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- Title
Partitioning stable and unstable expression level variation in cell populations: A theoretical framework and its application to the T cell receptor.
- Authors
Guzella, Thiago S.; Barreto, Vasco M.; Carneiro, Jorge
- Abstract
Phenotypic variation in the copy number of gene products expressed by cells or tissues has been the focus of intense investigation. To what extent the observed differences in cellular expression levels are persistent or transient is an intriguing question. Here, we develop a quantitative framework that resolves the expression variation into stable and unstable components. The difference between the expression means in two cohorts isolated from any cell population is shown to converge to an asymptotic value, with a characteristic time, τT, that measures the timescale of the unstable dynamics. The asymptotic difference in the means, relative to the initial value, measures the stable proportion of the original population variance Rα2. Empowered by this insight, we analysed the T-cell receptor (TCR) expression variation in CD4 T cells. About 70% of TCR expression variance is stable in a diverse polyclonal population, while over 80% of the variance in an isogenic TCR transgenic population is volatile. In both populations the TCR levels fluctuate with a characteristic time of 32 hours. This systematic characterisation of the expression variation dynamics, relying on time series of cohorts' means, can be combined with technologies that measure gene or protein expression in single cells or in bulk. Author summary: No two cells are identical. Even isogenic cells, living in the same environment and expressing the same set of genes display measurable differences or variation in the expression level of any of these genes. How much of the differences in expression levels are permanent and how much of these differences vanish in time has intrigued us for generations. We develop a theoretical framework based on a stochastic model and put it to work in the analysis of T cell receptor expression level in CD4 T cells. We show that T cell populations with genetically diverse receptors display stable variation in receptor expression but, surprisingly, we detect persistent differences in receptor levels among uniform transgenic T cells. The analysis, being based on the mean cohort expression levels logarithm, can be applied to techniques that measure expression at single-cell level and also to the myriad of genomics and proteomics techniques that measure expression in bulk populations.
- Subjects
T cell receptors; CELL populations; SINGLE cell proteins; T cells; CELL analysis; PROTEOMICS
- Publication
PLoS Computational Biology, 2020, Vol 16, Issue 8, p1
- ISSN
1553-734X
- Publication type
Article
- DOI
10.1371/journal.pcbi.1007910