{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,8,3]],"date-time":"2024-08-03T16:56:09Z","timestamp":1722704169013},"reference-count":50,"publisher":"Springer Science and Business Media LLC","issue":"S8","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Bioinformatics"],"published-print":{"date-parts":[[2009,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>The reaction of HIV protease to inhibitor therapy is characterized by the emergence of complex mutational patterns which confer drug resistance. The response of HIV protease to drugs often involves both primary mutations that directly inhibit the action of the drug, and a host of accessory resistance mutations that may occur far from the active site but may contribute to restoring the fitness or stability of the enzyme. Here we develop a probabilistic approach based on connected information that allows us to study residue, pair level and higher-order correlations within the same framework.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We apply our methodology to a database of approximately 13,000 sequences which have been annotated by the treatment history of the patients from which the samples were obtained. We show that including pair interactions is essential for agreement with the mutational data, since neglect of these interactions results in order-of-magnitude errors in the probabilities of the simultaneous occurence of many mutations. The magnitude of these pair correlations changes dramatically between sequences obtained from patients that were or were not exposed to drugs. Higher-order effects make a contribution of as much as 10% for residues taken three at a time, but increase to more than twice that for 10 to 15-residue groups. The sequence data is insufficient to determine the higher-order effects for larger groups. We find that higher-order interactions have a significant effect on the predicted frequencies of sequences with large numbers of mutations. While relatively rare, such sequences are more prevalent after multi-drug therapy. The relative importance of these higher-order interactions increases with the number of drugs the patient had been exposed to.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>Correlations are critical for the understanding of mutation patterns in HIV protease. Pair interactions have substantial qualitative effects, while higher-order interactions are individually smaller but may have a collective effect. Together they lead to correlations which could have an important impact on the dynamics of the evolution of cross-resistance, by allowing the virus to pass through otherwise unlikely mutational states. These findings also indicate that pairwise and possibly higher-order effects should be included in the models of protein evolution, instead of assuming that all residues mutate independently of one another.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2105-10-s8-s10","type":"journal-article","created":{"date-parts":[[2009,8,27]],"date-time":"2009-08-27T18:14:03Z","timestamp":1251396843000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Pairwise and higher-order correlations among drug-resistance mutations in HIV-1 subtype B protease"],"prefix":"10.1186","volume":"10","author":[{"given":"Omar","family":"Haq","sequence":"first","affiliation":[]},{"given":"Ronald M","family":"Levy","sequence":"additional","affiliation":[]},{"given":"Alexandre V","family":"Morozov","sequence":"additional","affiliation":[]},{"given":"Michael","family":"Andrec","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2009,8,27]]},"reference":[{"key":"3350_CR1","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/S0163-7258(00)00037-1","volume":"86","author":"R Swanstrom","year":"2000","unstructured":"Swanstrom R, Erona J: Human immunodeficiency virus type-1 protease inhibitors: Thereputic successes and failures, suppression and resistance. Pharmacol Ther 2000, 86: 145\u2013170. 