Identification of evolutionarily conserved non-AUG-initiated N-terminal extensions in human coding sequences.
In eukaryotes, it is generally assumed that translation initiation occurs at the AUG codon closest to the messenger RNA 5' cap. However, in certain cases, initiation can occur at codons differing from AUG by a single nucleotide, especially the codons CUG, UUG, GUG, ACG, AUA and AUU. While non-AUG initiation has been experimentally verified for a handful of human genes, the full extent to which this phenomenon is utilized--both for increased coding capacity and potentially also for novel regulatory mechanisms--remains unclear. To address this issue, and hence to improve the quality of existing coding sequence annotations, we developed a methodology based on phylogenetic analysis of predicted 5' untranslated regions from orthologous genes. We use evolutionary signatures of protein-coding sequences as an indicator of translation initiation upstream of annotated coding sequences. Our search identified novel conserved potential non-AUG-initiated N-terminal extensions in 42 human genes including VANGL2, FGFR1, KCNN4, TRPV6, HDGF, CITED2, EIF4G3 and NTF3, and also affirmed the conservation of known non-AUG-initiated extensions in 17 other genes. In several instances, we have been able to obtain independent experimental evidence of the expression of non-AUG-initiated products from the previously published literature and ribosome profiling data.
BioSciences Institute, University College Cork, Cork, Ireland. iivanov@genetics.utah.edu
Ivaylo P
IP
Ivanov
Andrew E
AE
Firth
Audrey M
AM
Michel
John F
JF
Atkins
Pavel V
PV
Baranov
D020121:5' Untranslated Regions; D017398:Alternative Splicing; D001483:Base Sequence; D015153:Blotting, Western; D018387:Codon, Initiator / Q000737:chemistry*; D017124:Conserved Sequence; D019143:Evolution, Molecular; D006801:Humans; D010802:Phylogeny; D012333:RNA, Messenger / Q000737:chemistry; D016415:Sequence Alignment; D017423:Sequence Analysis, RNA
D020121:5' Untranslated Regions; D018387:Codon, Initiator; D012333:RNA, Messenger
Nature. 1975 Mar 6;254(5495):34-8
803646
Biochemistry. 2002 Mar 19;41(11):3732-41
11888291
J Neurosci. 1995 Oct;15(10):6521-30
7472414
BMC Bioinformatics. 2006 Feb 16;7:75
16483358
Cell. 1986 Jul 18;46(2):235-43
3521891
Proc Natl Acad Sci U S A. 1990 Nov;87(21):8301-5
2236042
Curr Biol. 2008 Nov 25;18(22):1760-5
18993075
Proc Natl Acad Sci U S A. 2010 Oct 19;107(42):18056-60
20921384
Genome Res. 2002 Jan;12(1):198-202
11779845
Appl Environ Microbiol. 2002 Jul;68(7):3198-205
12088995
J Biol Chem. 1988 Jan 5;263(1):52-7
3275649
Eur J Biochem. 1999 Dec;266(3):848-54
10583378
Nucleic Acids Res. 1987 Oct 26;15(20):8125-48
3313277
Genome Biol. 2009;10(3):R25
19261174
Mol Cell. 2007 Apr 13;26(1):41-50
17434125
J Mol Biol. 2004 Jan 2;335(1):71-85
14659741
Cell. 2002 Feb 22;108(4):557-72
11909526
Nucleic Acids Res. 2007 Jan;35(Database issue):D61-5
17130148
Mol Cell Biol. 2001 Dec;21(23):8238-46
11710333
Mol Cell Biol. 2001 Mar;21(6):1899-907
11238926
J Biol Chem. 2008 Oct 10;283(41):27345-27349
18593708
J Virol. 1994 Jun;68(6):3879-87
8189525
J Biomol Struct Dyn. 2006 Aug;24(1):33-42
16780373
J Biol Chem. 2002 Jan 11;277(2):1066-75
11675387
J Mol Biol. 2000 Sep 8;302(1):205-17
10964570
Nature. 2010 Aug 12;466(7308):835-40
20703300
Mol Cell Biol. 1998 Jan;18(1):334-42
9418880
Annu Rev Microbiol. 2005;59:407-50
16153175
J Mol Biol. 2009 Nov 27;394(2):268-85
19751744
Mol Biol Evol. 2007 Aug;24(8):1586-91
17483113
Cell. 1988 Aug 26;54(5):621-32
3136928
Cell. 1991 May 17;65(4):551-68
1851669
Mol Cell Biol. 1989 Nov;9(11):5073-80
2601709
Science. 2009 Apr 10;324(5924):218-23
19213877
Genomics. 1996 Oct 1;37(1):68-76
8921372
J Biol Chem. 2008 Feb 8;283(6):3173-3180
18065417
J Biol Chem. 2008 May 23;283(21):14893-900
18321862
Nucleic Acids Res. 2004 Mar 18;32(5):1774-82
15031317
Cell. 1980 Nov;22(1 Pt 1):7-8
7000367
Cell. 1986 Jan 31;44(2):283-92
3943125
Nucleic Acids Res. 2007;35(6):1842-58
17332016
Biochem Biophys Res Commun. 2010 Mar 19;393(4):860-3
20171191
Nature. 2008 Sep 18;455(7211):416-20
18758445
Gene. 1999 Jul 8;234(2):187-208
10395892
Dev Dyn. 2001 Nov;222(3):450-8
11747079
Bioessays. 2008 Jul;30(7):683-91
18536038
J Biol Chem. 1989 Mar 25;264(9):5031-5
2538469
Genome Res. 2007 Dec;17(12):1823-36
17989253
Comput Appl Biosci. 1997 Oct;13(5):555-6
9367129
Nat Genet. 1993 Aug;4(4):332-3
8401577
J Biol Chem. 2007 Feb 23;282(8):5256-62
17182609
Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10079-84
18626014
J Biol Chem. 2010 Feb 12;285(7):4595-602
20018845
EMBO J. 1997 Feb 17;16(4):817-25
9049310
Nat Genet. 2002 Jun;31(2):200-4
12032567
RNA. 2004 Feb;10(2):221-30
14730021
Nucleic Acids Res. 2010 Jan;38(Database issue):D69-74
19783826
J Biol Chem. 1995 Jul 28;270(30):17680-4
7629066
Am J Physiol Lung Cell Mol Physiol. 2004 Jun;286(6):L1194-201
14751852
Science. 2001 May 4;292(5518):897-902
11340196
J Cell Biochem. 2004 Oct 15;93(3):579-87
15378603
J Biol Chem. 2004 Apr 2;279(14):13778-85
14734560
Gene. 2002 Oct 16;299(1-2):1-34
12459250
Biochem J. 2007 Feb 15;402(1):187-96
17123353
Cancer Immunol Immunother. 2002 May;51(3):121-9
11941450
Mol Cell Proteomics. 2007 Jun;6(6):1000-6
17317662
Nucleic Acids Res. 2009 Jan;37(Database issue):D72-6
18984623
Nat Rev Mol Cell Biol. 2010 Feb;11(2):113-27
20094052
Nucleic Acids Res. 2005 Jan 1;33(Database issue):D54-8
15608257
Nucleic Acids Res. 2004 Mar 19;32(5):1792-7
15034147
Genomics. 2005 Mar;85(3):360-71
15718103
Mol Cell Biol. 2004 Jul;24(13):5788-96
15199135