The Simons Center for Systems Biology - Research

Research interests at The Simons Center for Systems Biology include genetics and genomics, polymorphisms and molecular aspects of evolution, signal transduction pathways and networks, stress responses and pharmacogenomics in cancer biology. Members of the group explore the linkage between theoretical and experimental biology. The group has developed algorithms that have led to the discovery of correlations and signals that are characteristic of viruses, diseases such as cancer, and traits such as embryonic development and longevity. Researchers also are investigating protein-protein interaction networks, including the prediction of protein-protein interactions from sequence analysis, and the dynamics of mRNA and protein expression in gene circuits.

Using tools from statistical mechanics and information theory, Members are addressing problems in population genetics and association studies, haplotype structure and gene selection in the p53 pathway, and uncovering epistatic interactions between single nucleotide polymorphisms related to cell apoptosis as well as developing protocols for molecular profiling of cancer; studying evolutionary genetics, and patterns of mutations correlated with longevity. They are exploring the bioinformatics of DNA and RNA sequences with applications including patterns of re-assortment in viruses, optimal RNA expression for vaccines and chromatin structure as a function of DNA sequence; and developing numerically efficient theoretical methods to describe quantum effects experimentally observed in enzymatic reactions.

The Center’s first publication from research on genetic predispositions to cancer, A Single Nucleotide Polymorphism in the MDM2 Promoter Attenuates the p53 Tumor Suppressor Pathway and Accelerates Tumor Formation in Humans, appeared in the journal Cell in November 2004.

A selection of other papers includes:

Blaho, J. A. "Human cytomegalovirus infection in pregnant women and neonates: A new risk factor for cardiovascular disease?" Archives of Clinical Microbiology 2010, Vol. 1, No. 1:5.

Peña, K. C., Adelson, M. E., Mordechai, E., Blaho,J. A. "Genital Herpes Simplex Virus Type 1 in Women: Detection in Cervicovaginal Specimens from Gynecological Practices in the United States" Journal of Clinical Microbiology, Jan. 2010, p. 150-153.

Grochola, L. F., Vazquez, A., Bond, E. E., Würl, P., Taubert, Helge, Müller, T. H., Levine, A. J., Bond, G. L. "Recent Natural Selection Identifies a Genetic Variant in a Regulatory Subunit of Protein Phosphatase 2A that Associates with Altered Cancer Risk and Survival" Clin Cancer Res (October 1, 2009) 15 (19), 6301-6308.

Kulkarni, D. A., Vazquez, A., Haffty, B. G., Bandera, E. V., Hu, W., Sun, Y. Y., Toppmeyer, D. L., Levine, A. J., Hirshfield, K. M. "A polymorphic variant in human MDM4 associates with accelerated age of onset of estrogen receptor negative breast cancer" Carcinogenesis 2009, Vol. 30, No. 11, pp. 1910-1915.

Belyi, V. A., AK, P. A., Markert, E., Wang, H., Hu, W., Puzio-Kuter, A., Levine, A. J. "The Origins and Evolution of the p53 Family of Genes" Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a001198 published online December 16, 2009.

Cocco, S. and Monasson, R. "Inference of a random potential from random walk realizations: Formalism and application to the one-dimensional Sinai model with a drift" International Workshop on Statistical-Mechanical Informatics 2009, IOP Publishing, Journal of Physics: Conference Series 197 (2009) 012005.

Belyi, V. A. and Levine, A. J. “One Billion Years of p53/p63/p73 Evolution” Proc. Natl. Acad. Sci. (October 20, 2009) 106 (42) 17609-17610.

Chen, X., Wang, H., Zhou, G., Zhang, X., Dong, X., Zhi, L., Jin, L., He, F. "Molecular Population Genetics of Human CYP3A Locus: Signatures of Positive Selection and Implications for Evolutionary Environmental Medicine" Environmental Health Perspectives (October 2009) Vol. 117, No. 10, 1541-1548.

Vazquez, A. “Optimal Drug Combinations and Minimal Hitting Sets” BMC Systems Biology (August 6, 2009) 3:81.

Vazquez, A. “Finding hypergraph communities: a Bayesian approach and variational solution” Journal of Statistical Mechanics: Theory and Experiment (July 1, 2009).