10.1016\/S0163-7258(00)00037-1","journal-title":"Pharmacol Ther"},{"key":"3350_CR2","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1038\/nrg1246","volume":"5","author":"A Rambaut","year":"2004","unstructured":"Rambaut A, Posada D, Crandall KA, Holmes EC: The causes and consequences of HIV evolution. Nat Rev Genet 2004, 5: 52\u201361. 10.1038\/nrg1246","journal-title":"Nat Rev Genet"},{"key":"3350_CR3","doi-asserted-by":"publisher","first-page":"4836","DOI":"10.1128\/JVI.77.8.4836-4847.2003","volume":"77","author":"TD Wu","year":"2003","unstructured":"Wu TD, Schiffer CA, Gonzales MJ, Taylor J, Kantor R, Chou S, Israelski D, Zolopa AR, Fessel WJ, Shafer RW: Mutation patterns and structural correlates in human immunodeficiency virus type 1 protease following different protease inhibitor treatments. J Virol 2003, 77: 4836\u20134847. 10.1128\/JVI.77.8.4836-4847.2003","journal-title":"J Virol"},{"key":"3350_CR4","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1016\/S0042-6822(03)00484-7","volume":"314","author":"NG Hoffman","year":"2003","unstructured":"Hoffman NG, Schiffer CA, Swanstrom R: Covariation of amino acid positions in HIV-1 protease. Virology 2003, 314: 536\u2013548. 10.1016\/S0042-6822(03)00484-7","journal-title":"Virology"},{"key":"3350_CR5","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/1745-6150-1-14","volume":"1","author":"L Chen","year":"2006","unstructured":"Chen L, Lee C: Distinguishing HIV-1 drug resistance, accessory, and viral fitness mutations using conditional selection pressure analysis of treated versus untreated patient samples. Biology Direct 2006, 1: 14. 10.1186\/1745-6150-1-14","journal-title":"Biology Direct"},{"key":"3350_CR6","doi-asserted-by":"publisher","first-page":"e87","DOI":"10.1371\/journal.pcbi.0030087","volume":"3","author":"SY Rhee","year":"2007","unstructured":"Rhee SY, Liu TF, Holms SP, Shafer RW: HIV-1 subtype B protease and reverse transcriptase amino acid covariation. PLoS Comput Biol 2007, 3: e87. 10.1371\/journal.pcbi.0030087","journal-title":"PLoS Comput Biol"},{"key":"3350_CR7","doi-asserted-by":"publisher","first-page":"e814","DOI":"10.1371\/journal.pone.0000814","volume":"2","author":"Q Wang","year":"2007","unstructured":"Wang Q, Lee C: Distinguishing functional amino acid covariation from background linkage disequilibrium in HIV protease and reverse transcriptase. PLoS ONE 2007, 2: e814. 10.1371\/journal.pone.0000814","journal-title":"PLoS ONE"},{"key":"3350_CR8","doi-asserted-by":"publisher","first-page":"2975","DOI":"10.1093\/bioinformatics\/btl508","volume":"22","author":"K Deforche","year":"2006","unstructured":"Deforche K, Silander T, Camacho R, Grossman Z, Soares MA, Van Laethem K, Kantor R, Moreau Y, Vandamme A-M: Analysis of the HIV-1 pol sequences using Bayesian Networks: implications for drug resistance. Bioinformatics 2006, 22: 2975\u20132979. 10.1093\/bioinformatics\/btl508","journal-title":"Bioinformatics"},{"key":"3350_CR9","doi-asserted-by":"publisher","first-page":"2015","DOI":"10.1128\/AAC.49.5.2015-2025.2005","volume":"49","author":"V Svicher","year":"2005","unstructured":"Svicher V, Ceccherini-Silberstein F, Erba F, Santoro M, Gori C, Bellocchi MC, Gianella S, Trotta MP, Monforte A, Antinori A, Perno CF: Novel human immunodeficiency virus type 1 protease mutations potentially involved in resistance to protease inhibitors. Antimicrob Agents Chemother 2005, 49: 2015\u20132025. 10.1128\/AAC.49.5.2015-2025.2005","journal-title":"Antimicrob Agents Chemother"},{"key":"3350_CR10","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1093\/bioinformatics\/btn110","volume":"24","author":"Y Liu","year":"2008","unstructured":"Liu Y, Eyal E, Bahar I: Analysis of correlated mutations in HIV-1 protease using spectral clustering. Bioinformatics 2008, 24: 1243\u20131250. 10.1093\/bioinformatics\/btn110","journal-title":"Bioinformatics"},{"key":"3350_CR11","volume-title":"Discrete Multivariate Analysis: Theory and Practice","author":"YM Bishop","year":"1975","unstructured":"Bishop YM, Fienberg SE, Holland PW: Discrete Multivariate Analysis: Theory and Practice. The MIT Press; 1975."