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Locating protein-coding sequences under selection for additional, overlapping functions in 29 mammalian genomes.

Michael F Lin1, Pouya Kheradpour, Stefan Washietl

  • 1Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

Genome Research
|October 14, 2011
PubMed
Summary

Mammalian genes often contain hidden overlapping functions, like regulatory elements, within their protein-coding sequences. These regions show high evolutionary conservation, indicating selection for dual roles.

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Area of Science:

  • Genomics
  • Evolutionary Biology
  • Molecular Biology

Background:

  • The genetic code's degeneracy enables DNA and RNA sequences to encode multiple functions.
  • Sequences with dual functions under selection are predicted to exhibit higher evolutionary conservation, particularly at synonymous sites.

Purpose of the Study:

  • To systematically identify regions within human open reading frames (ORFs) with unusually low synonymous substitution rates across placental mammals.
  • To investigate the functional significance of these conserved regions, suggesting overlapping functions.

Main Methods:

  • Utilized genome alignments of 29 placental mammals to analyze evolutionary conservation.
  • Employed statistical methods to detect short regions (down to nine-codon windows) with significant synonymous constraint within human ORFs.

Main Results:

  • Identified over 10,000 conserved regions within more than a quarter of human protein-coding genes.
  • These regions constitute approximately 2% of all synonymous sites and show evidence of selection for overlapping functions.
  • Evidence supports roles in splicing regulation, dual-coding, RNA secondary structures, microRNA targeting, and enhancer activity.

Conclusions:

  • Overlapping functional elements are prevalent in mammalian genes, contrary to expectations given the genome's size.
  • Synonymous site conservation serves as a strong indicator for identifying these multi-functional genomic regions.