Greenbaum, B., Rabadan, R., Levine A. “Patterns of Oligonucleotide Sequences in Viral and Host Cell RNA Identify Mediators of the Host Innate Immune System” PLoS ONE (June 18, 2009) 4 (6): e5969.

Beckman, R. A. “Mutator Mutations Enhance Tumorigenic Efficiency across Fitness Landscapes” PLoS ONE (June 10, 2009) 4 (6): e5860.

Trifonov, V., Khiabanian, H., Greenbaum, B., Rabadan, R. “The origin of the recent swine influenza A (H1N1) virus infecting humans”. Euro Surveill. (April 30, 2009); 14 (17).

Wang, H., Jin, G., Wang, H., Liu, G., Qian, J., Jin, L., Wei, Q., Shen, H., Huang, W., Lu, D. “Genetic Susceptibility of Lung Cancer Associated With Common Variants in the 3' Untranslated Regions of the Adenosine Triphosphate-Binding Cassett B1 (ABCB1) and ABCC1 Candidate Transporter Genes for Carcinogen Export”. Cancer (February 1, 2009) p. 595-607.

Venkatesan, K., Rual, J-F., Vazquez, A. et al. “An empirical framework for binary interactome mapping”. Nature Methods (January 2009) 6 (1), 83-90.

Oliveira, J. G., Vazquez, A. “Impact of interactions on human dynamics”. Physica A (2009) 388: 187-192.

Vazquez, A., Bond, E. E., Levine, A. J., Bond, G. L. “The genetics of the p53 pathway, apoptosis and cancer therapy”. Nature Reviews Drug Discovery (December 2008) 7: 979-987.

Zhang, Y., Shin, H., Song, J. S., Lei, Y. and Liu, X. S. “Identifying Positioned Nucleosomes with Epigenetic Marks in Human from ChIP-Seq.” BMC Genomics  (November 13, 2008) 9: 537. 

Ozsolak F., Poling, L. L., Wang, Z., Liu, H., Liu, X. S., Roeder, R. G., Zhang, X., Song, J. S. and Fisher, D. E. “Chromatin Structure Analyses Identify miRNA Promoters”. Genes & Development  (2008) 22: 3172—3183

Chan, C. S. and Song, J. S. “CCCTC-Binding Factor Confines the Distal Action of Estrogen Receptor”. Cancer Research (November 1, 2008) 68: (21), 9041-9049. 

Alexe, G., Satya, R.V., Seiler, M., Platt, D., Bhanot, T., Hui, S., Tanaka, M., Levine, A.J., Bhanot, G. “PCA and Clustering Reveal Alternate mtDNA Phylogeny of N and M Clades”. J Mol Evol (2008) 67:465-487.

Yu, H., Vazquez, A. et al “High-Quality Binary Protein Interaction Map of the Yeast Interactome Network”. Science (October 3, 2008) 322: 104-110.

Vazquez, A., de Menezes, M. A., Barabási, A-L, Oltvai, Z. N. “Impact of Limited Solvent Capacity on Metabolic Rate, Enzyme Activities, and Metabolite Concentrations of S. cerevisiae Glycolysis". PLoS Computational Biology (October 10, 2008) 4 (10): e1000195.

Krasnitz, M., Rabadan, R., Levine, A.J. “Anomalies in the Influenza Virus Genome Database: New Biology or Laboratory Errors?” Journal of Virology (September 2008) 82 (17): 8947-8950. 

Huang, Y., Krasnitz, M., Rabadan, R., Witten, D. M., Song, Y., Levine, A. J., Ho, D. D., Robins, H. “A recoding method to improve the humoral immune response to an HIV DNA vaccine”. PLoS ONE (September 15, 2008), 3(9):e3214.

Holmes, K. A., Song, J. S., Liu, X. S., Brown, M. and Carroll, J. S. “Nkx3-1 and LEF-1 Function as Transcriptional Inhibitors of Estrogen Receptor Activity”. Cancer Research (September 15,2008) 68: (18), 7380-7385. 

Song, J. S., Liu, X, Liu, S., He, X. “A high-resolution map of nucleosome positioning on a fission yeast centromere”. Genome Research (2008) 18:1064-1072.

Robins, H., Krasnitz, M., Levine, A.J.  “The Computational Detection of Functional Nucleotide Sequence Motifs in the Coding Regions of Organisms”.  Exp Biol andMed. (2008)233: 665-673.