},{"key":"3350_CR12","doi-asserted-by":"publisher","first-page":"238701","DOI":"10.1103\/PhysRevLett.91.238701","volume":"91","author":"E Schneidman","year":"2003","unstructured":"Schneidman E, Still S, Berry MJ II, Bialek W: Network information and connected correlations. Phys Rev Lett 2003, 91: 238701. 10.1103\/PhysRevLett.91.238701","journal-title":"Phys Rev Lett"},{"key":"3350_CR13","volume-title":"Probabilistic Reasoning in Intelligent Systems: Networks of Plausible Inference","author":"J Pearl","year":"1988","unstructured":"Pearl J: Probabilistic Reasoning in Intelligent Systems: Networks of Plausible Inference. Morgan Kaufmann Publishers; 1988."},{"key":"3350_CR14","doi-asserted-by":"publisher","first-page":"3227","DOI":"10.1016\/j.jspi.2007.03.007","volume":"137","author":"C Ahn","year":"2007","unstructured":"Ahn C, Koch GG, Paynter L, Preisser JS, Seillier-Moiseiwitsch F: Log-linear models for mutations in the HIV genome. J Stat Plan Inf 2007, 137: 3227\u20133239. 10.1016\/j.jspi.2007.03.007","journal-title":"J Stat Plan Inf"},{"key":"3350_CR15","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1073\/pnas.0805923106","volume":"106","author":"M Weigt","year":"2009","unstructured":"Weigt M, White RA, Szurmant H, Hoch JA, Hwa T: Identification of direct residue contacts in protein-protein interaction by message passing. Proc Natl Acad Sci USA 2009, 106: 67\u201372. 10.1073\/pnas.0805923106","journal-title":"Proc Natl Acad Sci USA"},{"key":"3350_CR16","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1093\/nar\/gkg100","volume":"31","author":"R Kantor","year":"2003","unstructured":"Kantor R, Betts BJ, Ravela J, Rhee SY, Gonzales MJ, Shafer RW: Human immunodeficiency virus reverse transcriptase and protease sequence database. Nucleic Acids Res 2003, 31: 298\u2013303. 10.1093\/nar\/gkg100","journal-title":"Nucleic Acids Res"},{"key":"3350_CR17","first-page":"138","volume":"16","author":"VA Johnson","year":"2008","unstructured":"Johnson VA, Brun-V\u00e9zinet F, Clotet B, G\u00fcnthard HF, Kuritzkes DR, Pillay D, Schapiro JM, Richman DD: Update of the drug resistance mutations in HIV-1: December 2008. Topics in HIV Medicine 2008, 16: 138\u2013145.","journal-title":"Topics in HIV Medicine"},{"key":"3350_CR18","doi-asserted-by":"publisher","first-page":"15029","DOI":"10.1021\/bi035701y","volume":"42","author":"JC Clemente","year":"2003","unstructured":"Clemente JC, Hemrajani R, Blum LE, Goodenow MM, Dunn BM: Secondary mutations M36I and A71V in the human immunodeficiency virus type 1 protease can provide an advantage of the emergence of the primary mutation D30N. Biochemistry 2003, 42: 15029\u201315035. 10.1021\/bi035701y","journal-title":"Biochemistry"},{"key":"3350_CR19","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1021\/bi027019u","volume":"42","author":"S Muzammil","year":"2003","unstructured":"Muzammil S, Ross P, Freire E: A major role for a set of non-active site mutations in the development of HIV-1 protease drug resistance. Biochemistry 2003, 42: 631\u2013638. 10.1021\/bi027019u","journal-title":"Biochemistry"},{"key":"3350_CR20","first-page":"1","volume-title":"Human retroviruses and AIDS, theoretical biology and biophysics","author":"RW Shafer","year":"2001","unstructured":"Shafer RW, Dupnik K, Winters MA, Eshleman SH: A guide to HIV-1 reverse transcriptase and protease sequencing for drug resistance studies. In Human retroviruses and AIDS, theoretical biology and biophysics. Los Alamos, NM: Los Alamos National Laboratories; 2001:1\u201351."},{"key":"3350_CR21","doi-asserted-by":"publisher","first-page":"17355","DOI":"10.1073\/pnas.0607274103","volume":"103","author":"SY Rhee","year":"2006","unstructured":"Rhee SY, Taylor J, Wadhera G, Ben-Hur A, Brutlag DL, Shafer RW: Genotypic predictors of human immunodeficiency virus type 1 drug resistance. Proc Natl Acad Sci USA 2006, 103: 17355\u201317360. 10.1073\/pnas.0607274103","journal-title":"Proc Natl Acad Sci USA"},{"key":"3350_CR22","first-page":"67","volume":"10","author":"RW Shafer","year":"2008","unstructured":"Shafer RW, Schapiro JM: HIV-1 drug resistance mutations: An updated framework for the second decade of HAART. AIDS Rev 2008, 10: 67\u201384.","journal-title":"AIDS Rev"},{"key":"3350_CR23","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1097\/QAD.0b013e328011e691","volume":"21","author":"RW Shafer","year":"2007","unstructured":"Shafer RW, Rhee SY, Pillay D, Miller V, Sandstrom P, Schapiro JM, Kuritzkes DR, Bennett D: HIV-1 protease and reverse transcriptase mutations for drug resistance surveillance. AIDS 2007, 21: 215\u2013223. 