A First Look at ARFome: Dual-Coding Genes in Mammalian Genomes

Coding of multiple proteins by overlapping reading frames is not a feature one would associate with eukaryotic genes. Indeed, codependency between codons of overlapping protein-coding regions imposes a unique set of evolutionary constraints, making it a costly arrangement. Yet in cases of tightly coexpressed interacting proteins, dual coding may be advantageous. Here we show that although dual coding is nearly impossible by chance, a number of human transcripts contain overlapping coding regions. Using newly developed statistical techniques, we identified 40 candidate genes with evolutionarily conserved overlapping coding regions. Because our approach is conservative, we expect mammals to possess more dual-coding genes. Our results emphasize that the skepticism surrounding eukaryotic dual coding is unwarranted: rather than being artifacts, overlapping reading frames are often hallmarks of fascinating biology.

[1]  Sergei L. Kosakovsky Pond,et al.  HyPhy: hypothesis testing using phylogenies , 2005, Bioinform..

[2]  Stevan R. Hubbard,et al.  IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA , 2002, Nature.

[3]  Anton Nekrutenko,et al.  Oscillating Evolution of a Mammalian Locus with Overlapping Reading Frames: An XLαs/ALEX Relay , 2005, PLoS genetics.

[4]  Xiang Xu,et al.  Identification and functional characterization of a novel human misshapen/Nck interacting kinase-related kinase, hMINK beta. , 2004, The Journal of biological chemistry.

[5]  E. Appella,et al.  H-2RIIBP, a member of the nuclear hormone receptor superfamily that binds to both the regulatory element of major histocompatibility class I genes and the estrogen response element. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[6]  A. Nekrutenko,et al.  Functionality of unspliced XBP1 is required to explain evolution of overlapping reading frames. , 2006, Trends in genetics : TIG.

[7]  P. Keese,et al.  Origins of genes: "big bang" or continuous creation? , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[8]  R. Kaufman,et al.  The mammalian unfolded protein response. , 2003, Annual review of biochemistry.

[9]  Eugene V Koonin,et al.  Purifying and directional selection in overlapping prokaryotic genes. , 2002, Trends in genetics : TIG.

[10]  M. Kozak.  Extensively overlapping reading frames in a second mammalian gene , 2001, EMBO reports.

[11]  L. Landweber,et al.  A genome-wide study of dual coding regions in human alternatively spliced genes. , 2005, Genome research.

[12]  K. Ozato,et al.  Isolation of a full-length cDNA clone encoding a N-terminally variant form of the human retinoid X receptor beta. , 1992, Nucleic acids research.

[13]  Adam Eyre-Walker,et al.  Molecular Evolution by Wen-Hsiung Li. Published by Sinauer Associates, Sunderland, MA, USA. ISBN: 0-87893-463-4 (cloth). , 1997 .

[14]  Hiderou Yoshida,et al.  pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response , 2006, The Journal of cell biology.

[15]  K. Mori,et al.  XBP1 mRNA Is Induced by ATF6 and Spliced by IRE1 in Response to ER Stress to Produce a Highly Active Transcription Factor , 2001, Cell.

[16]  Tim F. Rayner,et al.  A Direct Interaction between the N Terminus of Adenylyl Cyclase AC8 and the Catalytic Subunit of Protein Phosphatase 2A , 2006, Molecular Pharmacology.

[17]  J. Vermylen,et al.  Functional polymorphisms in the paternally expressed XLalphas and its cofactor ALEX decrease their mutual interaction and enhance receptor-mediated cAMP formation. , 2003, Human molecular genetics.

[18]  H. Ploegh,et al.  Rapid Turnover of Unspliced Xbp-1 as a Factor That Modulates the Unfolded Protein Response* , 2006, Journal of Biological Chemistry.

[19]  F. Zindy,et al.  Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest , 1995, Cell.

[20]  Kenjiro Sakaki,et al.  Genetic Interactions Due to Constitutive and Inducible Gene Regulation Mediated by the Unfolded Protein Response in C. elegans , 2005, PLoS genetics.

[21]  Norinobu M. Watanabe,et al.  Molecular cloning of MINK, a novel member of mammalian GCK family kinases, which is up‐regulated during postnatal mouse cerebral development , 2000, FEBS letters.

[22]  D. Cooper,et al.  Residence of Adenylyl Cyclase Type 8 in Caveolae Is Necessary but Not Sufficient for Regulation by Capacitative Ca2+Entry* , 2002, The Journal of Biological Chemistry.

[23]  Xiang Xu,et al.  Identification and Functional Characterization of a Novel Human Misshapen/Nck Interacting Kinase-related Kinase, hMINKβ* , 2004, Journal of Biological Chemistry.

[24]  K. Mori.  Frame Switch Splicing and Regulated Intramembrane Proteolysis: Key Words to Understand the Unfolded Protein Response , 2003, Traffic.

[25]  Tom H. Pringle,et al.  The human genome browser at UCSC. , 2002, Genome research.

[26]  D. Cooper.  Regulation and organization of adenylyl cyclases and cAMP. , 2003, The Biochemical journal.

[27]  W. Huttner,et al.  Two overlapping reading frames in a single exon encode interacting proteins—a novel way of gene usage , 2001, The EMBO journal.

[28]  N. Sharpless,et al.  INK4a/ARF: a multifunctional tumor suppressor locus. , 2005, Mutation research.