Ludwig Institute for Cancer Research São Paulo Branch

Research Groups

Computational Biology

Group Leader: Sandro J. De Souza

We are mainly interested in the development of strategies to explore the human transcriptome. The group was involved in a large-scale sequencing project, in which more than a 1 million ESTs from tumor samples and their normal counterparts were generated. We were also involved in the development of new bioinformatics approaches to explore SAGE (Serial Analysis of Gene Expression) data. Regarding the human transcriptome, we are particularly interested in alternative splicing. We believe that strategies based on bioinformatics will provide answers to several important questions regarding the regulation of alternative splicing. Finally, we are also trying to understand the relationship between alternative splicing and tumorigenesis. Several splicing variants seem to be correlated with specific features of different types of tumors. We are testing whether these associations are sporadic or whether they reflect a broader relationship between alternative splicing and tumorigenesis. These studies may have several implications in cancer therapy and diagnosis.

Publications

• Gilbert, W and De Souza, SJ (1999) Introns and the RNA World. In: RNA World II, eds: Thomas Cech & John Atkins, pg. 221-231, CSHL Press.
• Roy, S., Nosaka, M., de Souza, S.J. and Gilbert, W. (1999) Centripetal modules and ancient introns. Gene 238:85-91.
• Sakarkhar, M., Long, M., Tan, T.W. and de Souza, S.J. (2000) ExInt: an exon/intron database. Nucleic Acids Res. 28:191-192.
• Dias-Neto, E., Correa, R.G., Verjovski-Almeida, S., Briones, M., Nagai, M.A., da Silva Junior, W., Zago, M.A., Bordin, S., Costa, F.F., Goldman, G.H., Carvalho, A.F., Matsukuma, A., Baia, G.S., Simpson, D.H., Brunstein, A., de Oliveira, P.S.L., Bucher, P., Jongeneel, C.V., Ohare, M.J., Soares, F., Brentani, R.R., Reis, L.F.L., de Souza, S.J. & Simpson, A.J.G. (2000) Shotgun sequencing of the human transcriptome with Open Reading Frame Expressed Sequence Tags. PNAS USA 97:3491-3496.
• Correa, R.G., de Carvalho, A.F., Pinheiro, N.A., Simpson, A.J.G. & de Souza, S.J. (2000) NABC1: Alternative splicing and down regulation in colorectal tumors. Genomics 65:299-302.
• Sackarkar, M., Kangueane, P., Woon, T.W., Tan, T.W., Long, M., Kolatkar, P.R. & de Souza, S.J. (2000) IEKb- An Exon Intron knowledge base from databases. Bioinformatics 16: 1151-1152.
• De Souza S.J. et al. (2000) Identification of human chromosome 22 transcribed sequences with ORF expressed sequence tags - PNAS USA 97:12690-12693.
• Sakharkar, M., Tan, T.W. and de Souza, S.J. (2001). Generation of a database containing discordant intron positions in eukaryotic genes (MIDB). Bioinformatics 17:671-675.
• Correa, R.G., Sasahara, R.M., Bengston, M.H., Katayama, M.L., Salim, A.C., Brentani, M.M., Sogayar, M.C., de Souza, S.J. & Simpson, A.J. (2001). Human semaphorin 6b. Genomics 73: 343-348.
• Camargo, A.A. et al. (2001). The contribution of 700,000 ORF sequence tags to the definition of the human transcriptome. PNAS USA, 98:12103-12108.
• Simpson, A.J., de Souza, S.J., Camargo, A.A. & Brentani, R.R. (2001). Definition of the gene content of the human genome: the need for deep experimental verification. Comparative and Functional Genomics, 2:169-175.
• Caballero, O.L., de Souza, S.J., Brentani, R.R. & Simpson, A.J. (2001). Alternative spliced transcript as cancer markers. Disease Markers, 17:67-75.
• Fedorov, A., Cao, X., Saxonov, S., de Souza, S.J., Roy, S.W., and Gilbert, W. (2001). Intron distribution difference for 276 ancient and 131 modern genes suggests the existence of ancient introns. PNAS USA 98:13177-13182.
• Sakharkar, M., Passetti, F., de Souza, J.E., Long, M., and de Souza, S.J. (2002) ExInt: An Exon Intron Database. Nucleic Acids Res. 30:191-194.
• Camargo, A.A, de Souza, S.J., Brentani, R.R. and Simpson, A.J.G. (2002) Human gene discovery through experimental definition of ranscribed regions of the human genome. Current Opinion in Chem. Biol. 6:13-16.
• Leerkes, M. Cabalero, O., Mackay, A., Torloni, H., O'Hare, M.J., Simpson, A.J.G. & de Souza, S.J. (2002) "In silico" comparison of the transcriptome derived from purified normal breast cells and breast tumor cell lines reveals candidate up-regulated genes in breast tumor cells. Genomics 79:257-265.
• Endo T., Fedorov, A., de Souza, S.J. and Gilbert, W. (2002) Do introns favor or avoid regions of amino acid conservation? Mol. Biol. Evol. 19: 521-522.
• Strausberg, R.L., Camargo, A.A., Riggins, G.J., Schaefer, C.F., de Souza, S.J., Grouse, L.H., Lal, L., Buetow, K.H., Boon, K., Greenhut, S. & Simpson, A.J. (2002) An international database of cancer expression. Pharmacogenomics 2:156-164.
