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Open Access Research article

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

Maayan Amit1, Noa Sela1, Hadas Keren1, Ze'ev Melamed1, Inna Muler123, Noam Shomron4, Shai Izraeli123 and Gil Ast1*

Author Affiliations

1 Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel

2 Chaim Sheba Cancer Research Center, Tel Hashomer, Israel

3 Pediatric Hemato-Oncology, Sheba Medical Center, Tel Hashomer, Israel

4 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

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BMC Molecular Biology 2007, 8:109  doi:10.1186/1471-2199-8-109

Published: 29 November 2007

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.