title: Towards precision medicine: advances in computational approaches for the analysis of human variants.
abstract: Variations and similarities in our individual genomes are part of our history, our heritage, and our identity. Some human genomic variants are associated with common traits such as hair and eye color, while others are associated with susceptibility to disease or response to drug treatment. Identifying the human variations producing clinically relevant phenotypic changes is critical for providing accurate and personalized diagnosis, prognosis, and treatment for diseases. Furthermore, a better understanding of the molecular underpinning of disease can lead to development of new drug targets for precision medicine. Several resources have been designed for collecting and storing human genomic variations in highly structured, easily accessible databases. Unfortunately, a vast amount of information about these genetic variants and their functional and phenotypic associations is currently buried in the literature, only accessible by manual curation or sophisticated text text-mining technology to extract the relevant information. In addition, the low cost of sequencing technologies coupled with increasing computational power has enabled the development of numerous computational methodologies to predict the pathogenicity of human variants. This review provides a detailed comparison of current human variant resources, including HGMD, OMIM, ClinVar, and UniProt/Swiss-Prot, followed by an overview of the computational methods and techniques used to leverage the available data to predict novel deleterious variants. We expect these resources and tools to become the foundation for understanding the molecular details of genomic variants leading to disease, which in turn will enable the promise of precision medicine.
authors: Department of Biological Sciences, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA. Electronic address: tpeters1@umbc.edu.
authors: Thomas A
authors: TA
authors: Peterson
authors: Emily
authors: E
authors: Doughty
authors: Maricel G
authors: MG
authors: Kann
mesh_terms: D019295:Computational Biology / Q000379:methods*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D017421:Sequence Analysis / Q000379:methods*
keywords: GWAS; Genome Wide Association Studies; HGVS; Human Genome Variation Society; LSDB; NCBI; National Center for Biotechnology Information; SVM; databases for human variants; function prediction; human disease variants; locus-specific database; support vector machine
references: Bioinformatics. 2010 Oct 1;26(19):2458-9
references: 20685956
references: Bioinformatics. 2010 Aug 15;26(16):1975-82
references: 20551136
references: Genome Biol. 2010;11(2):R20
references: 20158892
references: Database (Oxford). 2011 Nov 13;2011:bar049
references: 22083790
references: J Biotechnol. 2012 Oct 31;161(3):287-93
references: 22782143
references: Am J Hum Genet. 2012 Jan 13;90(1):7-24
references: 22243964
references: Amino Acids. 2013 Mar;44(3):847-55
references: 23064876
references: Hum Mutat. 2011 Jan;32(1):19-24
references: 20672376
references: Nucleic Acids Res. 2006 Mar 06;34(5):1317-25
references: 16522644
references: BMC Bioinformatics. 2009 Feb 05;10 Suppl 2:S6
references: 19208194
references: PLoS Biol. 2004 Nov;2(11):e309
references: 15383839
references: Bioinformatics. 2003 Sep 22;19(14):1858-60
references: 14512363
references: Science. 2012 Jul 6;337(6090):100-4
references: 22604722
references: Nucleic Acids Res. 2012 Jan;40(Database issue):D935-9
references: 22075996
references: Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W621-5
references: 16845085
references: Bioinformatics. 2012 Mar 1;28(5):724-5
references: 22257670
references: Nature. 2012 Nov 1;491(7422):56-65
references: 23128226
