Abstract
Mutation position imaging toolbox (MuPIT) interactive is a browser-based application for single-nucleotide variants (SNVs), which automatically maps the genomic coordinates of SNVs onto the coordinates of available three-dimensional (3D) protein structures. The application is designed for interactive browser-based visualization of the putative functional relevance of SNVs by biologists who are not necessarily experts either in bioinformatics or protein structure. Users may submit batches of several thousand SNVs and review all protein structures that cover the SNVs, including available functional annotations such as binding sites, mutagenesis experiments, and common polymorphisms. Multiple SNVs may be mapped onto each structure, enabling 3D visualization of SNV clusters and their relationship to functionally annotated positions. We illustrate the utility of MuPIT interactive in rationalizing the impact of selected polymorphisms in the PharmGKB database, somatic mutations identified in the Cancer Genome Atlas study of invasive breast carcinomas, and rare variants identified in the exome sequencing project. MuPIT interactive is freely available for non-profit use at http://mupit.icm.jhu.edu.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249
Aertgeerts K, Skene R, Yano J, Sang BC, Zou H, Snell G, Jennings A, Iwamoto K, Habuka N, Hirokawa A, Ishikawa T, Tanaka T, Miki H, Ohta Y, Sogabe S (2011) Structural analysis of the mechanism of inhibition and allosteric activation of the kinase domain of HER2 protein. J Biol chem 286:18756–18765
Bartek J, Lukas J (2003) Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 3:421–429
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The protein data bank. Nucleic Acids Res 28:235–242
Booton R, Ward T, Heighway J, Ashcroft L, Morris J, Thatcher N (2006) Glutathione-S-transferase P1 isoenzyme polymorphisms, platinum-based chemotherapy, and non-small cell lung cancer. J Thorac Oncol: Off Publ Int Assoc Study Lung Cancer 1:679–683
Bromberg Y, Rost B (2007) SNAP: predict effect of non-synonymous polymorphisms on function. Nucleic Acids Res 35:3823–3835
Cancer Genome Atlas N (2012) Comprehensive molecular portraits of human breast tumours. Nature 490:61–70
Carter H, Chen S, Isik L, Tyekucheva S, Velculescu VE, Kinzler KW, Vogelstein B, Karchin R (2009) Cancer-specific high-throughput annotation of somatic mutations: computational prediction of driver missense mutations. Cancer Res 69:6660–6667
Carter H, Douville C, Stenson PD, Cooper DN, Karchin R (2013) Identifying Mendelian disease genes with the variant effect scoring tool. BMC genomics 14(3):1−16
Lage H, Denkert C (2007) Resistance to chemotherapy in ovarian carcinoma. In: Dietel M (ed) Targeted therapies in cancer. Recent results in cancer research, vol 176. Springer Berlin Heidelberg, pp 51–60. doi:10.1007/978-3-540-46091-6_6
Douville C, Carter H, Kim R, Niknafs N, Diekhans M, Stenson PD, Cooper DN, Ryan M, Karchin R (2013) CRAVAT: cancer-related analysis of variants toolkit. Bioinformatics 29:647–648
Ellis MJ, Ding L, Shen D, Luo J, Suman VJ, Wallis JW, Van Tine BA, Hoog J, Goiffon RJ, Goldstein TC, Ng S, Lin L, Crowder R, Snider J, Ballman K, Weber J, Chen K, Koboldt DC, Kandoth C, Schierding WS, McMichael JF, Miller CA, Lu C, Harris CC, McLellan MD, Wendl MC, DeSchryver K, Allred DC, Esserman L, Unzeitig G, Margenthaler J, Babiera GV, Marcom PK, Guenther JM, Leitch M, Hunt K, Olson J, Tao Y, Maher CA, Fulton LL, Fulton RS, Harrison M, Oberkfell B, Du F, Demeter R, Vickery TL, Elhammali A, Piwnica-Worms H, McDonald S, Watson M, Dooling DJ, Ota D, Chang LW, Bose R, Ley TJ, Piwnica-Worms D, Stuart JM, Wilson RK, Mardis ER (2012) Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature 486:353–360
Ferrer-Costa C, Gelpi JL, Zamakola L, Parraga I, de la Cruz X, Orozco M (2005) PMUT: a web-based tool for the annotation of pathological mutations on proteins. Bioinformatics 21:3176–3178
Futreal PA, Coin L, Marshall M, Down T, Hubbard T, Wooster R, Rahman N, Stratton MR (2004) A census of human cancer genes. Nat Rev Cancer 4:177–183
Garcia-Closas M, Malats N, Silverman D, Dosemeci M, Kogevinas M, Hein DW, Tardon A, Serra C, Carrato A, Garcia-Closas R, Lloreta J, Castano-Vinyals G, Yeager M, Welch R, Chanock S, Chatterjee N, Wacholder S, Samanic C, Tora M, Fernandez F, Real FX, Rothman N (2005) NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish bladder cancer study and meta-analyses. Lancet 366:649–659
