Segredo-Otero Ernesto Alejandro, Gresham David
Center for Genomics and Systems Biology, Department of Biology, New York University, New York NY 10003.
bioRxiv. 2025 Jul 19:2025.07.18.665558. doi: 10.1101/2025.07.18.665558.
Understanding the sources of genetic diversity in Influenza A Virus (IAV) infections is crucial for understanding the mechanisms of viral evolution and immune escape. Whereas prior studies have characterized the effects of population bottlenecks during host-to-host transmission and intrahost tissue-to-tissue dissemination, the role of intracellular replication processes on IAV genetic diversity remains largely unexplored. In this study, we used stochastic mathematical modeling to simulate the replication of genetically distinct IAV strains within individual cells and tissues. Our results reveal significant bottleneck effects within a single infection cycle of individual cells. Intracellular bottleneck effects are driven by stochastic molecular processes and lead to the expansion or elimination of neutral variants creating large-scale differences between the initial and final frequencies of genetic variants in individual cells. By expanding our findings to a population-level tissue model, we show that IAV intracellular replication reduces the effective population size, thereby diminishing the impact of selection and increasing the role of genetic drift. Our findings highlight the important contribution of intracellular replication processes to the generation of genetic diversity in IAV.
了解甲型流感病毒（IAV）感染中遗传多样性的来源对于理解病毒进化和免疫逃逸机制至关重要。尽管先前的研究已经描述了宿主间传播和宿主体内组织间传播过程中群体瓶颈的影响，但细胞内复制过程对IAV遗传多样性的作用在很大程度上仍未得到探索。在本研究中，我们使用随机数学模型来模拟基因不同的IAV毒株在单个细胞和组织内的复制。我们的结果揭示了单个细胞在单个感染周期内存在显著的瓶颈效应。细胞内瓶颈效应由随机分子过程驱动，导致中性变异的扩增或消除，从而在单个细胞中产生遗传变异的初始频率和最终频率之间的大规模差异。通过将我们的研究结果扩展到群体水平的组织模型，我们表明IAV细胞内复制会减小有效群体大小，从而削弱选择的影响并增加遗传漂变的作用。我们的研究结果突出了细胞内复制过程对IAV遗传多样性产生的重要贡献。
