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PMID: 19181721 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Next generation tools for the annotation of human SNPs.

Briefings in bioinformatics ·Vol. 10 ·No. 1 ·2009-01-00 ·Pages 35-52

Karchin R

Abstract

Computational biology has the opportunity to play an important role in the identification of functional single nucleotide polymorphisms (SNPs) discovered in large-scale genotyping studies, ultimately yielding new drug targets and biomarkers. The medical genetics and molecular biology communities are increasingly turning to computational biology methods to prioritize interesting SNPs found in linkage and association studies. Many such methods are now available through web interfaces, but the interested user is confronted with an array of predictive results that are often in disagreement with each other. Many tools today produce results that are difficult to understand without bioinformatics expertise, are biased towards non-synonymous SNPs, and do not necessarily reflect up-to-date versions of their source bioinformatics resources, such as public SNP repositories. Here, I assess the utility of the current generation of webservers; and suggest improvements for the next generation of webservers to better deliver value to medical geneticists and molecular biologists.

MeSH Terms
Computational Biology/methods Databases, Genetic Genome, Human Genotype Humans Internet/trends Polymorphism, Single Nucleotide Schizophrenia/genetics Sequence Analysis, DNA/methods User-Computer Interface
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Karchin Rachel
Biomedical Engineering Department and Institute for Computational Medicine, Johns Hopkins University, 3400 N. Charles St, Baltimore, MD 212218, USA. [email protected]
References (87)
87 references, click to expand
  1. Prediction of nonsynonymous single nucleotide polymorphisms in human disease-associated genes.
    J Mol Med (Berl). 1999 Nov;77(11):754-60 PMID: 10619435
  2. The Ensembl genome database project.
    Nucleic Acids Res. 2002 Jan 1;30(1):38-41 PMID: 11752248
  3. ESEfinder: A web resource to identify exonic splicing enhancers.
    Nucleic Acids Res. 2003 Jul 1;31(13):3568-71 PMID: 12824367
  4. Night blindness-associated mutations in the ligand-binding, cysteine-rich, and intracellular domains of the metabotropic glutamate receptor 6 abolish protein trafficking.
    Hum Mutat. 2007 Aug;28(8):771-80 PMID: 17405131
  5. BIND--The Biomolecular Interaction Network Database.
    Nucleic Acids Res. 2001 Jan 1;29(1):242-5 PMID: 11125103
  6. PupaSuite: finding functional single nucleotide polymorphisms for large-scale genotyping purposes.
    Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W621-5 PMID: 16845085
  7. Single nucleotide polymorphism discovery and haplotype analysis of Ca2+-dependent K+ channel beta-1 subunit.
    Pharmacogenet Genomics. 2007 Apr;17(4):267-75 PMID: 17496725
  8. RESCUE-ESE identifies candidate exonic splicing enhancers in vertebrate exons.
    Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W187-90 PMID: 15215377
  9. Human Gene Mutation Database: towards a comprehensive central mutation database.
    J Med Genet. 2008 Feb;45(2):124-6 PMID: 18245393
  10. UCSF Chimera--a visualization system for exploratory research and analysis.
    J Comput Chem. 2004 Oct;25(13):1605-12 PMID: 15264254
  11. The function of the SNP in the MMP1 and MMP3 promoter in susceptibility to endometriosis in China.
    Mol Hum Reprod. 2005 Jun;11(6):423-7 PMID: 15879464
  12. MutDB services: interactive structural analysis of mutation data.
    Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W311-4 PMID: 15980479
  13. High-density genotyping and functional SNP localization in the CETP gene.
    J Lipid Res. 2007 Feb;48(2):434-43 PMID: 17108362
  14. PMUT: a web-based tool for the annotation of pathological mutations on proteins.
    Bioinformatics. 2005 Jul 15;21(14):3176-8 PMID: 15879453
  15. dbSNP: the NCBI database of genetic variation.