Gertz EM, Yu YK, Agarwala R, Schaffer AA, Altschul SF (2006) Composition-based statistics and translated nucleotide searches: improving the TBLASTN module of BLAST. BMC Biol 4:41
Harmar AJ, Hills RA, Rosser EM, Jones M, Buneman OP, Dunbar DR, Greenhill SD, Hale VA, Sharman JL, Bonner TI, Catterall WA, Davenport AP, Delagrange P, Dollery CT, Foord SM, Gutman GA, Laudet V, Neubig RR, Ohlstein EH, Olsen RW, Peters J, Pin JP, Ruffolo RR, Searls DB, Wright MW, Spedding M (2009) IUPHAR-DB: the IUPHAR database of G protein-coupled receptors and ion channels. Nucleic Acids Res 37:D680–D685
Howard M (2013) Jmol: an open-source Java viewer for chemical structures in 3D. http://www.jmol.org/
Karchin R, Monteiro AN, Tavtigian SV, Carvalho MA, Sali A (2007) Functional impact of missense variants in BRCA1 predicted by supervised learning. PLoS Comput Biol 3:e26
Kent WJ (2002) BLAT–the BLAST-like alignment tool. Genome Res 12:656–664
Kim HS, Kim MK, Chung HH, Kim JW, Park NH, Song YS, Kang SB (2009) Genetic polymorphisms affecting clinical outcomes in epithelial ovarian cancer patients treated with taxanes and platinum compounds: a Korean population-based study. Gynecol Oncol 113:264–269
Liu S, Shen T, Huynh L, Klisovic MI, Rush LJ, Ford JL, Yu J, Becknell B, Li Y, Liu C, Vukosavljevic T, Whitman SP, Chang KS, Byrd JC, Perrotti D, Plass C, Marcucci G (2005) Interplay of RUNX1/MTG8 and DNA methyltransferase 1 in acute myeloid leukemia. Cancer Res 65:1277–1284
Marcus PM, Vineis P, Rothman N (2000) NAT2 slow acetylation and bladder cancer risk: a meta-analysis of 22 case-control studies conducted in the general population. Pharmacogenetics 10:115–122
McDonagh EM, Whirl-Carrillo M, Garten Y, Altman RB, Klein TE (2011) From pharmacogenomic knowledge acquisition to clinical applications: the PharmGKB as a clinical pharmacogenomic biomarker resource. Biomark Med 5:795–806
Mi H, Lazareva-Ulitsky B, Loo R, Kejariwal A, Vandergriff J, Rabkin S, Guo N, Muruganujan A, Doremieux O, Campbell MJ, Kitano H, Thomas PD (2005) The PANTHER database of protein families, subfamilies, functions and pathways. Nucleic Acids Res 33:D284–D288
Morita S, Yano M, Tsujinaka T, Ogawa A, Taniguchi M, Kaneko K, Shiozaki H, Doki Y, Inoue M, Monden M (1998) Association between genetic polymorphisms of glutathione S-transferase P1 and N-acetyltransferase 2 and susceptibility to squamous-cell carcinoma of the esophagus. Int J Cancer 79:517–520
Ng PC, Henikoff S (2003) SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 31:3812–3814
Oakley AJ, Rossjohn J, Lo Bello M, Caccuri AM, Federici G, Parker MW (1997) The three-dimensional structure of the human Pi class glutathione transferase P1–1 in complex with the inhibitor ethacrynic acid and its glutathione conjugate. Biochemistry 36:576–585
Oliver AW, Paul A, Boxall KJ, Barrie SE, Aherne GW, Garrett MD, Mittnacht S, Pearl LH (2006) Trans-activation of the DNA-damage signalling protein kinase Chk2 by T-loop exchange. EMBO J 25:3179–3190
Reva B, Antipin Y, Sander C (2011) Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res 39:e118
Ruzzo A, Graziano F, Loupakis F, Rulli E, Canestrari E, Santini D, Catalano V, Ficarelli R, Maltese P, Bisonni R, Masi G, Schiavon G, Giordani P, Giustini L, Falcone A, Tonini G, Silva R, Mattioli R, Floriani I, Magnani M (2007) Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy. J Clin Oncol: Off J Am Soc Clin Oncol 25:1247–1254
Ryan M, Diekhans M, Lien S, Liu Y, Karchin R (2009) LS-SNP/PDB: annotated non-synonymous SNPs mapped to Protein Data Bank structures. Bioinformatics 25:1431–1432
Schwarz JM, Rodelsperger C, Schuelke M, Seelow D (2010) MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7:575–576
Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K (2001) dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 29:308–311
Shimamura T, Shiroishi M, Weyand S, Tsujimoto H, Winter G, Katritch V, Abagyan R, Cherezov V, Liu W, Han GW, Kobayashi T, Stevens RC, Iwata S (2011) Structure of the human histamine H1 receptor complex with doxepin. Nature 475:65–70
Sillanpaa P, Hirvonen A, Kataja V, Eskelinen M, Kosma VM, Uusitupa M, Vainio H, Mitrunen K (2005) NAT2 slow acetylator genotype as an important modifier of breast cancer risk. Int J Cancer 114:579–584
Singh A, Olowoyeye A, Baenziger PH, Dantzer J, Kann MG, Radivojac P, Heiland R, Mooney SD (2008) MutDB: update on development of tools for the biochemical analysis of genetic variation. Nucleic Acids Res 36:D815–D819
