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Selection on synonymous sites: the unwanted transcript hypothesis.

Sofia Radrizzani1,2, Grzegorz Kudla3, Zsuzsanna Izsvák4

  • 1Milner Centre for Evolution, Department of Life Sciences, University of Bath, Bath, UK.

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|January 31, 2024
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Summary
This summary is machine-generated.

Human synonymous mutations may protect against unwanted RNAs by influencing gene sequences. This selection favors high-GC content, avoiding AU/CpG-rich transcripts, which is crucial for native messenger RNAs (mRNAs) and RNA vaccines.

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Area of Science:

  • Genetics
  • Molecular Biology
  • Bioinformatics

Background:

  • Synonymous mutations in humans are subject to selection, but not primarily for translational efficiency.
  • The role of synonymous site selection in humans remains incompletely understood.
  • Previous hypotheses focused on codon usage bias related to tRNA abundance.

Purpose of the Study:

  • To propose and support a new hypothesis for synonymous site selection in humans.
  • To explain synonymous site selection as a mechanism for defense against unwanted RNAs.
  • To elucidate the role of RNA sequence composition and structure in gene regulation and recognition.

Main Methods:

  • Review and synthesis of existing literature on RNA processing, degradation, and cellular transport.
  • Analysis of sequence features (GC content, CpG suppression, intron presence) in native mRNAs.
  • Correlation of these features with cellular mechanisms that discriminate between native and unwanted transcripts.

Main Results:

  • Synonymous site selection in humans is hypothesized to protect against spurious, mis-spliced, or foreign RNAs.
  • High GC content and low CpG content, along with intron characteristics, are identified as features of functional native mRNAs.
  • Cellular processes like transcription, nuclear export, and RNA degradation favor GC-rich transcripts and suppress AU/CpG-rich ones.
  • Codon usage has evolved to avoid AU/CpG-rich sequences, which are targeted by cellular 'traps'.
  • These RNA filters also impact endosomal RNA import, supporting the hypothesis.

Conclusions:

  • Synonymous site selection in humans serves as a defense mechanism against unwanted RNA molecules.
  • The observed selection pressures shape native mRNA sequences to be recognized as such by cellular machinery.
  • This understanding provides insights into the design principles for successful transgenes and RNA vaccines.