Published online 1 March 2005
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Leaky ribosomal scanning in mammalian genomes: significance of histone H4 alternative translation in vivo
1Department of Orthopaedic Surgery, University of Southern California Los Angeles, CA 90033, USA 2Department of Biochemistry and Molecular Biology, University of Southern California Los Angeles, CA 90033, USA 3Department of Pediatrics, University of Southern California Los Angeles, CA 90033, USA 4Institute for Genetic Medicine, University of Southern California Los Angeles, CA 90033, USA 5Children's Hospital Los Angeles, CA 90033, USA 6Department of Molecular and Computational Biology, University of Southern California Los Angeles, CA 90033, USA 7Institute for Biomedical Engineering, Swiss Federal Institute of Technology (ETH) and University of Zurich 8044 Zurich, Switzerland 8Bone Laboratory, The Hebrew University of Jerusalem Jerusalem 91120, Israel
*To whom correspondence should be addressed at Institute for Genetic Medicine, University of Southern California, 2250 Alcazar Street, CSC/IGM 240 Los Angeles, CA 90033, USA. Tel: +1 323 442 1322; Fax: +1 323 442 2764; Email: frenkel{at}usc.edu
Received September 21, 2004. Revised December 12, 2004. Accepted January 24, 2005.
Like alternative splicing, leaky ribosomal scanning (LRS), which occurs at suboptimal translational initiation codons, increases the physiological flexibility of the genome by allowing alternative translation. Comprehensive analysis of 22 208 human mRNAs indicates that, although the most important positions relative to the first nucleotide of the initiation codon, –3 and +4, are usually such that support initiation (A–3 = 42%, G–3 = 36% and G+4 = 47%), only 37.4% of the genes adhere to the purine (R)–3/G+4 rule at both positions simultaneously, suggesting that LRS may occur in some of the remaining (62.6%) genes. Moreover, 12.5% of the genes lack both R–3 and G+4, potentially leading to sLRS. Compared with 11 genes known to undergo LRS, 10 genes with experimental evidence for high fidelity A+1T+2G+3 initiation codons adhered much more strongly to the R–3/G+4 rule. Among the intron-less histone genes, only the H3 genes adhere to the R–3/G+4 rule, while the H1, H2A, H2B and H4 genes usually lack either R–3 or G+4. To address in vivo the significance of the previously described LRS of H4 mRNAs, which results in alternative translation of the osteogenic growth peptide, transgenic mice were engineered that ubiquitously and constitutively express a mutant H4 mRNA with an A+1
T+1 mutation. These transgenic mice, in particular the females, have a high bone mass phenotype, attributable to increased bone formation. These data suggest that many genes may fulfill cryptic functions by LRS.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
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