Dual‐coding Regions in Alternatively Spliced Human Genes

Han Liang, University of Chicago, Chicago, Illinois, USA
Laura F Landweber, Princeton University, Princeton, New Jersey, USA

Published online: March 2008

DOI: 10.1002/9780470015902.a0020780

By using different exon combinations, alternatively spliced genes may contain dual-coding regions, where more than one reading frame encodes amino acid sequences. These special coding regions generate functionally related but distinct protein products and evolve under unusual selective forces.

Keywords: alternative splicing; reading frame; in-frame stop; overlapping genes

Figure 1. Three known examples of dual-coding genes in mammals. (a) A transcript of the Gnas1 gene contains two reading frames and produces two structurally unrelated proteins, XLs and ALEX, using different translation start sites. (b) A newly transcribed XBP1 mRNA can only produce protein XBP1U from ORF A. Removal of a 26-bp spacer (dark gray rectangle) joins the beginning of ORF A with ORF B and translation produces a different product, XBP1S. (c) Ink4a generates two splice variants that use different reading frames within exon E2 to produce the proteins p16Ink4a and p19ARF. Reproduced with permission from Chung et al. (2007).
Figure 2. Schematic representation of a dual-coding region in the human ITGB4BP gene. Exons are represented by boxes and introns by connecting lines. Numbers inside the boxes refer to base pairs. Roman numerals indicate intron phases. The dual-coding region is marked by a black horizontal arrow. Orthologous sequences for this region are shown in other species, and in-frame stop codons are marked by an underlined X. Bioinformatic supporting evidence for the use of both reading frames in humans is shown in the table on the left. The table on the right summarizes the presence of stop codons in orthologous sequences in two reading frames. White arrows indicate direction of data flow for bioinformatics analysis. NM_181466 and NM_181467 are RefSeq accession numbers. Reproduced from Liang and Landweber (2006) by permission of Cold Spring Harbor Laboratory Press.
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 References
    Calfon M, Zeng H, Urano F et al. (2002) IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415: 92–96.
    Chung WY, Wadhawan S, Szklarczyk R, Pond SK and Nekrutenko A (2007) A first look at ARFome: dual-coding genes in mammalian genomes. PLoS Computational Biology 3: e91.
    Kozasa T, Itoh H, Tsukamoto T and Kaziro Y (1988) Isolation and characterization of the human Gs alpha gene. Proceedings of the National Academy of Sciences of the USA 85: 2081–2085.
    Liang H and Landweber LF (2006) A genome-wide study of dual coding regions in human alternatively spliced genes. Genome Research 16: 190–196.
    Nekrutenko A and He J (2006) Functionality of unspliced XBP1 is required to explain evolution of overlapping reading frames. Trends in Genetics 22: 645–648.
    Nekrutenko A, Wadhawan S, Goetting-Minesky P and Makova KD (2005) Oscillating evolution of a mammalian locus with overlapping reading frames: an XLs/ALEX relay. PLoS Genetics 1: e18.
    Normark S, Bergstrom S, Edlund T et al. (1983) Overlapping genes. Annual Review of Genetics 17: 499–525.
    Peleg O, Kirzhner V, Trifonov E and Bolshoy A (2004) Overlapping messages and survivability. Journal of Molecular Evolution 59: 520–527.
    Shao X, Shepelev V and Fedorov A (2006) Bioinformatic analysis of exon repetition, exon scrambling and trans-splicing in humans. Bioinformatics (Oxford, England) 22: 692–698.
    Sharpless NE (2005) INK4a/ARF: a multifunctional tumor suppressor locus. Mutation Research 576: 22–38.
    Tress ML, Martelli PL, Frankish A et al. (2007) The implications of alternative splicing in the ENCODE protein complement. Proceedings of the National Academy of Sciences of the USA 104: 5495–5500.
    Veeramachaneni V, Makalowski W, Galdzicki M, Sood R and Makalowska I (2004) Mammalian overlapping genes: the comparative perspective. Genome Research 14: 280–286.
    Williams BA, Slamovits CH, Patron NJ, Fast NM and Keeling PJ (2005) A high frequency of overlapping gene expression in compacted eukaryotic genomes. Proceedings of the National Academy of Sciences of the USA 102: 10936–10941.
 Further Reading
    ENCODE Project Consortium (2007) Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447: 799–816.
    Freson K, Jaeken J, Van Helvoirt M et al. (2003) Functional polymorphisms in the paternally expressed XLs and its cofactor ALEX decrease their mutual interaction and enhance receptor-mediated cAMP formation. Human Molecular Genetics 12: 1121–1130.
    Huynen MA, Konings DA and Hogeweg P (1993) Multiple coding and the evolutionary properties of RNA secondary structure. Journal of Theoretical Biology 165: 251–267.
    Klemke M, Kehlenbach RH and Huttner WB (2001) Two overlapping reading frames in a single exon encode interacting proteins – a novel way of gene usage. The EMBO Journal 20: 3849–3860.
    Kozak M (2001) Extensively overlapping reading frames in a second mammalian gene. EMBO Reports 2: 768–769.
    Modrek B and Lee CJ (2003) Alternative splicing in the human, mouse and rat genomes is associated with an increased frequency of exon creation and/or loss. Nature Genetics 34: 177–180.
    Quelle DE, Zindy F, Ashmun RA and Sherr CJ (1995) Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 83: 993–1000.
    Robertson U, Navik JA, Walden KKO and Honegger HW (2007) The bursicon gene in mosquitoes: An unusual example of mRNA trans-splicing. Genetics 176: 1351–1353.
    Scorilas A, Kyriakopoulou L, Yousef GM et al. (2001) Molecular cloning, physical mapping, and expression analysis of a novel gene, BCL2L12, encoding a proline-rich protein with a highly conserved BH2 domain of the Bcl-2 family. Genomics 72: 217–221.
    Szklarczyk R, Heringa J, Pond SK and Nekrutenko A (2007) Rapid asymmetric evolution of a dual-coding tumor suppressor INK4a/ARF locus contradicts its function. Proceedings of the National Academy of Sciences of the USA 104: 12807–12812.
    Zhao FQ, Zheng Y, Dong B and Oka T (2004) Cloning, genomic organization, expression, and effect on -casein promoter activity of a novel isoform of the mouse Oct-1 transcription factor. Gene 326: 175–187.

Related Sub-Topics:

Molecular Evolution | Protein Evolution | Human Evolution | Posttranscriptional Modification | Evolution of Coding and Functional Modules
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Article Title: Dual‐coding Regions in Alternatively Spliced Human Genes
 
How to Cite close
Liang, Han, and Landweber, Laura F(Mar 2008) Dual‐coding Regions in Alternatively Spliced Human Genes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020780]