title: Automated protein subfamily identification and classification.
abstract: Function prediction by homology is widely used to provide preliminary functional annotations for genes for which experimental evidence of function is unavailable or limited. This approach has been shown to be prone to systematic error, including percolation of annotation errors through sequence databases. Phylogenomic analysis avoids these errors in function prediction but has been difficult to automate for high-throughput application. To address this limitation, we present a computationally efficient pipeline for phylogenomic classification of proteins. This pipeline uses the SCI-PHY (Subfamily Classification in Phylogenomics) algorithm for automatic subfamily identification, followed by subfamily hidden Markov model (HMM) construction. A simple and computationally efficient scoring scheme using family and subfamily HMMs enables classification of novel sequences to protein families and subfamilies. Sequences representing entirely novel subfamilies are differentiated from those that can be classified to subfamilies in the input training set using logistic regression. Subfamily HMM parameters are estimated using an information-sharing protocol, enabling subfamilies containing even a single sequence to benefit from conservation patterns defining the family as a whole or in related subfamilies. SCI-PHY subfamilies correspond closely to functional subtypes defined by experts and to conserved clades found by phylogenetic analysis. Extensive comparisons of subfamily and family HMM performances show that subfamily HMMs dramatically improve the separation between homologous and non-homologous proteins in sequence database searches. Subfamily HMMs also provide extremely high specificity of classification and can be used to predict entirely novel subtypes. The SCI-PHY Web server at http://phylogenomics.berkeley.edu/SCI-PHY/ allows users to upload a multiple sequence alignment for subfamily identification and subfamily HMM construction. Biologists wishing to provide their own subfamily definitions can do so. Source code is available on the Web page. The Berkeley Phylogenomics Group PhyloFacts resource contains pre-calculated subfamily predictions and subfamily HMMs for more than 40,000 protein families and domains at http://phylogenomics.berkeley.edu/phylofacts/.
authors: Department of Bioengineering, University of California, Berkeley, California, United States of America.
authors: Duncan P
authors: DP
authors: Brown
authors: Nandini
authors: N
authors: Krishnamurthy
authors: Kimmen
authors: K
authors: Sjölander
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D001185:Artificial Intelligence; D008390:Markov Chains; D008969:Molecular Sequence Data; D010363:Pattern Recognition, Automated / Q000379:methods*; D011506:Proteins / Q000737:chemistry* / Q000145:classification*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D016415:Sequence Alignment / Q000379:methods*; D020539:Sequence Analysis, Protein / Q000379:methods*
chemical_list: D011506:Proteins
references: Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12091-5
references: 7991589
references: BMC Bioinformatics. 2005 Aug 05;6:198
references: 16083500
references: Proteins. 2003;53 Suppl 6:491-6
references: 14579338
references: Bioinformatics. 1998;14(10):846-56
references: 9927713
references: Proteins. 2000 Oct 1;41(1):98-107
references: 10944397
references: Bioinformatics. 1999 May;15(5):391-412
references: 10366660
references: Methods Enzymol. 1996;266:460-80
references: 8743700
references: Proteins. 2005;61 Suppl 7:201-213
references: 16187363
references: Math Biosci. 2005 Feb;193(2):223-34
references: 15748731
references: J Mol Biol. 1998 Dec 11;284(4):1201-10
references: 9837738
references: BMC Bioinformatics. 2002 May 16;3:14
references: 12028595
references: J Mol Biol. 1995 Apr 7;247(4):536-40
references: 7723011
