Dual‐Coding Regions in Alternatively Spliced Human Genes

Han Liang, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Laura F Landweber, Princeton University, Princeton, New Jersey, USA

Published online: April 2013

DOI: 10.1002/9780470015902.a0020780.pub2

In eukaryotes, a coding deoxyribonucleic acid (DNA) sequence usually encodes amino acids in one reading frame only. However, by using different exon combinations, alternatively spliced genes may contain dual-coding regions, where more than one reading frame encodes amino acid sequences. In recent years, quite a few studies have systematically identified such dual-coding regions in the human genome. These special coding regions generate functionally related but distinct protein products, and they have evolved under unusual selective forces, with fewer synonymous sites. This article will first introduce the concept of dual-coding regions in alternatively spliced genes through several well-characterised examples, and then discusses the computational methods for detecting such regions and elucidating their evolutionary constraints and finally discusses the potential selective advantages.

Key Concepts:

  • The open reading frame in a DNA sequence defines the encoded amino acid sequences.
  • Particularly low synonymous substitution rate suggests the presence of overlapping reading frames.
  • During translation, ribosomes move along an mRNA not by one nucleotide, but by one codon at a time.
  • The presence of in-frame stop codons indicates that the ORF no longer encodes a functional protein product.
  • Two reading frames of a dual-coding region resulting from alternative splicing are in the same strand whereas those resulting from other mechanisms may be in different strands.

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

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 grey 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). © PloS.
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 summarises 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.
close
 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.
    Guo H, Ingolia NT, Weissman JS and Bartel DP (2010) Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466: 835–840.
    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. EMBO Journal 20: 3849–3860.
    Kovacs E, Tompa P, Liliom K and Kalmar L (2010) Dual coding in alternative reading frames correlates with intrinsic protein disorder. Proceedings of the National Academy of Sciences of the USA 107: 5429–5434.
    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.
    Lin MF, Kheradpour P, Washietl S et al. (2011) Locating protein-coding sequences under selection for additional, overlapping functions in 29 mammalian genomes. Genome Research 21: 1916–1928.
    Michel AM, Choudhury KR, Firth AE et al. (2012) Observation of dually decoded regions of the human genome using ribosome profiling data. Genome Research 22: 2219–2229.
    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.
    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.
    Shao X, Shepelev V and Fedorov A (2006) Bioinformatic analysis of exon repetition, exon scrambling and trans-splicing in humans. Bioinformatics 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.
    Xu H, Wang P, Fu Y et al. (2010) Length of the ORF, position of the first AUG and the Kozak motif are important factors in potential dual-coding transcripts. Cell Research 20: 445–457.
    Yoshida H, Oku M, Suzuki M and Mori K (2006) pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response. Journal of Cell Biology 172: 565–575.
 Further Reading
    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.
    Kozak M (2001) Extensively overlapping reading frames in a second mammalian gene. EMBO Reports 2: 768–769.
    Ribrioux S, Brungger A, Baumgarten B, Seuwen K and John MR (2008) Bioinformatics prediction of overlapping frameshifted translation products in mammalian transcripts. BMC Genomics 9: 122.
    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.
    Sabath N and Graur D (2010) Detection of functional overlapping genes: simulation and case studies. Journal of Molecular Evolution 71: 308–316.
    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.

Related Sub-Topics:

Molecular Evolution | Protein Evolution | Human Evolution | Evolution of Coding and Functional Modules
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Dual‐Coding Regions in Alternatively Spliced Human Genes
 
How to Cite close
Liang, Han, and Landweber, Laura F(Apr 2013) Dual‐Coding Regions in Alternatively Spliced Human Genes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020780.pub2]