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A Phylogenetic Codon Substitution Model for Antibody Lineages.

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.

SUBMITTER: Hoehn KB

PROVIDER: S-EPMC5419485 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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A Phylogenetic Codon Substitution Model for Antibody Lineages.

Hoehn Kenneth B KB Lunter Gerton G Pybus Oliver G OG

Genetics 20170317 1

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 show ...[more]

PMID: 28315836

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Project description:BackgroundNucleotide and amino acid substitution tendencies are characteristic of each species, organelle, and protein family. Hence, various empirical amino acid substitution rate matrices have needed to be estimated for phylogenetic analysis: JTT, WAG, and LG for nuclear proteins, mtREV for mitochondrial proteins, cpREV10 and cpREV64 for chloroplast-encoded proteins, and FLU for influenza proteins. On the other hand, in a mechanistic codon substitution model, in which each codon substitution rate is proportional to the product of a codon mutation rate and the ratio of fixation depending on the type of amino acid replacement, mutation rates and the strength of selective constraint on amino acids can be tailored to each protein family with additional 11 parameters. As a result, in the evolutionary analysis of codon sequences it outperforms codon substitution models equivalent to empirical amino acid substitution matrices. Is it superior even for amino acid sequences, among which synonymous substitutions cannot be identified?ResultsNucleotide mutations are assumed to occur independently of codon positions but multiple nucleotide changes in infinitesimal time are allowed. Selective constraints on the respective types of amino acid replacements are tailored to each gene with a linear function of a given estimate of selective constraints, which were estimated by maximizing the likelihood of an empirical amino acid or codon substitution frequency matrix, each of JTT, WAG, LG, and KHG. It is shown that the mechanistic codon substitution model with the assumption of equal codon usage yields better values of Akaike and Bayesian information criteria for all three phylogenetic trees of mitochondrial, chloroplast, and influenza-A hemagglutinin proteins than the empirical amino acid substitution models with mtREV, cpREV64, and FLU, which were designed specifically for those protein families, respectively. The variation of selective constraint across sites fits the datasets significantly better than variable codon mutation rates, confirming that substitution rate variations across sites detected by amino acid substitution models are caused primarily by the variation of selective constraint against amino acid substitutions rather than the variation of codon mutation rate.ConclusionsThe mechanistic codon substitution model is superior to amino acid substitution models even in the evolutionary analysis of protein sequences.

Project description:Antibodies are glycoproteins produced by the immune system as a dynamically adaptive line of defense against invading pathogens. Very elegant and specific mutational mechanisms allow B lymphocytes to produce a large and diversified repertoire of antibodies, which is modified and enhanced throughout all adulthood. One of these mechanisms is somatic hypermutation, which stochastically mutates nucleotides in the antibody genes, forming new sequences with different properties and, eventually, higher affinity and selectivity to the pathogenic target. As somatic hypermutation involves fast mutation of antibody sequences, this process can be described using a Markov substitution model of molecular evolution. Here, using large sets of antibody sequences from mice and humans, we infer an empirical amino acid substitution model AB, which is specific to antibody sequences. Compared with existing general amino acid models, we show that the AB model provides significantly better description for the somatic evolution of mice and human antibody sequences, as demonstrated on large next generation sequencing (NGS) antibody data. General amino acid models are reflective of conservation at the protein level due to functional constraints, with most frequent amino acids exchanges taking place between residues with the same or similar physicochemical properties. In contrast, within the variable part of antibody sequences we observed an elevated frequency of exchanges between amino acids with distinct physicochemical properties. This is indicative of a sui generis mutational mechanism, specific to antibody somatic hypermutation. We illustrate this property of antibody sequences by a comparative analysis of the network modularity implied by the AB model and general amino acid substitution models. We recommend using the new model for computational studies of antibody sequence maturation, including inference of alignments and phylogenetic trees describing antibody somatic hypermutation in large NGS data sets. The AB model is implemented in the open-source software CodonPhyML (http://sourceforge.net/projects/codonphyml) and can be downloaded and supplied by the user to ProGraphMSA (http://sourceforge.net/projects/prographmsa) or other alignment and phylogeny reconstruction programs that allow for user-defined substitution models.

Dataset Information

A Phylogenetic Codon Substitution Model for Antibody Lineages.

Publications

A Phylogenetic Codon Substitution Model for Antibody Lineages.

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