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Cis to trans: small ORF functions emerging through evolution.

Casimiro Baena-Angulo1, Ana Isabel Platero1, Juan Pablo Couso1

  • 1Centro Andaluz de Biología del Desarrollo, CSIC, Universidad Pablo de Olavide, Carretera de Utrera Km1, Sevilla 41013, Spain.

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|November 27, 2024
PubMed
Summary
This summary is machine-generated.

Thousands of small open reading frames (smORFs) are translated and have functions, not discarded as nonfunctional. These smORFs can be regulatory or coding, with some evolving into new genes from noncoding sequences.

Keywords:
lncRNAsmicroproteinsshort ORFssmORF-encoded peptidessmall ORFs

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Area of Science:

  • Genomics
  • Molecular Biology
  • Evolutionary Biology

Background:

  • Small open reading frames (smORFs), typically under 100 codons, are abundant in genomes, particularly within long noncoding RNAs (lncRNAs) and mRNA 5' leaders.
  • Historically, smORFs were often overlooked and presumed nonfunctional.
  • Emerging evidence suggests a significant number of smORFs are actively translated and possess biological roles.

Purpose of the Study:

  • To investigate the functional significance and evolutionary origins of translated smORFs.
  • To characterize the diverse roles of smORFs, ranging from cis-regulatory functions to peptide-coding capabilities.
  • To propose a mechanism for the de novo evolution of new genes from noncoding sequences via smORFs.

Main Methods:

  • Utilized ribosomal profiling (RiboSeq) to identify actively translated smORFs across various genomic contexts.
  • Analyzed the functional characteristics of smORFs, distinguishing between regulatory and coding roles.
  • Examined the evolutionary trajectories of smORFs to understand their emergence from noncoding regions.

Main Results:

  • Ribosomal profiling confirmed that thousands of smORFs are translated, challenging their prior dismissal as nonfunctional.
  • Identified two primary functional categories for smORFs: cis-noncoding regulatory roles and full coding functions.
  • Demonstrated that robustly translated smORF peptides often mediate cellular and physiological functions, including roles as membrane-associated regulators.
  • Evolutionary analysis indicated that many smORFs originate de novo from noncoding sequences.

Conclusions:

  • smORFs represent a significant, previously underestimated, source of functional genetic elements.
  • The dual functionality of smORFs (regulatory and coding) provides a pathway for the evolution of new genes.
  • Cis-noncoding functions of smORFs may serve as evolutionary precursors, creating niches for the subsequent development of peptide-coding capabilities.