    Nucleic Acids Res. 2001 Jan 1;29(1):308-11 PMID: 11125122
  16. Molecular basis of inherited diseases: a structural perspective.
    Trends Genet. 2003 Sep;19(9):505-13 PMID: 12957544
  17. Promoter SNPs in G1/S checkpoint regulators and their impact on the susceptibility to childhood leukemia.
    Blood. 2007 Jan 15;109(2):683-92 PMID: 17008550
  18. MINT: the Molecular INTeraction database.
    Nucleic Acids Res. 2007 Jan;35(Database issue):D572-4 PMID: 17135203
  19. MutaGeneSys: estimating individual disease susceptibility based on genome-wide SNP array data.
    Bioinformatics. 2008 Feb 1;24(3):440-2 PMID: 18048395
  20. An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis.
    Nat Genet. 2003 Dec;35(4):341-8 PMID: 14608356
  21. The RCSB Protein Data Bank: a redesigned query system and relational database based on the mmCIF schema.
    Nucleic Acids Res. 2005 Jan 1;33(Database issue):D233-7 PMID: 15608185
  22. Large-scale evaluation of candidate genes identifies associations between VEGF polymorphisms and bladder cancer risk.
    PLoS Genet. 2007 Feb 23;3(2):e29 PMID: 17319747
  23. Systematic identification and analysis of exonic splicing silencers.
    Cell. 2004 Dec 17;119(6):831-45 PMID: 15607979
  24. Evaluation of resequencing on number of tag SNPs of 13 atherosclerosis-related genes in Thai population.
    J Hum Genet. 2008;53(1):74-86 PMID: 18043865
  25. RASMOL: biomolecular graphics for all.
    Trends Biochem Sci. 1995 Sep;20(9):374 PMID: 7482707
  26. SNPs, protein structure, and disease.
    Hum Mutat. 2001 Apr;17(4):263-70 PMID: 11295823
  27. F-SNP: computationally predicted functional SNPs for disease association studies.
    Nucleic Acids Res. 2008 Jan;36(Database issue):D820-4 PMID: 17986460
  28. Finding local community structure in networks.
    Phys Rev E Stat Nonlin Soft Matter Phys. 2005 Aug;72(2 Pt 2):026132 PMID: 16196669
  29. Association analyses of GIP and GIPR polymorphisms with traits of the metabolic syndrome.
    Mol Nutr Food Res. 2007 Aug;51(8):1046-52 PMID: 17624916
  30. Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium.
    Am J Hum Genet. 2004 Jan;74(1):106-20 PMID: 14681826
  31. The Protein Mutant Database.
    Nucleic Acids Res. 1999 Jan 1;27(1):355-7 PMID: 9847227
  32. SCOP: a Structural Classification of Proteins database.
    Nucleic Acids Res. 1999 Jan 1;27(1):254-6 PMID: 9847194
  33. SNPeffect v2.0: a new step in investigating the molecular phenotypic effects of human non-synonymous SNPs.
    Bioinformatics. 2006 Sep 1;22(17):2183-5 PMID: 16809394
  34. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.
    Nat Genet. 2000 May;25(1):25-9 PMID: 10802651
  35. The Universal Protein Resource (UniProt): an expanding universe of protein information.
    Nucleic Acids Res. 2006 Jan 1;34(Database issue):D187-91 PMID: 16381842
  36. PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia.
    Schizophr Res. 2008 Apr;101(1-3):36-49 PMID: 18394866
  37. Polymorphisms in MGMT and DNA repair genes and the risk of esophageal adenocarcinoma.
    Int J Cancer. 2008 Jul 1;123(1):174-80 PMID: 18386788
  38. SNP Function Portal: a web database for exploring the function implication of SNP alleles.
    Bioinformatics. 2006 Jul 15;22(14):e523-9 PMID: 16873516
  39. The Jalview Java alignment editor.
    Bioinformatics. 2004 Feb 12;20(3):426-7 PMID: 14960472
  40. Evidence of an association between the vasopressin V1b receptor gene (AVPR1B) and childhood-onset mood disorders.
    Arch Gen Psychiatry. 2007 Oct;64(10):1189-95 PMID: 17909131
  41. Natriuretic peptide precursor a gene polymorphisms and risk of blood pressure progression and incident hypertension.
    Hypertension. 2007 Dec;50(6):1114-9 PMID: 17984371
  42. Human non-synonymous SNPs: server and survey.
    Nucleic Acids Res. 2002 Sep 1;30(17):3894-900 PMID: 12202775
  43. Correlating observed odds ratios from lung cancer case-control studies to SNP functional scores predicted by bioinformatic tools.