references: Bioinformatics. 2006 Jul 1;22(13):1658-9
references: 16731699
references: Nucleic Acids Res. 2005 Jan 1;33(Database issue):D192-6
references: 15608175
references: J Mol Biol. 1994 Nov 4;243(4):574-8
references: 7966282
references: Nucleic Acids Res. 2003 Jul 1;31(13):3829-32
references: 12824430
references: J Mol Biol. 2001 Dec 14;314(5):1041-52
references: 11743721
references: Science. 2004 Apr 2;304(5667):66-74
references: 15001713
references: Nucleic Acids Res. 2000 Jan 1;28(1):254-6
references: 10592239
references: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D138-41
references: 14681378
references: J Mol Evol. 2001 Jun;52(6):540-2
references: 11443357
references: Nucleic Acids Res. 1995 Jul 25;23(14):2715-23
references: 7651832
references: Nucleic Acids Res. 2001 Jan 1;29(1):346-9
references: 11125133
references: Bioinformatics. 2005 Aug 1;21(15):3241-7
references: 15905279
references: Pac Symp Biocomput. 2005;:322-33
references: 15759638
references: PLoS Comput Biol. 2005 Oct;1(5):e45
references: 16217548
references: Bioinformatics. 2003 Dec 12;19(18):2484-5
references: 14668239
references: J Mol Biol. 2000 Oct 13;303(1):61-76
references: 11021970
references: Trends Genet. 2001 Aug;17(8):429-31
references: 11485799
references: Nucleic Acids Res. 2003 Jul 1;31(13):3799-803
references: 12824422
references: Arch Immunol Ther Exp (Warsz). 2002;50(3):159-67
references: 12098931
references: Bioinformatics. 2004 Jan 22;20(2):170-9
references: 14734307
references: Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W313-7
references: 15215401
references: Bioinformatics. 2002 Jul;18(7):908-21
references: 12117788
references: Biochemistry. 2006 Feb 28;45(8):2545-55
references: 16489747
references: Annu Rev Genet. 2004;38:525-52
references: 15568985
references: Trends Genet. 1999 Apr;15(4):132-3
references: 10203816
references: Nucleic Acids Res. 2004 Sep 30;32(17):5231-8
references: 15459293
references: Bioinformatics. 2002 Jan;18(1):77-82
references: 11836214
references: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D189-92
references: 14681391
references: Nucleic Acids Res. 2007 Jul;35(Web Server issue):W27-32
references: 17488835
references: In Silico Biol. 1998;1(1):55-67
references: 11471243
references: Proc Natl Acad Sci U S A. 1987 Jul;84(13):4355-8
references: 3474607
references: Nucleic Acids Res. 2003 Jan 1;31(1):294-7
references: 12520006
references: Proteins. 2003 Nov 15;53(3):683-92
references: 14579359
references: Genome Biol. 2006;7(9):R83
references: 16973001
references: J Mol Biol. 1994 Feb 4;235(5):1501-31
references: 8107089
references: Biochem Biophys Res Commun. 2001 Apr 6;282(3):832-8
references: 11401539
references: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D115-9
references: 14681372
references: PLoS Comput Biol. 2006 Jun 30;2(6):e77
references: 16846248
references: Genome Res. 2003 Sep;13(9):2178-89
references: 12952885
references: Methods Biochem Anal. 2003;44:501-7
references: 12647401
references: Comput Appl Biosci. 1996 Aug;12(4):327-45
references: 8902360
references: Proc Int Conf Intell Syst Mol Biol. 1998;6:165-74
references: 9783222
references: Curr Opin Chem Biol. 1999 Oct;3(5):548-56
references: 10508675
references: Science. 2001 Feb 16;291(5507):1304-51
references: 11181995
references: Bioinformatics. 1998;14(9):755-63
references: 9918945
references: BMC Bioinformatics. 2004 Nov 18;5:178
references: 15550167
references: Bioinformatics. 2002 Jan;18(1):147-59
references: 11836223
references: Genome Res. 1998 Mar;8(3):163-7
references: 9521918
references: Bioinformatics. 2002 Jan;18(1):92-9
references: 11836216
references: Nucleic Acids Res. 1998 Sep 15;26(18):4291-300
references: 9722651
references: Mol Biol Evol. 2001 Aug;18(8):1435-41
references: 11470834
references: Nucleic Acids Res. 2004 Mar 19;32(5):1792-7
references: 15034147
references: Brief Bioinform. 2006 Sep;7(3):225-42
references: 16772267