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Translation initiation downstream from annotated start codons in human mRNAs coevolves with the Kozak context.

Maria S Benitez-Cantos1,2, Martina M Yordanova1, Patrick B F O'Connor1

  • 1School of Biochemistry and Cell Biology, University College Cork, Cork, T12 XF62 Ireland.

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|July 17, 2020
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Summary

Weak start codons in mRNA can lead to alternative translation initiation sites, influencing protein diversity and gene evolution. This study reveals selection pressures favoring downstream AUGs to reduce wasteful protein synthesis.

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Area of Science:

  • Molecular Biology
  • Genetics
  • Evolutionary Biology

Background:

  • Eukaryotic translation initiation relies on the preinitiation ribosomal complex scanning mRNA.
  • Start codon selection is influenced by the AUG codon and its surrounding nucleotide context (Kozak context).
  • Weak Kozak contexts can cause leaky scanning, where ribosomes bypass the annotated start codon.

Purpose of the Study:

  • To investigate the relationship between the context of annotated start codons and the occurrence of downstream AUG codons.
  • To explore the evolutionary implications of downstream start codons and their impact on protein synthesis.
  • To confirm alternative translation initiation events experimentally.

Main Methods:

  • Analysis of the frequency and frame of downstream AUG codons relative to annotated start codons.
  • Ribosome profiling to confirm translation initiation at downstream start codons.
  • Reporter construct experiments in human genes to test alternative start codon usage.

Main Results:

  • Downstream AUG codons occur more frequently in-frame following weak start codons compared to strong start codons.
  • Translation initiation at downstream start codons was more productive than at annotated start codons in tested human genes.
  • Optimizing Kozak context did not always abolish downstream initiation, highlighting other influencing factors.

Conclusions:

  • Evolutionary selection may favor in-frame downstream AUGs to minimize wasteful out-of-frame protein synthesis and enable proteoform diversity.
  • Translation initiation is more complex than solely relying on Kozak context, with other sequence features influencing start codon selection.
  • This study uncovers novel evolutionary forces shaping protein-coding genes and the plurality of translation initiation.