references: Sci Am. 2010 Oct;303(4):60-7
references: 20923130
references: J Am Med Inform Assoc. 2011 Jul-Aug;18(4):352-3
references: 21672904
references: Hum Mutat. 2013 Jan;34(1):42-9
references: 22903802
references: Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6544-9
references: 20308572
references: Nature. 2010 Oct 28;467(7319):1061-73
references: 20981092
references: BMC Bioinformatics. 2009 Aug 27;10 Suppl 8:S2
references: 19758466
references: BMC Bioinformatics. 2013 Mar 22;14:104
references: 23517090
references: PLoS Biol. 2009 Nov;7(11):e1000247
references: 19956802
references: BMC Genomics. 2012 Jun 18;13 Suppl 4:S10
references: 22759648
references: Nucleic Acids Res. 2003 Jul 1;31(13):3812-4
references: 12824425
references: Bioinformatics. 2011 Sep 15;27(18):2595-7
references: 21791533
references: Hum Mutat. 2008 Mar;29(3):333-44
references: 18058827
references: Nucleic Acids Res. 2007 Jan;35(Database issue):D700-6
references: 17142238
references: Nucleic Acids Res. 2012 Jan;40(Database issue):D940-6
references: 22080554
references: Hum Mutat. 2011 May;32(5):557-63
references: 21520333
references: Nucleic Acids Res. 2010 Jul;38(Web Server issue):W755-62
references: 20513647
references: PLoS Comput Biol. 2010 Dec 02;6(12):e1001025
references: 21152010
references: Hum Mutat. 2011 Apr;32(4):358-68
references: 21412949
references: Bioinformatics. 2005 Jul 15;21(14):3176-8
references: 15879453
references: Nucleic Acids Res. 2001 Jan 1;29(1):308-11
references: 11125122
references: Nat Rev Genet. 2011 Jan;12(1):56-68
references: 21164525
references: Nucleic Acids Res. 2012 Jan;40(Database issue):D1308-12
references: 22140107
references: J Am Med Inform Assoc. 2012 Mar-Apr;19(2):275-83
references: 22319177
references: Hum Mutat. 2000;15(1):7-12
references: 10612815
references: Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W382-8
references: 15980494
references: Hum Mutat. 2013 Feb;34(2):275-82
references: 23169447
references: Pac Symp Biocomput. 2010;:337-47
references: 19908386
references: Hum Mutat. 2006 Dec;27(12):1200-8
references: 17004234
references: BMC Bioinformatics. 2007 Nov 16;8:450
references: 18005451
references: Nucleic Acids Res. 2000 Jan 1;28(1):283-5
references: 10592247
references: Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W642-4
references: 16845090
references: Genome Res. 2005 Aug;15(8):1034-50
references: 16024819
references: Nucleic Acids Res. 2010 Jan;38(Database issue):D586-92
references: 19864252
references: Science. 2013 Mar 29;339(6127):1546-58
references: 23539594
references: J Am Med Inform Assoc. 2011 Jul-Aug;18(4):441-8
references: 21515544
references: Science. 2011 Mar 25;331(6024):1553-8
references: 21436442
references: Nucleic Acids Res. 2008 Jan;36(Database issue):D820-4
references: 17986460
references: PLoS Comput Biol. 2007 Feb 2;3(2):e16
references: 17274683
references: Nucleic Acids Res. 1999 Jan 1;27(1):355-7
references: 9847227
references: Bioinformatics. 2011 Dec 1;27(23):3286-92
references: 21998155
references: Science. 2003 Apr 11;300(5617):286-90
references: 12690187
references: Hum Mutat. 2012 Aug;33(8):1166-74
references: 22505138
references: J Biomed Inform. 2012 Oct;45(5):842-50
references: 22564364
references: Electrophoresis. 1996 Mar;17(3):566-72
references: 8740181
references: Methods Enzymol. 2006;411:340-52
references: 16939799
references: PLoS Comput Biol. 2012;8(12):e1002827
references: 23300417
references: BMC Genomics. 2013;14 Suppl 3:S2
references: 23819846
references: Nat Genet. 2000 May;25(1):25-9
references: 10802651
references: Proteins. 2007 Jan 1;66(1):41-52
references: 17068801
references: BMC Genomics. 2010 Dec 02;11 Suppl 4:S24
references: 21143808
references: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D749-51
references: 16381973