Stoehlmacher J, Park DJ, Zhang W, Yang D, Groshen S, Zahedy S, Lenz HJ (2004) A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer. Br J Cancer 91:344–354
Sunyaev S, Ramensky V, Koch I, Lathe W 3rd, Kondrashov AS, Bork P (2001) Prediction of deleterious human alleles. Hum Mol Genet 10:591–597
UniProt C (2012) Reorganizing the protein space at the universal protein resource (UniProt). Nucleic Acids Res 40:D71–D75
van der Hel OL, Peeters PH, Hein DW, Doll MA, Grobbee DE, Kromhout D, Bueno de Mesquita HB (2003) NAT2 slow acetylation and GSTM1 null genotypes may increase postmenopausal breast cancer risk in long-term smoking women. Pharmacogenetics 13:399–407
Wang C, Chung BC, Yan H, Lee SY, Pitt GS (2012) Crystal structure of the ternary complex of a NaV C-terminal domain, a fibroblast growth factor homologous factor, and calmodulin. Structure 20:1167–1176
Weber WW (1987) The acetylator genes and drug response. Oxford University Press, New York
Yue P, Melamud E, Moult J (2006) SNPs3D: candidate gene and SNP selection for association studies. BMC Bioinformatics 7:166
Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D, Easton J, Chen X, Wang J, Rusch M, Lu C, Chen SC, Wei L, Collins-Underwood JR, Ma J, Roberts KG, Pounds SB, Ulyanov A, Becksfort J, Gupta P, Huether R, Kriwacki RW, Parker M, McGoldrick DJ, Zhao D, Alford D, Espy S, Bobba KC, Song G, Pei D, Cheng C, Roberts S, Barbato MI, Campana D, Coustan-Smith E, Shurtleff SA, Raimondi SC, Kleppe M, Cools J, Shimano KA, Hermiston ML, Doulatov S, Eppert K, Laurenti E, Notta F, Dick JE, Basso G, Hunger SP, Loh ML, Devidas M, Wood B, Winter S, Dunsmore KP, Fulton RS, Fulton LL, Hong X, Harris CC, Dooling DJ, Ochoa K, Johnson KJ, Obenauer JC, Evans WE, Pui CH, Naeve CW, Ley TJ, Mardis ER, Wilson RK, Downing JR, Mullighan CG (2012) The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481:157–163
Acknowledgments
We used the Broad Institute Firehose standardization run from 7 July, 2012, which may be found here in the TCGA Data Coordination Center: http://gdac.broadinstitute.org/runs/stddata__2012_07_07/data/BRCA/20120707/gdac.broadinstitute.org_BRCA.Mutation_Packager_Calls.Level_3.2012070700.0.0.tar.gz.
National Institutes of Health CA152432, 3U24CA143858-2S1, National Science Foundation DBI 0845275.
Conflict of interest
None declared.
Author information
Authors and Affiliations
Corresponding author
Additional information
N. Niknafs and D. Kim these authors contributed equally.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Supplementary Figure Captions
Suppl. Fig. 1. N-acetyltransferase 2 in complex with coenzyme A (coA). PharmGKB polymorphic variant associated with the slow acetylator phenotype and increased risk for several cancers and drug toxicity, is adjacent to the coenzyme A binding site. Acetylation of carcinogens and other toxic substrates requires transfer of an acetyl group from acetyl coA. The variant potentially interferes with coA binding. Variant positions appear as green balls.
Supp Fig 2. Receptor tyrosine-protein kinase erbB-2. Four TCGA breast cancer somatic mutations mapped onto the PDB structure 3pp0 (Aertgeerts et al. 2011). One of the mutations lies adjacent to the ATP binding site (pink), whereas another is adjacent to the active site (blue). Variant positions appear as green balls.
Supp Fig 3. Checkpoint kinase-2 in complex with ADP. A single TCGA breast cancer somatic mutation mapped onto the PDB structure 2cn5 (Oliver et al. 2006). CHEK2 is a known breast cancer susceptibility gene. The mutation depicted is directly adjacent to the active site. Variant positions appear as green balls.
Appendix: server-side implementation details
Appendix: server-side implementation details
MuPIT is a Java servlet, accessible to users via a web browser equipped with the Java plugin. The servlet encapsulates a series of Django applications: A Jmol applet for PDB visualization, a database (DB) interfacer, and an overview page constructor (Howard 2013). Javascript functions are used to allow for user interactions between the overview tables and the 3D visualization.
The MuPIT servlet runs on a Dell PowerEdge C1100 server, with four six-core Intel Xeon E5645 2.4 GHz cpus (24 cores total), and 96 GB of RAM.
Rights and permissions
About this article
Cite this article
Niknafs, N., Kim, D., Kim, R. et al. MuPIT interactive: webserver for mapping variant positions to annotated, interactive 3D structures. Hum Genet 132, 1235–1243 (2013). https://doi.org/10.1007/s00439-013-1325-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-013-1325-0