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Published October 18, 2023 | Published
Journal Article Open

Studying stochastic systems biology of the cell with single-cell genomics data

  • 1. ROR icon California Institute of Technology

Abstract

Recent experimental developments in genome-wide RNA quantification hold considerable promise for systems biology. However, rigorously probing the biology of living cells requires a unified mathematical framework that accounts for single-molecule biological stochasticity in the context of technical variation associated with genomics assays. We review models for a variety of RNA transcription processes, as well as the encapsulation and library construction steps of microfluidics-based single-cell RNA sequencing, and present a framework to integrate these phenomena by the manipulation of generating functions. Finally, we use simulated scenarios and biological data to illustrate the implications and applications of the approach.

Copyright and License

© 2023 Elsevier.

Acknowledgement

G.G. and L.P. were partially funded by NIH 5UM1HG012077-02 and NIH U19MH114830. J.J.V. was partially funded by NIH 1U19NS118246-01. The RNA, DNA, and cDNA illustrations were derived from the DNA Twemoji by Twitter, Inc., used under the CC-BY 4.0 license. The authors thank Dr. A. Sina Booeshaghi, Maria Carilli, Tara Chari, Taleen Dilanyan, Dr. Kristján Eldjárn Hjörleifsson, Meichen Fang, Catherine Felce, and Delaney Sullivan for fruitful discussions of co-regulation, contamination, transient behaviors, catalysis, fragmentation, genomic alignment, and a variety of other phenomena and processes. Part of this work was performed during G.G.'s Data Sciences Co-op with Celsius Therapeutics, Inc.

Contributions

G.G. performed all computational experiments. G.G. and J.J.V. developed the theoretical framework. All authors conceptualized the work and wrote the manuscript.

Data Availability

  • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.
  • All original code has been deposited at https://github.com/pachterlab/GVP_2023 and Zenodo: 8132976, and is publicly available as of the date of publication. DOIs are listed in the key resources table.
  • This paper analyzes existing, publicly available data. These accession numbers for the datasets are listed in the key resources table. Pseudoaligned count matrices in the mtx format have been deposited at Zenodo: 8132976. The data, Monod fits, and analysis scripts used to generate Figures 5D and 5E, originating from Gorin et al.,21 were previously deposited at Zenodo: 7388133.

Conflict of Interest

The authors declare no competing interests.
 

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Additional details

Created:
October 30, 2023
Modified:
January 9, 2024