references: Nucleic Acids Res. 2004 Jan 02;32(1):135-42
references: 14704350
references: Nucleic Acids Res. 2012 Jan;40(Database issue):D130-5
references: 22121212
references: Am J Hum Genet. 2011 Apr 8;88(4):440-9
references: 21457909
references: Bioinformatics. 2006 Jul 15;22(14):e523-9
references: 16873516
references: J Biomed Semantics. 2014 Feb 25;5(1):11
references: 24568600
references: Biopolymers. 2013 Mar;99(3):218-22
references: 23023942
references: Hum Mutat. 2010 Mar;31(3):335-46
references: 20052762
references: J Bioinform Comput Biol. 2007 Dec;5(6):1261-75
references: 18172928
references: Comput Methods Programs Biomed. 2009 Aug;95(2):181-9
references: 19327864
references: Curr Protoc Bioinformatics. 2012 Sep;Chapter 1:1.13.1-1.13.20
references: 22948725
references: J Med Genet. 2006 Apr;43(4):295-305
references: 16014699
references: Nucleic Acids Res. 2010 Sep;38(16):e164
references: 20601685
references: Nucleic Acids Res. 2012 Jan;40(Database issue):D700-5
references: 22110037
references: Nucleic Acids Res. 2002 Sep 1;30(17):3894-900
references: 12202775
references: Am J Hum Genet. 2012 Dec 7;91(6):1022-32
references: 23217326
references: Nat Methods. 2010 Aug;7(8):575-6
references: 20676075
references: Hum Mutat. 1999;13(5):344-50
references: 10338088
references: BMC Bioinformatics. 2010 Nov 08;11:548
references: 21059217
references: Hum Mutat. 2005 Sep;26(3):184-91
references: 16086365
references: Biochem Biophys Res Commun. 2001 Sep 14;287(1):288-91
references: 11549289
references: Nucleic Acids Res. 2011 Jan;39(Database issue):D945-50
references: 20952405
references: Bioinformatics. 2009 Sep 1;25(17):2281-2
references: 19542150
references: Genomics. 2002 Apr;79(4):464-70
references: 11944974
references: Hum Mutat. 2011 May;32(5):564-7
references: 21472891
references: Protein Sci. 2002 Nov;11(11):2714-26
references: 12381853
references: Pharmacogenomics. 2012 Dec;13(16):1967-78
references: 23215889
references: Nucleic Acids Res. 2007;35(11):3823-35
references: 17526529
references: Nature. 2012 Sep 6;489(7414):57-74
references: 22955616
references: Protein Eng Des Sel. 2009 Sep;22(9):553-60
references: 19561092
references: Nat Genet. 2007 Oct;39(10):1217-24
references: 17873874
references: Mol Cancer. 2011 May 16;10:54
references: 21575214
references: Bioinformatics. 2006 Oct 15;22(20):2567-9
references: 16882651
references: Nucleic Acids Res. 2010 Jan;38(Database issue):D142-8
references: 19843607
references: Hum Mutat. 2010 Jul;31(7):763-80
references: 20506312
references: Nucleic Acids Res. 2003 Jan 1;31(1):365-70
references: 12520024
references: Endocrinology. 2007 Oct;148(10):4642-8
references: 17628007
references: BMC Med Genomics. 2010 Oct 13;3:45
references: 20942928
references: Clin Pharmacol Ther. 2012 Oct;92(4):414-7
references: 22992668
references: Bioinformatics. 2011 Aug 1;27(15):2156-8
references: 21653522
references: Fly (Austin). 2012 Apr-Jun;6(2):80-92
references: 22728672
references: Bioinformatics. 2006 Nov 15;22(22):2729-34
references: 16895930
references: Nat Rev Genet. 2005 Feb;6(2):95-108
references: 15716906
references: Genome Res. 2006 Jul;16(7):855-63
references: 16769978
references: Hum Mutat. 2012 Sep;33(9):1340-4
references: 22581678
references: Stud Health Technol Inform. 2007;129(Pt 1):330-4
references: 17911733
references: J Mol Biol. 2006 Mar 10;356(5):1263-74
references: 16412461
references: Nucleic Acids Res. 2009 Jan;37(1):1-13
references: 19033363
references: Science. 2001 Feb 16;291(5507):1304-51
references: 11181995
references: Bioinformatics. 2009 Nov 1;25(21):2744-50
references: 19734154
references: Nucleic Acids Res. 2011 Sep 1;39(17):e118
references: 21727090
references: Genome Biol. 2010;11(8):R88
references: 20796305
references: BMC Bioinformatics. 2005;6 Suppl 1:S1
references: 15960821
