Dual‐Coding Regions in Alternatively Spliced Human Genes


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, XLαs 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.. © 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 by permission of Cold Spring Harbor Laboratory Press.



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Further Reading

Freson K, Jaeken J, Van Helvoirt M et al. (2003) Functional polymorphisms in the paternally expressed XLαs and its cofactor ALEX decrease their mutual interaction and enhance receptor‐mediated cAMP formation. Human Molecular Genetics 12: 1121–1130.

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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.

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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]