Hoehn Kenneth B, Lunter Gerton, Pybus Oliver G
Department of Zoology, University of Oxford, OX1 3PS, United Kingdom
Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN, United Kingdom.
Genetics. 2017 May;206(1):417-427. doi: 10.1534/genetics.116.196303. Epub 2017 Mar 17.
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.
系统发育方法在理解广泛中和抗体谱系（bNAbs）的发展方面显示出了前景。然而，产生这些谱系的突变过程，即体细胞高频突变，受到热点基序的影响而存在偏差，这违反了大多数系统发育替代模型中的重要假设。在此，我们开发了一种改进的GY94型替代模型，该模型在计算过程中部分考虑了这种上下文依赖性，同时保留了位点的独立性。与标准的GY94模型相比，该模型对三个特征明确的bNAb谱系的拟合效果要好得多。我们还展示了如何使用我们的模型来检验关于不同热点和冷点基序在B细胞谱系进化中作用的假设。此外，我们探讨了热点基序数量以及可能总体突变率预计会随着时间在单个bNAb谱系中衰减这一观点的后果。