Bilal, E., Rabadan, R., Alexe, G., Fuku, N., Ueno, H., Nishigaki, Y., Fujita, Y., Ito, M., Arai, Y., Hirose, N., Ruckenstein, A., Bhanot, G., Tanaka, M. “Mitochondrial DNA Haplogroup D4a is a Marker for Extreme Longevity in Japan”. PLoS ONE (June 11, 2008) 3 (6): e2421. 

Vazquez, A. “Population stratification using a statistical model on hypergraphs”. Phys. Rev. E 77, 066106 (June 10, 2008).

Greenbaum, B. D., Levine, A. J., Bhanot, G., Rabadan, R. “Patterns of Evolution and Host Gene Mimicry in Influenza and other RNA Viruses”. PLoS Pathogens (June 6, 2008)4(6):1-9. 

Atwal, G., Rabadan, R., Lozano, G., Strong, L. C., Ruijs, M.W.G., Schmidt, M. K., van ´t Veer, L. J., Nevanlinna, H., Tommiska, J., Aittomäki, K., Bougeard, G., Frebourg, T., and Levine, A. J., Bond, G. L. “An Information-Theoretic Analysis of Genetics, Gender and Age in Cancer Patients”. PLoS ONE (April 9, 2008) 3 (4): e1951. 

Borghuis, B. G., Ratliff, C. P., Smith, R. G., Sterling, P., and Balasubramanian, V. “Design of a Neuronal Array”. The Journal of Neuroscience (March 19, 2008) 28 (12):3178-3189. 

Marsh, G.A., Rabadan, R., Levine, A.J., Palese, P. “Highly conserved regions of influenza A virus polymerase gene segments are critical for efficient viral RNA packaging”. Journal of Virology (March 2008) 82(5):2295-2304.

Vazquez, A. , Beg, Q. K., de Menezes, M. A, Ernst, J., Bar-Joseph, Z., Barabási, A-L, Boros, L.G., and Oltvai, Z.N. “Impact of the solvent capacity constraint on E. coli metabolism”. BMC Systems Biology (January 23, 2008) 2:7.

Rabadan, R., Levine, A.J., Krasnitz, M. “Non-random reassortment in human influenza A viruses”. Influenza and Other Respiratory Viruses (2008)2 (1), 9-22. 

Johnson, D. S., Song, J. S. et al. “Systematic evaluation of variability in simulated ChIP-chip experiments using predefined DNA targets” Genome Research (2008) 18:393-403.

Rabadan R., Robins H. “Evolution of the Influenza A Virus: Some New Advances” Evolutionary Bioinformatics Online 2007: 299-307. 

Yeang, C-H, Haussler, D. “Detecting Coevolution in and among Protein Domains”. PLoS Computational Biology (November 2007) 3(11):e211. 

Dalgin, G. S., Alexe, G., Scanfeld, D., Tamayo, P., Mesirov, J. P., Ganesan, S., Delisi, C., Bhanot, G.  “Portraits of Breast Cancer Progression”, BMC Bioinformatics (August 6, 2007) 8: 291.

Beg, Q.K., Vazquez, A., Ernst, J., de Menezes, M.A., Bar-Joseph, Z., Barabási, A.-L., and Oltvai, Z.N. “Intracellular crowding defines the mode and sequence of substrate uptake by Escherichia coli and constrains its metabolic activity”. PNAS (July 31, 2007) vol. 104 no. 31 (12663-12668).

Calderwood, M.A., Venkatesa, K., Xing, L., Chase, M.R., Vazquez, A., Holthaus, A.M., Ewence, A.E., Li, N., Hirozane-Kishikawa, T., Hill, D.E., Vidal, M., Kieff, E., and Johannsen, E. “Epstein-Barr virus and virus human protein interaction maps”.  PNAS (May 1, 2007) vol. 104 no. 18 (7606-7611). 

Vazquez, A., Rácz, B., Lukács, A., and Barabási, A-L. “Impact of Non-Poissonian Activity Patterms on Spreading Processes”.  Physical Review Letters (Week ending April 13, 2007) 98 (15), 158702 (1-4).

Atwal, G.S., Bond, G.L., Metsuyanim, S., Papa, M., Friedman, E., Distelman-Menachem, T., Asher, E.B., Lancet, D., Ross, D.A., Sninsky, J., White, T.J., Levine, A.J., and Yarden, R. “Haplotype structure and selection of the MDM2 oncogene in humans”. PNAS (March 13, 2007) vol. 104 no. 11 (4525-4529).