10.1097\/QAD.0b013e328011e691","journal-title":"AIDS"},{"key":"3350_CR24","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1097\/00002030-200006160-00018","volume":"14","author":"K Hertogs","year":"2000","unstructured":"Hertogs K, Bloor S, Kemp SD, Van de Eynde C, Alcorn TM, Pauwels R, Van Houtte M, Staszewski S, Miller V, Larder BA: Phenotypic and genotypic analysis of clinical HIV-1 isolates reveals extensive protease inhibitor cross-resistance: A survey of over 6000 samples. AIDS 2000, 14: 1203\u20131210. 10.1097\/00002030-200006160-00018","journal-title":"AIDS"},{"key":"3350_CR25","doi-asserted-by":"publisher","first-page":"13659","DOI":"10.1021\/bi0350405","volume":"42","author":"H Ohtaka","year":"2003","unstructured":"Ohtaka H, Schon A, Freire E: Multidrug resistance to HIV-1 protease inhibition requires cooperative coupling between distal mutations. Biochemistry 2003, 42: 13659\u201313666. 10.1021\/bi0350405","journal-title":"Biochemistry"},{"key":"3350_CR26","first-page":"119","volume":"15","author":"VA A Johnson","year":"2007","unstructured":"Johnson VAA, Brun-V\u00e9zinet F, Clotet B, G\u00fcnthard HFF, Kuritzkes DRR, Pillay D, Schapiro JMM, Richman DDD: Update of the drug resistance mutations in HIV-1 2007. Topics in HIV Medicine 2007, 15: 119\u2013125.","journal-title":"Topics in HIV Medicine"},{"key":"3350_CR27","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1006\/jmbi.1998.2601","volume":"287","author":"DD Pollock","year":"1999","unstructured":"Pollock DD, Taylor WR, Goldman N: Coevolving proteing residues: Maximum likelihood indentification and relationship to structure. Journal of Molecular Biology 1999, 287: 187\u2013198. 10.1006\/jmbi.1998.2601","journal-title":"Journal of Molecular Biology"},{"key":"3350_CR28","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1093\/bioinformatics\/btg072","volume":"19","author":"ERM Tiller","year":"2003","unstructured":"Tiller ERM, Lui TWH: Using muliple interdependency to separate functional from phylogenetic correlations in protein alignments. Bioinformatics 2003, 19: 750\u2013755. 10.1093\/bioinformatics\/btg072","journal-title":"Bioinformatics"},{"key":"3350_CR29","doi-asserted-by":"publisher","first-page":"7156","DOI":"10.1021\/bi050293e","volume":"44","author":"GB Gloor","year":"2005","unstructured":"Gloor GB, Martin LC, Wahl LM, Dunn SM: Mutual information in protein multiple sequence alignments reveals two classes of coevolving positions. Biochemistry 2005, 44: 7156\u20137165. 10.1021\/bi050293e","journal-title":"Biochemistry"},{"key":"3350_CR30","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1534\/genetics.105.053249","volume":"173","author":"MA Flares","year":"2006","unstructured":"Flares MA, Travers SAA: A novel method for detecting intramolecular co-evolution: Adding a further dimension to selective constraints analyses. Genetics 2006, 173: 9\u201323. 10.1534\/genetics.105.053249","journal-title":"Genetics"},{"key":"3350_CR31","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.bpc.2005.09.010","volume":"119","author":"R Perez-Jimenez","year":"2006","unstructured":"Perez-Jimenez R, Godoy-Ruiz R, Parody-Morreale A, Ibarra-Molero B, Sanchez-Ruiz JM: A simple tool to explore the distance distribution of correlated mutations in proteins. Biophys Chem 2006, 119: 240\u2013246. 10.1016\/j.bpc.2005.09.010","journal-title":"Biophys Chem"},{"key":"3350_CR32","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1002\/prot.20098","volume":"56","author":"AA Fodor","year":"2004","unstructured":"Fodor AA, Aldrich RW: Influence of conservation on calculations of amino acid covariance in multiple sequence alignments. Proteins 2004, 56: 211\u2013221. 