development of the tumor are compared, showing therapy is most effective during the sub-clinical stage, before the cancer subpopulation is selected for growth.
The collection of immunoglobulin genes in an individuals germline, which gives rise to B cell receptors via recombination, is known to vary significantly across individuals. In humans, for example, each individual has only a fraction of the several hundred known V alleles. Furthermore, the currently-accepted set of known V alleles is both incomplete (particularly for non-European samples), and contains a significant number of spurious alleles. The resulting uncertainty as to which immunoglobulin alleles are present in any given sample results in inaccurate B cell receptor sequence annotations, and in particular inaccurate inferred naive ancestors. In this paper we first show that the currently widespread practice of aligning each sequence to its closest match in the full set of IMGT alleles results in a very large number of spurious alleles that are not in the samples true set of germline V alleles. We then describe a new method for inferring each individuals germline gene set from deep sequencing data, and show that it improves upon existing methods by making a detailed comparison on a variety of simulated and real data samples. This new method has been integrated into the partis annotation and clonal family inference package, available at https://github.com/psathyrella/partis, and is run by default without affecting overall run time.
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