Bond, G.L., and Levine, A.J. “A single nucleotide polymorphism in the p53 pathway interacts with gender, environmental stresses and tumor genetics to influence cancer in humans”. Oncogene (2007) 26, 1317-1323.

Vazquex, Alexei. “Epidemic outbreaks on structured populations”. Journal of Theoretical Biology 245 (2007) 125-129.

Rabadan, R., Levine, A.J., and Robins, H.  “Comparison of Avian and Human Influenza A Viruses Reveals a Mutational Bias on the Viral Genomes”. Journal of Virology, (December 2006) vol. 80, no. 23 (11887-11891). 

Vazquez, Alexei.  “Spreading dynamics on heterogeneous populations: Multi-type network approach”.  Physical Review E 74 (December 21, 2006) 066114.

Vazquez, Alexei.  “Spreading dynamics on small-world networks with connectivity fluctuations and correlations”.  Physical Review E 74 (November 1, 2006) 056101.

Press, W.H. and Robins, H.  “Isochores Exhibit Evidence of Genes Interacting With the Large-Scale Genomic Environment”. Genetics (October 2006) vol. 174 (1029-1040).

Haimovich, A.D., Byrne, B., Ramaswamy, R., and Welsh, W.J.  “Wavelet Analysis of DNA Walks”. Journal of Computational Biology (September 2006) vol. 13 no. 7 (1289-1298).

Bond, G. L., Menin, C., Bertorelle, R., Alhorpuro, P., Aaltonen, L. A., and Levine, A. J. “MDM2 SNP309 Accelerates colorectal tumour formation in women”. Journal of Medical Genetics (published online July 6, 2006).

Bond, G.L., Hirshfield, K.M. Kirchhoff, T., Alexe, G., Bond, E.E., Robins, H., Bartel, F., Taubert, H., Wuerl, P., Hait, W., et al.  “MDM2 SNP309 Accelerates Tumor Formation in a Gender Specific and Hormonal Dependent Manner”.  Cancer Research (May 15, 2006) 66(10) (5104-10).

Alexe, G., Dalgin, G.S., Ramaswamy, R., Delisi, C., Bhanot, G. “Data Perturbation Independent Diagnosis and Validation of Breast Cancer Subtypes Using Clustering and Patterns”. Cancer Informatics, Online (2006) 2, 243-274.

Vijaya-Satya, R., Mukherjee, A., Alexe, G., Parida, L., Bhanot, G. “Constructing Near-Perfect Phylogenies with Multiple Homoplasy Events”, ISMB, Bioinformatics, (2006), 514-522.

Bhanot, G., Alexe, G., Venkataraghavan, B., Levine, A.J. “A robust meta-classification strategy for cancer detection from mass spectrometry data.”  Proteomics, (December 8, 2005) 6(2):592-604.

Robins, H., Krasnitz, M., Barak, H., Levine, A. “A Relative Entropy Algorithm for Genomic Fingerprinting Captures Host-Phage Similarities”. Journal of Bacteriology, (December 2005) vol. 187 no. 24 (8370-8374).

Harris, S., Gil, G., Robins, H., Hu, W., Hirshfield, K., Bond, E., Bond, G., Levine, A. “Detection of functional single nucleotide polymorphisms that affect apoptosis”. PNAS (November 8, 2005) vol. 102 no. 45 (16297-16302).

Robins, H., Press, W.H. “Human microRNAs target a functionally distinct population of genes with AT-rich 3’UTRs”. PNAS (October 25, 2005) vol. 102 no. 43 (15557-15562).

Alexe, G., Alexe, S., Axelrod, D.E., Hammer, P.L., and Weissmann, D. “Logical analysis of diffuse large B-cell lymphomas”. Artificial Intelligence in Medicine (July 2005) vol. 34 issue 3 (235-267).

Arva, N.C., Gopen, T.R., Talbott, K.E., Campbell, L.E., Chicas, A., White, D.E., Bond G.L., Levine, A.J., and Bargonetti, J. “A Chromatin-Associated and Transcriptionally Inactive p53-Mdm2 Complex Occurs in Mdm2 SNP309 Homozygous Cells”. Journal of Biological Chemistry (July 22, 2005) vol. 280 issue 29 (26776-26787).

