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Modelling the Decay of Hotspot Motifs in Broadly Neutralizing Antibody Lineages

Kenneth B Hoehn, Gerton Lunter, Oliver G Pybus
doi: https://doi.org/10.1101/055517
Kenneth B Hoehn
1Department of Zoology, University of Oxford, South Parks Road, Oxford, OX1 3PS, UK
2Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK
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Gerton Lunter
2Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK
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Oliver G Pybus
1Department of Zoology, University of Oxford, South Parks Road, Oxford, OX1 3PS, UK
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Abstract

Phylogenetic methods have shown great promise in understanding the development of broadly neutralizing antibody lineages (bNAbs). However, mutational process for generating these lineages - somatic hypermutation (SHM) - is biased by hotspot motifs, which violates important assumptions in most phylogenetic substitution models. Here, we develop a modified GY94-type substitution model which partially accounts for this context-dependency while preserving independence of sites in calculation. This model shows a substantially better fit to three well-characterized bNAb lineages than the standard GY94 model. We show through simulations that accounting for this can lead to reduced bias of other substitution parameters, and more accurate ancestral state reconstructions. We further explore other implications of this model; namely, that the number of hotspot motifs - and therefore likely the mutation rate in general - is expected to decay over time in individual bNAb lineages.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted May 26, 2016.
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Modelling the Decay of Hotspot Motifs in Broadly Neutralizing Antibody Lineages
Kenneth B Hoehn, Gerton Lunter, Oliver G Pybus
bioRxiv 055517; doi: https://doi.org/10.1101/055517
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Modelling the Decay of Hotspot Motifs in Broadly Neutralizing Antibody Lineages
Kenneth B Hoehn, Gerton Lunter, Oliver G Pybus
bioRxiv 055517; doi: https://doi.org/10.1101/055517

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