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. 2017 May;206(1):417-427.
doi: 10.1534/genetics.116.196303. Epub 2017 Mar 17.

A Phylogenetic Codon Substitution Model for Antibody Lineages

Kenneth B Hoehn  1   2 , Gerton Lunter  2 , Oliver G Pybus  1
Affiliations

A Phylogenetic Codon Substitution Model for Antibody Lineages

Kenneth B Hoehn et al. Genetics. 2017 May.

Abstract

Phylogenetic methods have shown promise in understanding the development of broadly neutralizing antibody lineages (bNAbs). However, the mutational process that generates these lineages, somatic hypermutation, is biased by hotspot motifs which violates important assumptions in most phylogenetic substitution models. Here, we develop a modified GY94-type substitution model that partially accounts for this context dependency while preserving independence of sites during calculation. This model shows a substantially better fit to three well-characterized bNAb lineages than the standard GY94 model. We also demonstrate how our model can be used to test hypotheses concerning the roles of different hotspot and coldspot motifs in the evolution of B-cell lineages. Further, we explore the consequences of the idea that the number of hotspot motifs, and perhaps the mutation rate in general, is expected to decay over time in individual bNAb lineages.

Keywords: B-cell receptor; Genetics of Immunity; antibody; evolution; lineage; phylogenetic tree.

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Figures

Figure 1
Figure 1
Proposed evolutionary model for antibody lineages. All sequences descend from given germline node G, which has sequence g. Arrows indicate the direction of evolutionary change. Note that this known ancestor G is not necessarily the most recent common ancestor of the lineage, which is node R and sequence x. See similarities to tree in Boussau and Gouy (2006).
Figure 2
Figure 2
Proportional error in parameter estimation compared to true values for the VRC01 B-cell lineage, fully context-dependent simulations. Values of ω, κ, tree length, and ratio of internal to external branch lengths are shown in (A), (B), (C), and (D), respectively. Estimates obtained under the GY94 are in orange (h = 0) and estimates obtained under the HLP17 model are in blue (h estimated using ML). The edges and centers of box plots show the first, second, and third quartiles, while the whiskers show range. Similar results for B-cell lineages CH103 and VRC26 are shown in Figure S5 in File S1.
See this image and copyright information in PMC

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