Bond, G.L., Hu, W., and Levine, A. “A Single Nucleotide Polymorphism in the MDM2 Gene: From a Molecular and Cellular Explanation to Clinical Effect”.  Cancer Research (July 1, 2005) 65(13): (5481-5484) (NOTE: This is a Review).

Robins, H., Li, Y., and Padgett, R.W. “Incorporating structure to predict microRNA targets”. PNAS (March 15, 2005) vol. 102 no. 11 (4006-4009).

Ma, B., Pan, Y., Gunasekaran, K., Venkataraghavan, B., Levine, A.J., and Nussinov, R. “Comparison of the protein-protein interfaces in the p53-DNA crystal structures: Towards elucidation of the biological interface”. PNAS (March 15, 2005) vol. 102 no. 11 (3988-3993).

Ramaswamy, R. “The natural effectiveness of mathematics in the biological sciences”.Current Science (Bangalore) (10 Feb 2005) vol. 88 no. 3 (381-387).

Pan, Y., Ma, B., Venkataraghavan, B., Levine, A.J., and Nussinov, R. “In the Quest for Stable Rescuing Mutants of p53: Computational Mutagenesis of Flexible Loop L1”. Biochemistry (February 8, 2005) 44 (1423-1432).

Bhanot, G., Alexe, G., Venkataraghavan, B., Levine, A.J. A robust meta-classification strategy for cancer detection from mass spectrometry data (patent application with IBM Research and IAS, January 2005).

Alexe, G., Bhanot, G., Levine, A.J., Stolovitzky, G. “Robust diagnosis of non-Hodgkin lymphoma phenotypes validated on gene expression data from different laboratories”, Genome Informatics (2005) 16(1): 233-244.

Abramson, S., Alexe, G., Hammer, P.L., Kohn, J. “A computational approach to predicting cell growth on polymeric biomaterials”.  J Biomed Mater Res A. (2005) 73A (1):116-24.

Levine, A.J., Bargonetti, J., Bond, G.L., Hoh, J., Onel, K., Overholtzer, M., Stoffel, A., Teresky, A.K., Walsh, C.A., Jin, S. “The p53 Network”. In The p53 Tumor Suppressor. (2005) (ed.) G. Zambetti, Springer Science and Business Media, New York, pp. 1-23.

Bond, G.L., Hu, W., and Levine, A. “Mdm2 is a Central Node in the p53 Pathway: 12 Years and Counting”. Current Cancer Drug Targets (2005) (5): 3-8.

Robins, H., Alexe, G., Harris, S., Levine, A.J. “The first twenty five years of p53 research”. In : 25 Years of P53 Research, Hainaut, Pierre; Wiman, Klas (Eds.) Ch 1, 2005.

Bond, G.L., Hu, W., Bond, E.E., Robins, H., Lutzker, S., Arva, N., Bargonetti, J., Bartel, F., Taubert, H., Wuerl, P., Onel, K., Linwah, Y., Hwang, S-J., Strong, L., Lozano, G., Levine, A. “A Single Nucleotide Polymorphism in the MDM2 Promoter Attenuates the p53 Tumor Suppressor Pathway and Accelerates Tumor Formation in Humans”.  Cell (November 4, 2004) vol. 119 (591-602).

Plotkin, J.B., Robins, H. and Levine, A.J.. “Tissue-specific codon usage and the expression of human genes”. PNAS (August 24, 2004) vol. 101 no. 34 (12588-12591).

Alexe, G., Alexe, S., Hammer, P.L., Liotta, L., Petricoin, E., Reiss, M. “Ovarian cancer detection by logical analysis of proteomic data”. Proteomics 4 (2004) 766-783.

Bhanot, G. “Results from Modeling of B-Cell receptors binding to antigen”, Prog. Biophysics and Mol. Bio. (2004) 85, 2-3 (343-352).

Bhanot, G., Zhu, J., Louzoun, Y., and Delisi, C. “The Importance of Thermodynamic Equilibrium for High Throughput Gene Expression Arrays”, Biophysical Journal 84 (2003) 124-135.

Bhanot, G., Louzoun, Y., Weigert, M. “Dynamical Analysis of a Degenerate Primary and Secondary Humoral Immune Response”, Bulletin of Mathematical Biology 65 (2003) 535-545.