references: Bioinformatics. 2005 Jun 15;21(12):2814-20
references: 15827081
references: Nat Methods. 2010 Apr;7(4):248-9
references: 20354512
references: PLoS Comput Biol. 2012;8(2):e1002375
references: 22383865
references: N Engl J Med. 2012 Feb 9;366(6):489-91
references: 22256780
references: Hum Mutat. 2009 Aug;30(8):1237-44
references: 19514061
references: Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W635-41
references: 16845089
references: Nucleic Acids Res. 2009 Jan;37(Database issue):D832-6
references: 19015121
references: Lancet. 2010 May 1;375(9725):1525-35
references: 20435227
references: Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
references: 9254694
references: Am J Hum Genet. 2007 Sep;81(3):559-75
references: 17701901
references: Genome Med. 2010 Apr 15;2(4):24
references: 20398331
references: Genome Med. 2009 Jan 22;1(1):13
references: 19348700
references: BMC Genomics. 2012 Jun 18;13 Suppl 4:S2
references: 22759650
references: Pac Symp Biocomput. 2010;:315-26
references: 19908384
references: J Am Med Inform Assoc. 2010 May-Jun;17(3):229-36
references: 20442139
references: BMC Genomics. 2013;14 Suppl 3:S6
references: 23819482
references: Genome Biol. 2008;9 Suppl 2:S7
references: 18834498
references: Bioinformatics. 2008 Aug 15;24(16):i241-7
references: 18689832
references: Nature. 2001 Feb 15;409(6822):860-921
references: 11237011
references: Nucleic Acids Res. 2013 Jan;41(Database issue):D64-9
references: 23155063
references: Nat Rev Genet. 2012 Jan 18;13(2):135-45
references: 22251874
references: PLoS One. 2010 Feb 12;5(2):e9186
references: 20169194
references: Nucleic Acids Res. 2012 Jan;40(Database issue):D84-90
references: 22086963
references: Bioinformatics. 2001 Nov;17(11):1027-34
references: 11724731
references: Hum Genomics. 2010 Oct;5(1):1-4
references: 21106485
references: Genome Res. 2005 Jul;15(7):978-86
references: 15965030
references: Bioinformatics. 2009 Aug 15;25(16):2078-9
references: 19505943
references: Bioinformatics. 2007 Jul 15;23(14):1862-5
references: 17495998
references: Hum Mutat. 2000;15(1):13-5
references: 10612816
references: PLoS Comput Biol. 2007 Dec;3(12):e254
references: 18166073
references: Science. 2013 Mar 29;339(6127):1563-6
references: 23539596
references: BMC Genomics. 2013;14 Suppl 3:S5
references: 23819456
references: Science. 2012 Jul 6;337(6090):64-9
references: 22604720
references: Bioinformatics. 2004 May 1;20(7):1006-14
references: 14751981
references: Science. 2004 Oct 22;306(5696):636-40
references: 15499007
references: BMC Bioinformatics. 2011;12 Suppl 4:S3
references: 21992054
references: Nucleic Acids Res. 2007 Jan;35(Database issue):D823-8
references: 17178747
references: Protein Sci. 2004 Jan;13(1):71-80
references: 14691223
references: Nat Rev Genet. 2011 Mar;12(3):224
references: 21301474
references: Nucleic Acids Res. 2013 Jan;41(Database issue):D545-52
references: 23161694
references: J Biomed Inform. 2012 Oct;45(5):835-41
references: 22683993
references: Bioinformatics. 2004 Mar 1;20(4):557-68
references: 14990452
references: Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W480-2
references: 15980516
references: Genome Res. 2003 Sep;13(9):2129-41
references: 12952881
references: Bioinformatics. 2011 Feb 1;27(3):408-15
references: 21138947
references: Hum Mutat. 2010 Sep;31(9):1026-32
references: 20629180
references: J Mol Biol. 2007 Oct 5;372(5):1261-77
references: 17727879
references: Genome Res. 2002 May;12(5):680-8
references: 11997335
references: Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W306-10
references: 15980478
references: Nucleic Acids Res. 2007 Jul;35(Web Server issue):W384-92
references: 17537826
references: Hum Mutat. 2007 Jun;28(6):554-62
references: 17326095
references: Nature. 2002 Dec 5;420(6915):520-62
references: 12466850