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POPULATION DYNAMICS IN CLONED CHO CELL LINES

机译：克隆CHO细胞系中的种群动态

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The inherent nature of cloned CHO cell lines includes the presence of genetic and phenotypic drift that leads to heterogeneous populations. The genetic heterogeneity exhibited by these cells can be exploited to understand the population dynamics of cloned cell lines. One way to track heterogeneity within populations is by utilizing genetic sequence variants (SVs) as biomarkers for distinct populations. In the experiments described here, cell lines with varying levels of sequence variants resulting from a single nucleotide change in the gene of interest were used to study population dynamics in cloned CHO cell lines. Analysis of four different monoclonal antibody-expressing cell lines with known sequence variants under varying continuous culture conditions provided insight into transcription and translation rates of SV-containing cell lines and allowed us to generate population dynamic models leading to better understanding of SVs and the genetic heterogeneity of clonal cell lines. Early time points of these cell lines were further subcloned and analyzed to gain further understanding of subpopulation dynamics in cloned cell lines and the results of these experiments will be presented. Subclones of these four clonal cell lines proved varying degrees of heterogeneity while falling into distinct population dynamics models. Additionally, mixing of subclones expressing the same mAb, with and without SVs at similar growth rates allowed us to evaluate how populations shift over time. A range of expected and unexpected outcomes was observed with these intentionally mixed populations demonstrating the complexity of clonal cell line heterogeneity. This study will further our understanding on the interplay between clonality, heterogeneity and population dynamics of 'clonal' cell lines and will allow for critical assessment of overarching cell line development methods and strategies.
机译：克隆的CHO细胞系的固有性质包括导致异质群体的遗传漂移和表型漂移。这些细胞表现出的遗传异质性可以用来了解克隆细胞系的种群动态。跟踪种群异质性的一种方法是利用遗传序列变异体（SVs）作为不同种群的生物标记。在此处所述的实验中，使用了由目标基因中的单个核苷酸变化引起的序列变异水平不同的细胞系，以研究克隆的CHO细胞系的种群动态。在不断变化的连续培养条件下对四种具有已知序列变异体的不同表达单克隆抗体的细胞系进行分析，可深入了解含SV的细胞系的转录和翻译速率，并使我们能够生成种群动态模型，从而更好地了解SV和遗传异质性克隆细胞系。这些细胞系的早期时间点被进一步亚克隆和分析，以进一步了解克隆的细胞系中的亚种群动态，并将介绍这些实验的结果。这四个克隆细胞系的亚克隆表现出不同程度的异质性，同时落入不同的种群动力学模型。此外，混合表达相同mAb的亚克隆（有无SV和无SV的增长率）使我们能够评估种群随时间的变化。这些有意混合的群体观察到一系列预期和意想不到的结果，表明克隆细胞系异质性的复杂性。这项研究将进一步了解“克隆”细胞系的克隆性，异质性和种群动态之间的相互作用，并有助于对总体细胞系开发方法和策略进行严格评估。

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