Biased exonization of transposed elements in duplicated genes: A lesson from the TIF-IA gene

BMC Mol Biol. 2007 Nov 29:8:109. doi: 10.1186/1471-2199-8-109.

Abstract

Background: Gene duplication and exonization of intronic transposed elements are two mechanisms that enhance genomic diversity. We examined whether there is less selection against exonization of transposed elements in duplicated genes than in single-copy genes.

Results: Genome-wide analysis of exonization of transposed elements revealed a higher rate of exonization within duplicated genes relative to single-copy genes. The gene for TIF-IA, an RNA polymerase I transcription initiation factor, underwent a humanoid-specific triplication, all three copies of the gene are active transcriptionally, although only one copy retains the ability to generate the TIF-IA protein. Prior to TIF-IA triplication, an Alu element was inserted into the first intron. In one of the non-protein coding copies, this Alu is exonized. We identified a single point mutation leading to exonization in one of the gene duplicates. When this mutation was introduced into the TIF-IA coding copy, exonization was activated and the level of the protein-coding mRNA was reduced substantially. A very low level of exonization was detected in normal human cells. However, this exonization was abundant in most leukemia cell lines evaluated, although the genomic sequence is unchanged in these cancerous cells compared to normal cells.

Conclusion: The definition of the Alu element within the TIF-IA gene as an exon is restricted to certain types of cancers; the element is not exonized in normal human cells. These results further our understanding of the delicate interplay between gene duplication and alternative splicing and of the molecular evolutionary mechanisms leading to genetic innovations. This implies the existence of purifying selection against exonization in single copy genes, with duplicate genes free from such constrains.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alu Elements
  • Animals
  • Base Sequence
  • Cell Cycle Proteins
  • Cell Line
  • Co-Repressor Proteins
  • DNA Transposable Elements / genetics*
  • DNA-Binding Proteins
  • Exons / genetics*
  • Genes, Duplicate / genetics*
  • Genome, Human
  • Humans
  • Introns / genetics
  • Molecular Sequence Data
  • Mutagenesis, Insertional
  • Nuclear Proteins / genetics
  • Pan troglodytes / genetics
  • Point Mutation / genetics
  • Pol1 Transcription Initiation Complex Proteins
  • Protein Biosynthesis
  • Species Specificity
  • Transcription Factors / genetics*
  • Transcription, Genetic

Substances

  • Cell Cycle Proteins
  • Co-Repressor Proteins
  • DNA Transposable Elements
  • DNA-Binding Proteins
  • GON4L protein, human
  • Nuclear Proteins
  • Pol1 Transcription Initiation Complex Proteins
  • RRN3 protein, human
  • Transcription Factors
  • YY1AP1 protein, human