    Mutat Res. 2008 Mar 1;639(1-2):80-8 PMID: 18191955
  44. Mutation analysis and characterization of HSD17B2 sequence variants in breast cancer cases from French Canadian families with high risk of breast and ovarian cancer.
    J Mol Endocrinol. 2008 Apr;40(4):161-72 PMID: 18372405
  45. Complete mutagenesis of the HIV-1 protease.
    Nature. 1989 Aug 3;340(6232):397-400 PMID: 2666861
  46. Systematic mutation of bacteriophage T4 lysozyme.
    J Mol Biol. 1991 Nov 5;222(1):67-88 PMID: 1942069
  47. The Swiss-Prot variant page and the ModSNP database: a resource for sequence and structure information on human protein variants.
    Hum Mutat. 2004 May;23(5):464-70 PMID: 15108278
  48. Bioinformatics approaches and resources for single nucleotide polymorphism functional analysis.
    Brief Bioinform. 2005 Mar;6(1):44-56 PMID: 15826356
  49. SNAP: predict effect of non-synonymous polymorphisms on function.
    Nucleic Acids Res. 2007;35(11):3823-35 PMID: 17526529
  50. CYP24 splicing variants are associated with different patterns of constitutive and calcitriol-inducible CYP24 activity in human prostate cancer cell lines.
    J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):334-7 PMID: 17368180
  51. SNPselector: a web tool for selecting SNPs for genetic association studies.
    Bioinformatics. 2005 Nov 15;21(22):4181-6 PMID: 16179360
  52. Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders.
    Nucleic Acids Res. 2005 Jan 1;33(Database issue):D514-7 PMID: 15608251
  53. Characterization of single-nucleotide polymorphisms in coding regions of human genes.
    Nat Genet. 1999 Jul;22(3):231-8 PMID: 10391209
  54. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene.
    Am J Hum Genet. 2008 Apr;82(4):809-21 PMID: 18313022
  55. KEGG Atlas mapping for global analysis of metabolic pathways.
    Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W423-6 PMID: 18477636
  56. Genetic variation in adiponectin receptor 1 and adiponectin receptor 2 is associated with type 2 diabetes in the Old Order Amish.
    Diabetes. 2005 Jul;54(7):2245-50 PMID: 15983228
  57. The UCSC genome browser database: update 2007.
    Nucleic Acids Res. 2007 Jan;35(Database issue):D668-73 PMID: 17142222
  58. Screening of functional and positional candidate genes in families with common variable immunodeficiency.
    BMC Immunol. 2008 Feb 07;9:3 PMID: 18254984
  59. PSIC: profile extraction from sequence alignments with position-specific counts of independent observations.
    Protein Eng. 1999 May;12(5):387-94 PMID: 10360979
  60. Seizure 6-like (SEZ6L) gene and risk for lung cancer.
    Cancer Res. 2007 Sep 1;67(17):8406-11 PMID: 17804757
  61. Predicting the effects of amino acid substitutions on protein function.
    Annu Rev Genomics Hum Genet. 2006;7:61-80 PMID: 16824020
  62. SNP500Cancer: a public resource for sequence validation, assay development, and frequency analysis for genetic variation in candidate genes.
    Nucleic Acids Res. 2006 Jan 1;34(Database issue):D617-21 PMID: 16381944
  63. What is a support vector machine?
    Nat Biotechnol. 2006 Dec;24(12):1565-7 PMID: 17160063
  64. Predicting the insurgence of human genetic diseases associated to single point protein mutations with support vector machines and evolutionary information.
    Bioinformatics. 2006 Nov 15;22(22):2729-34 PMID: 16895930
  65. STAT3 mutations in the hyper-IgE syndrome.
    N Engl J Med. 2007 Oct 18;357(16):1608-19 PMID: 17881745
  66. Genetic variation including nonsynonymous polymorphisms of a major aggrecanase, ADAMTS-5, in susceptibility to osteoarthritis.
