Abstract
Exclusive stochastic gene choice combines precision with diversity. This regulation enables most T-cells to express exactly one T-cell receptor isoform chosen from a large repertoire, and to react precisely against diverse antigens. Some cells express two receptor isoforms, revealing the stochastic nature of this process. A similar regulation of odorant receptors and protocadherins enable cells to recognize odors and confer individuality to cells in neuronal interaction networks, respectively. We explored whether genes in other families are expressed exclusively by analyzing single-cell RNA-seq data with a simple metric. This metric can detect exclusivity independently of the mean value and the monoallelic nature of gene expression. Chromosomal segments and gene families are more likely to express genes concurrently than exclusively, possibly due to the evolutionary and biophysical aspects of shared regulation. Nonetheless, gene families with exclusive gene choice were detected in multiple cell types, most of them are membrane proteins involved in ion transport and cell adhesion, suggesting the coordination of these two functions. Thus, stochastic exclusive expression extends beyond the prototypical families, permitting precision in gene choice to be combined with the diversity of intercellular interactions.
Highlights
The combinatorial principle plays an important role in the evolution of complex organisms
We analyzed RNA-seq datasets consisting of at least 100 single cell measurements of a well-defined cell type isolated from the mouse Mus musculus
Undifferentiated cell types were represented by embryonic stem cells isolated from embryos (Cheng et al, 2019) and embryonic stem cell (ESC) cultures (Klein et al, 2015)
Summary
The combinatorial principle plays an important role in the evolution of complex organisms. A large proportion of the mammalian genomes encodes regulators, especially transcription factors (Vaquerizas et al, 2009), which determine what combination of genes will be turned on and off. The study of the combinatorial expression patterns of genes belonging to a gene family or gene array is of particular relevance, among which the exclusive gene choice of the odorant and T-cell receptors has received widespread attention. Each olfactory neuron expresses a single odorant receptor isoform randomly selected from more than a thousand gene isoforms (Massah et al, 2015; Khamlichi and Feil, 2018) and triggers a signal in response to a particular odor. Precision of expression in a single cell is combined with diversity in a cell population. A similar principle underlies the immune response: each lymphocyte expresses a single antigen receptor randomly chosen from a large repertoire.
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