10.1002\/prot.20098","journal-title":"Proteins"},{"key":"3350_CR33","doi-asserted-by":"publisher","first-page":"2349","DOI":"10.1097\/00002030-199912030-00006","volume":"13","author":"M Nijhuis","year":"1999","unstructured":"Nijhuis M, Schuurman R, de Jong D, Erickson J, Gustchina E, Albert J, Schipper P, Gulnik S, Boucher CAB: Increased fitness of drug resistant HIV-1 protease as a result of acquisition of compensatory mutations during suboptimal therapy. AIDS 1999, 13: 2349\u20132359. 10.1097\/00002030-199912030-00006","journal-title":"AIDS"},{"key":"3350_CR34","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1086\/323604","volume":"184","author":"CF Perno","year":"2001","unstructured":"Perno CF, Cozzi-Lepri A, Balotta C, Forbici F, Violin M, Bertoli A, Facchi G, Pezzotti P, Cadeo G, Tositti G, Pasquinucci S, Pauluzzi S, Scalzini A, Salassa B, Vincenti A, Phillips A, Dianzani F, Appice A, Angarano G, Monno L, Ippolito G, Moroni M, Monforte A, Italian Cohort Naive Antiretroviral (I.CO.N.A.) Study Groupa: Secondary mutations in the protease region of human immunodeficiency virus and virologic failure in drug-naive patients treated with protease inhibitor-based therapy. The Journal of Infectious Diseases 2001, 184: 983\u2013991. 10.1086\/323604","journal-title":"The Journal of Infectious Diseases"},{"key":"3350_CR35","doi-asserted-by":"publisher","first-page":"2393","DOI":"10.1110\/ps.0206702","volume":"11","author":"S Piana","year":"2002","unstructured":"Piana S, Carloni P, Rothlisberger U: Drug resistance in HIV-1 protease: Flexibility-assisted mechanism of compensatory mutations. Protein Science 2002, 11: 2393\u20132402. 10.1110\/ps.0206702","journal-title":"Protein Science"},{"issue":"3","key":"3350_CR36","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1128\/AAC.46.3.708-715.2002","volume":"46","author":"W Sugiura","year":"2002","unstructured":"Sugiura W, Matsuda Z, Yokomaku Y, Hertogs K, Larder B, Oishi T, Okano A, Shiino T, Tatsumi M, Matsuda M, et al.: Interference between D30N and L90M in selection and development of protease inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother 2002, 46(3):708\u2013715. 10.1128\/AAC.46.3.708-715.2002","journal-title":"Antimicrob Agents Chemother"},{"key":"3350_CR37","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1038\/nature04701","volume":"440","author":"E Schneidman","year":"2006","unstructured":"Schneidman E, Berry MJ II, Segev R, Bialek W: Weak pairwise correlations imply strongly correlated network states in a neural population. Nature 2006, 440: 1007\u20131012. 10.1038\/nature04701","journal-title":"Nature"},{"key":"3350_CR38","doi-asserted-by":"publisher","DOI":"10.1017\/CBO9780511790492","volume-title":"Biological Sequence Analysis","author":"R Durbin","year":"1998","unstructured":"Durbin R, Eddy S, Krogh A, Mitchison G: Biological Sequence Analysis. Cambridge University Press; 1998."},{"key":"3350_CR39","first-page":"397","volume":"5","author":"JC Gower","year":"1985","unstructured":"Gower JC: Measures of Similarity, Dissimilarity, Distance, Encyclopedia of Statistical Sciences. 1985, 5: 397\u2013405.","journal-title":"Measures of Similarity, Dissimilarity, Distance, Encyclopedia of Statistical Sciences"},{"key":"3350_CR40","doi-asserted-by":"publisher","first-page":"3096","DOI":"10.1103\/PhysRevE.62.3096","volume":"62","author":"H Matsuda","year":"2000","unstructured":"Matsuda H: Physical nature of higher-order mutual information: Intrinsic correlations and frustration. Phys Rev E 2000, 62: 3096\u20133102. 10.1103\/PhysRevE.62.3096","journal-title":"Phys Rev E"},{"key":"3350_CR41","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1089\/aid.2005.21.1016","volume":"21","author":"PB Gilbert","year":"2005","unstructured":"Gilbert PB, Novitsky V, Essex M: Covariability of selected amino acid positions for HIV type 1 subtypes C and B. AIDS Res. Human Retrovir 2005, 21: 1016\u20131030. 