    Arthritis Rheum. 2008 Feb;58(2):435-41 PMID: 18240210
  67. Understanding the molecular machinery of genetics through 3D structures.
    Nat Rev Genet. 2008 Feb;9(2):141-51 PMID: 18160966
  68. SNPs3D: candidate gene and SNP selection for association studies.
    BMC Bioinformatics. 2006 Mar 22;7:166 PMID: 16551372
  69. Snap: an integrated SNP annotation platform.
    Nucleic Acids Res. 2007 Jan;35(Database issue):D707-10 PMID: 17135198
  70. Common variants in glutamine:fructose-6-phosphate amidotransferase 2 (GFPT2) gene are associated with type 2 diabetes, diabetic nephropathy, and increased GFPT2 mRNA levels.
    J Clin Endocrinol Metab. 2004 Feb;89(2):748-55 PMID: 14764791
  71. Predicting deleterious amino acid substitutions.
    Genome Res. 2001 May;11(5):863-74 PMID: 11337480
  72. Repair and recombination induced by triple helix DNA.
    Front Biosci. 2007 May 01;12:4288-97 PMID: 17485375
  73. LS-SNP: large-scale annotation of coding non-synonymous SNPs based on multiple information sources.
    Bioinformatics. 2005 Jun 15;21(12):2814-20 PMID: 15827081
  74. Interleukin-13 genetic polymorphisms in Singapore Chinese children correlate with long-term outcome of minimal-change disease.
    Nephrol Dial Transplant. 2005 Apr;20(4):728-34 PMID: 15728267
  75. FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization.
    Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W635-41 PMID: 16845089
  76. PANTHER version 6: protein sequence and function evolution data with expanded representation of biological pathways.
    Nucleic Acids Res. 2007 Jan;35(Database issue):D247-52 PMID: 17130144
  77. Accurate prediction of enzyme mutant activity based on a multibody statistical potential.
    Bioinformatics. 2007 Dec 1;23(23):3155-61 PMID: 17977887
  78. Characterization of novel mutations in the catalytic domain of the PCSK9 gene.
    J Intern Med. 2008 Apr;263(4):420-31 PMID: 18266662
  79. Polymorphisms in the CD3Z gene influence TCRzeta expression in systemic lupus erythematosus patients and healthy controls.
    J Immunol. 2008 Jan 15;180(2):1060-70 PMID: 18178846
  80. Molecular heterogeneity in fetal forms of type II lissencephaly.
    Hum Mutat. 2007 Oct;28(10):1020-7 PMID: 17559086
  81. Genetic studies of the lac repressor. XIV. Analysis of 4000 altered Escherichia coli lac repressors reveals essential and non-essential residues, as well as "spacers" which do not require a specific sequence.
    J Mol Biol. 1994 Jul 29;240(5):421-33 PMID: 8046748
  82. Variation in the miRNA-433 binding site of FGF20 confers risk for Parkinson disease by overexpression of alpha-synuclein.
    Am J Hum Genet. 2008 Feb;82(2):283-9 PMID: 18252210
  83. Predicting the functional consequences of non-synonymous single nucleotide polymorphisms: structure-based assessment of amino acid variation.
    J Mol Biol. 2001 Mar 23;307(2):683-706 PMID: 11254390
  84. Nucleotide-excision repair and prostate cancer risk.
    Cancer Lett. 2005 Apr 8;220(2):125-35 PMID: 15766587
  85. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis.
    Lancet Neurol. 2008 May;7(5):409-16 PMID: 18396105
  86. Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory.
    Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20552-7 PMID: 18077373
  87. nsSNPAnalyzer: identifying disease-associated nonsynonymous single nucleotide polymorphisms.
    Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W480-2 PMID: 15980516
Article Info
Journal
Briefings in bioinformatics
Abbr.
Brief Bioinform
ISSN
1477-4054
DOI
10.1093/bib/bbn047
Email
[email protected]
Published
2009-01-00
Pages
35-52
Language
English
Region
England
NLM ID
100912837
PMCID
PMC2638621
Subset
IM
External Links
PubMed source DOI: 10.1093/bib/bbn047 PMC Full Text View journal details
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