title: Detection of functional overlapping genes: simulation and case studies.
abstract: As far as protein-coding genes are concerned, there is a non-zero probability that at least one of the five possible overlapping sequences of any gene will contain an open-reading frame (ORF) of a length that may be suitable for coding a functional protein. It is, however, very difficult to determine whether or not such an ORF is functional. Recently, we proposed a method that predicts functionality of an overlapping ORF if it can be shown that it has been subject to purifying selection during its evolution. Here, we use simulation to test this method under several conditions and compare it with the method of Firth and Brown. We found that under most conditions, our method detects functional overlapping genes with higher sensitivity than Firth and Brown's method, while maintaining high specificity. Further, we tested the hypothesis that the two aminoacyl tRNA synthetase classes have originated from a pair of overlapping genes. A central piece of evidence ostensibly supporting this hypothesis is the assertion that an overlapping ORF of a heat-shock protein-70 gene, which exhibits some similarity to class 2 aminoacyl tRNA synthetases, is functional. We found signature of purifying selection only in highly divergent sequences, suggesting that the method yields false-positives in high sequence divergence and that the overlapping ORF is not a functional gene. Finally, we examined three cases of overlap in the human genome. We find varying signatures of purifying selection acting on these overlaps, raising the possibility that two of the overlapping genes may not be functional.
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA. nsabath@gmail.com
authors.forename: Niv
authors.initials: N
authors.lastname: Sabath
authors.forename: Dan
authors.initials: D
authors.lastname: Graur
mesh_terms: D000818:Animals; D003198:Computer Simulation; D016373:DNA, Antisense / Q000235:genetics; D005807:Genes, Overlapping / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D051379:Mice; D016366:Open Reading Frames / Q000235:genetics; D012641:Selection, Genetic
chemical_list: D016373:DNA, Antisense
references.citation: Virol J. 2009 Nov 06;6:193
references.pmid: 19895695
references.citation: Orig Life Evol Biosph. 1995 Dec;25(6):565-89
references.pmid: 7494636
references.citation: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D493-6
references.pmid: 14681465
references.citation: Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9489-93
references.pmid: 1329098
references.citation: Bioinformatics. 2005 Feb 1;21(3):282-92
references.pmid: 15347574
references.citation: Virol J. 2008 May 20;5:62
references.pmid: 18492230
references.citation: Biol Direct. 2008 Aug 21;3:36
references.pmid: 18717987
references.citation: BMC Genomics. 2008 Jul 15;9:335
references.pmid: 18627618
references.citation: Bioinformatics. 2007 May 1;23(9):1080-9
references.pmid: 17341494
references.citation: Genetics. 1998 Mar;148(3):929-36
references.pmid: 9539414
references.citation: Virol J. 2008 Apr 14;5:48
references.pmid: 18489030
references.citation: Biol Chem. 1997 Dec;378(12):1521-30
references.pmid: 9461351
references.citation: Mol Cell. 2002 Oct;10(4):705-8
references.pmid: 12419215
references.citation: Bioinformatics. 2007 Nov 15;23(22):2978-86
references.pmid: 17921171
references.citation: Virol J. 2009 Mar 17;6:32
references.pmid: 19292925
references.citation: Genome Biol Evol. 2009 Jun 05;1:114-8
references.pmid: 20333182
references.citation: Gene. 1997 Jul 18;194(1):143-55
references.pmid: 9266684
references.citation: Genome Res. 2006 Feb;16(2):190-6
references.pmid: 16365380
references.citation: Trends Genet. 2006 Dec;22(12):645-8
references.pmid: 17034899
references.citation: Nucleic Acids Res. 1999 Dec 1;27(23):4636-41
references.pmid: 10556321
references.citation: PLoS One. 2008;3(12):e3996
references.pmid: 19098983
references.citation: EMBO J. 2001 Jul 16;20(14):3849-60
references.pmid: 11447126
references.citation: BMC Bioinformatics. 2008 Jul 10;9:304
references.pmid: 18616801
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12807-12
references.pmid: 17652172
references.citation: BMC Bioinformatics. 2006 Feb 16;7:75
references.pmid: 16483358
references.citation: Nature. 1990 Nov 8;348(6297):125-32
references.pmid: 2122258
references.citation: Cell. 2001 Dec 28;107(7):881-91
references.pmid: 11779464
references.citation: Trends Biochem Sci. 2004 Feb;29(2):88-94
references.pmid: 15102435
references.citation: Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):211-6
references.pmid: 12506196
references.citation: PLoS Comput Biol. 2007 May;3(5):e91
references.pmid: 17511511
references.citation: Virol J. 2009 Sep 17;6:144
references.pmid: 19761605
references.citation: Cell Res. 2010 Apr;20(4):445-57
references.pmid: 20157333
references.citation: Curr Protoc Bioinformatics. 2002 Aug;Chapter 2:Unit 2.3
references.pmid: 18792934
references.citation: Mol Biol Evol. 2009 Feb;26(2):445-50
references.pmid: 19037009
references.citation: Arch Virol. 2008;153(7):1379-83
references.pmid: 18535758
references.citation: PLoS Genet. 2005 Aug;1(2):e18
references.pmid: 16110341
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5897-902
references.pmid: 18408156
references.citation: Mol Biol Evol. 2005 Dec;22(12):2472-9
references.pmid: 16107592
references.citation: Proc Natl Acad Sci U S A. 1988 Apr;85(7):2081-5
references.pmid: 3127824
references.citation: J Mol Evol. 1995 Oct;41(4):414-20
references.pmid: 7563128
references.citation: Nature. 1978 Apr 6;272(5653):532-5
references.pmid: 692657
references.citation: BMC Genomics. 2008 Mar 06;9:122
references.pmid: 18325113
references.citation: Brief Bioinform. 2008 Jul;9(4):299-306
references.pmid: 18417537
references.citation: Genome Res. 2002 Jan;12(1):198-202
references.pmid: 11779845
references.citation: FEMS Microbiol Lett. 2000 Feb 15;183(2):307-12
references.pmid: 10675602
references.citation: J Mol Biol. 1990 Oct 5;215(3):403-10
references.pmid: 2231712
references.citation: Genomics. 1991 Oct;11(2):478-9
references.pmid: 1769666
references.citation: Cell. 1995 Dec 15;83(6):993-1000
references.pmid: 8521522
references.citation: Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):10038-43
references.pmid: 9707596
references.citation: Nature. 2002 Dec 5;420(6915):520-62
references.pmid: 12466850