10.1089\/aid.2005.21.1016","journal-title":"Human Retrovir"},{"key":"3350_CR42","doi-asserted-by":"crossref","first-page":"2637","DOI":"10.1128\/AAC.42.10.2637","volume":"42","author":"AK Patick","year":"1998","unstructured":"Patick AK, Duran M, Cao Y, Shugarts D, Keller MR, Mazabel E, Knowles M, Chapman S, Kuritzkes DR, Markowitz M: Genotypic and phenotypic characterization of human immunodeficiency virus type 1 variants isolated from patients treated with the protease inhibitor nelfinavir. Antimicrob Agents Chemother 1998, 42: 2637\u20132644.","journal-title":"Antimicrob Agents Chemother"},{"key":"3350_CR43","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1126\/science.286.5438.295","volume":"286","author":"W Steve","year":"1999","unstructured":"Steve W: Lockless and Rama Ranganathan. Evolutionarily conserved pathways of energetic connectivity in protein families. Science 1999, 286: 295\u2013299. 10.1126\/science.286.5438.295","journal-title":"Science"},{"key":"3350_CR44","doi-asserted-by":"publisher","first-page":"12376","DOI":"10.1073\/pnas.0805909105","volume":"105","author":"V Mustonen","year":"2008","unstructured":"Mustonen V, Kinney J Jr, Callan CG, L\u00e4ssig M: Energy-dependent fitness: A quantitative model for the evolution of yeast transcription factor binding sites. Proc Natl Acad Sci USA 2008, 105: 12376\u201312381. 10.1073\/pnas.0805909105","journal-title":"Proc Natl Acad Sci USA"},{"key":"3350_CR45","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1038\/nrg1672","volume":"6","author":"MA DePristo","year":"2005","unstructured":"DePristo MA, Weinreich DM, Hartl DL: Missense meanderings in sequence space: A biophysical view of protein evolution. Nat Rev Genet 2005, 6: 678\u2013687. 10.1038\/nrg1672","journal-title":"Nat Rev Genet"},{"key":"3350_CR46","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1126\/science.1123539","volume":"312","author":"DM Weinreich","year":"2006","unstructured":"Weinreich DM, Delaney NF, DePristo MA, Hartl DL: Darwinian evolution can follow only very few mutational paths to fitter proteins. Science 2006, 312: 111\u2013114. 10.1126\/science.1123539","journal-title":"Science"},{"key":"3350_CR47","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1093\/bioinformatics\/btm540","volume":"24","author":"K Deforche","year":"2008","unstructured":"Deforche K, Camacho R, Van Laethem K, Lemey P, Rambaut A, Moreau Y, Vandamme A-M: Estimation of an in vivo fitness landscape experienced by HIV-1 under drug selective pressure useful for prediction of drug resistance evolution during treatment. Bioinformatics 2008, 24: 34\u201341. 10.1093\/bioinformatics\/btm540","journal-title":"Bioinformatics"},{"key":"3350_CR48","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1214\/aoms\/1177704014","volume":"34","author":"IJ Good","year":"1963","unstructured":"Good IJ: Maximum entropy for hypothesis formulation, especially for multidimensional contingency tables. Ann Math Stat 1963, 34: 911\u2013934. 10.1214\/aoms\/1177704014","journal-title":"Ann Math Stat"},{"key":"3350_CR49","volume-title":"Numerical Recipes in C: The Art of Scientific Computing","author":"WH Press","year":"1992","unstructured":"Press WH, Teukolsky SA, Vetterling WT, Flannery BP: Numerical Recipes in C: The Art of Scientific Computing. Cambridge University Press, Cambridge; 1992."},{"key":"3350_CR50","volume-title":"R: A Language and Environment for Statistical Computing","author":"R Development Core Team","year":"2005","unstructured":"R Development Core Team: R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria; 2005."}],"container-title":["BMC Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2105-10-S8-S10.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T01:45:30Z","timestamp":1630460730000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcbioinformatics.biomedcentral.com\/articles\/10.1186\/1471-2105-10-S8-S10"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,8]]},"references-count":50,"journal-issue":{"issue":"S8","published-print":{"date-parts":[[2009,8]]}},"alternative-id":["3350"],"URL":"https:\/\/doi.org\/10.1186\/1471-2105-10-s8-s10","relation":{},"ISSN":["1471-2105"],"issn-type":[{"value":"1471-2105","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,8]]},"assertion":[{"value":"27 August 2009","order":1,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"S10"}}