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Pervasive noise in human splice site selection.

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Biological noise significantly impacts RNA splicing, leading to cryptic splicing and low-fidelity splice site usage. Rapid nuclear degradation highlights extensive RNA quality control mechanisms in human cells.

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Area of Science:

  • Molecular Biology
  • Genomics
  • Transcriptomics

Background:

  • Historically, RNA splicing was considered highly efficient and accurate.
  • Recent findings suggest biological noise contributes to transcriptome diversity.
  • Quantitative analysis of stochastic splicing variations is difficult due to transcript degradation.

Purpose of the Study:

  • To investigate stochastic variations in RNA splicing.
  • To quantify cryptic splicing and low-fidelity splice site usage.
  • To understand the degradation pathways of non-productive RNA transcripts.

Main Methods:

  • Ultra-deep sequencing across cellular RNA compartments.
  • Tracking of splicing intermediates in human cells.
  • Analysis of genomic features associated with splicing noise.

Main Results:

  • Abundant cryptic splicing linked to genomic features promoting splicing noise was observed.
  • Pervasive use of low-fidelity splice sites, likely due to spliceosome stochasticity, was detected.
  • Evidence suggests rapid nuclear degradation of non-productive transcripts, not translation-dependent degradation.

Conclusions:

  • RNA processing mechanisms exhibit a significant propensity for error.
  • Widespread surveillance and rapid quality control mechanisms exist for non-productive RNA transcripts.
  • Findings offer new insights into alternative splice site regulation across genes.