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在量化的亲和力景观上重演生发中心演变。

Replaying germinal center evolution on a quantified affinity landscape.

作者信息

DeWitt William S, Vora Ashni A, Araki Tatsuya, Galloway Jared G, Alkutkar Tanwee, Bortolatto Juliana, Castro Tiago B R, Dumm Will, Jennings-Shaffer Chris, Jia Tongqiu, Mesin Luka, Ozorowski Gabriel, Pae Juhee, Ralph Duncan K, Bloom Jesse D, Nourmohammad Armita, Song Yun S, Ward Andrew B, Starr Tyler N, Matsen Frederick A, Victora Gabriel D

机构信息

Department of Genome Sciences, University of Washington, Seattle, WA, USA.

Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

出版信息

bioRxiv. 2025 Jun 5:2025.06.02.656870. doi: 10.1101/2025.06.02.656870.

Abstract

Darwinian evolution of immunoglobulin genes within germinal centers (GC) underlies the progressive increase in antibody affinity following antigen exposure. Whereas the mechanics of how competition between GC B cells drives increased affinity are well established, the dynamical evolutionary features of this process remain poorly characterized. We devised an experimental evolution model in which we "replay" over one hundred instances of a clonally homogenous GC reaction and follow the selective process by assigning affinities to all cells using deep mutational scanning. Our data reveal how GCs achieve predictable evolutionary outcomes through the cumulative effects of many rounds of imperfect selection, acting on a landscape shaped heavily by somatic hypermutation (SHM) targeting biases. Using time-calibrated models, we show that apparent features of GC evolution such as permissiveness to low-affinity lineages and early plateauing of affinity are best explained by survivorship biases that distort our view of how affinity progresses over time.

摘要

生发中心(GC)内免疫球蛋白基因的达尔文式进化是抗原暴露后抗体亲和力逐渐增加的基础。虽然GC B细胞之间的竞争如何驱动亲和力增加的机制已得到充分确立,但这一过程的动态进化特征仍未得到很好的描述。我们设计了一个实验进化模型,在该模型中,我们“重演”了一百多个克隆同质的GC反应实例,并通过使用深度突变扫描为所有细胞分配亲和力来跟踪选择过程。我们的数据揭示了GC如何通过多轮不完美选择的累积效应,作用于由体细胞高频突变(SHM)靶向偏差严重塑造的景观,从而实现可预测的进化结果。使用时间校准模型,我们表明,GC进化的明显特征,如对低亲和力谱系的宽容性和亲和力的早期平稳,最好用生存偏差来解释,这些偏差扭曲了我们对亲和力随时间如何进展的看法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/72bf/12258878/1a024bc72957/nihpp-2025.06.02.656870v1-f0001.jpg

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