• Reymond, A., Camargo, A.A., Deutsch, S., Stevenson, B.J., Parmigiani, R.B., Ucla, S., Betton, F., Rossier, C., Lyle, R., Guipponni, M., de Souza, S.J., Iseli, C., Jongeneel, C.V., Bucher, P., Simpson, AJG & Antonorakis, S.E. (2002). The dynamic process of gene discovery: characterization of 19 novel transcripts from human chromosome 21. Genomics 79: 824-832.
• Iseli, C., Stevenson, B.J., de Souza, S.J., Samaia, H.B., Camargo, AA, Buetow, K.H., Strausberg, R.L., Simpson, A.J.G. & Jongeneel, C.V. (2002). Long-range heterogeneity at the 3' end of human mRNAs. Genome Res. 12:1068-1074.
• Boon, K., Osorio, E.C., Greenhut, S.F., Schaefer, C.F., Shoemaker, J., Polyak, K., Morin, P.J., Buetow, K., Strausberg, R.L., de Souza, S.J., Riggins, G.J. (2002). An anatomy of normal and malignant gene expression. Proc. Natl. Acad. Sci. USA 99:11287-11292.
• de Souza, S.J. (2003). The emergence of a synthetic theory on intron evolution. Genetica 118: 117-121.
• Osorio, E.C., de Souza, J.E., Zaiats, A.C., de Oliveira, P.S.L. & de Souza, S.J. (2003). pp-Blast: a "pseudo-parallel" Blast. Brazilian J. Med. Biol. Res. 36:463-464.
• Silva, A.P., Salim, A.C., Bulgarelli, A., de Souza, J.E., Cabarello, O.L., Iseli, C., Stevenson, B.J., Jongeneel, C.V., de Souza, S.J., Simpson, A.J. and Camargo, A.A. (2003) Identification of 9 novel transcripts and two RGSL genes within the hereditary prostate cancer region (HPC1) at 1q25. Gene 310:49-57.
• Cerutti, J.M., Riggins, G.J. & de Souza, S.J. (2003) What can digital transcript profiling reveal about human cancers? Brazilian J. Med Biol. Res. 36:975-985.
• Brentani, H. et al. (2003) The generation and utilization of a cancer oriented representation of the human transcriptome using expressed sequence tags. PNAS USA 100:13418-13423.
• Sakabe, N.J., de Souza, J.E., Galante, P.F.A., de Oliveira, P.S.L., Passetti, F., Brentani, H., Osório, E.C., Zaiats, A.C., Leerkes, M.R., Kitajima, J.P., Brentani, R.R., Strausberg, R.L., Simpson, A.J. and de Souza, S.J. (2003). Orestes are enriched in exon variants affecting the encoded proteins. C.R. Biol. 326:979-985.
• Lopes, G.M.P. & de Souza, S.J. (2004) Dissection of the human spliceosome through bioinformatics and proteomics tools. Journal of Bioinformatics and Computational Biology 1: 743-750.
• Galante, P.A.F., Sakabe, N.J., Kirschbaum-Slager, N. & de Souza, S.J. (2004). Detection and evaluation of intron retention in the human transcriptome. RNA 10:757-765.
• Imanishi, T. et al. (2004). Integrative Annotation of 21,037 Human Genes Validated by Full-Length cDNA Clones. PloS Biology 2:856-875.
• Sogayar, M.C. et al. (2004). A transcript finishing initiative for closing gaps in the human transcriptome. Genome Research 14:1413-1423.
• Nunes, F.M.F. et al. (2004). The use of Open Reading Frame ESTs (ORESTES) for analysis of the honeybee transcriptome. BMC Genomics 5:84.
• Silva, A.P.M., de Souza, J.E.S., Galante, P.A.F., Riggins, G.J., de Souza, S.J. & Camargo, A.A. (2004). The impact of SNPs on the interpretation of SAGE and MPSS experimental data. Nucleic Acids Res. 32:6104-6110.
• Ferreira, E.N. et al. (2004) Identification and characterization of new human genes through the use of mouse orthologs and testis cDNA sequences. Gen. Mol. Res. 3:493-511.
• Kirschbaum - Slager, N., Lopes, G.M.P., Galante, P.A.F., Riggins, G.J. and de Souza, S.J. (2004) Splicing factors are differentially expressed in tumors. Gen. Mol. Res. 3:512-520.
• Sakabe, N.J., Vibranovski, M.D. and de Souza, S.J. (2004) A bioinformatics analysis of alternative exon usage in human genes coding for extracellular matrix proteins. Gen. Mol. Res. 3:532-540.
• de Souza, S.J., Galante, P.A.F. and Soares, R. (2005) Using ORESTES ESTs to mine gene cancer expression data. In: Encyclopedia of Genetics, Genomics, Proteomics and Bioinformatics, in press. John Wiley and sons Ltd.
• Tanino, M. et al (2005). The Human Anatomic Gene Expression Library (H-ANGEL), the H-Inv Integrative Display of Human Gene Expression across Disparate Technologies and Platforms. Nucleic Acids Res. 33:567-572.
• Sakharkar, MK, Kangueane, P., Long, M, de Souza, S.J. (2005) ExInt - An Exon Intron database. Encyclopedia of Medical Genomics & Proteomics (EMGP), Marcel Dekker, 16 (12 2000) 1151-1152.
• Vibranovski, M.D., Sakabe, N., Soares, R. & de Souza, S.J. (2005) Signs of ancient and modern exon shuffling are correlated to the distribution of ancient and modern domains along proteins. J. Mol. Evol. 60:1-10.
• Martins, V.R., de Souza, S.J., Brentani, R.R. (2005) Chasing the elusive cellular prion receptor. In: Protein Discovery, in press.
• Brentani, R.R., Carraro, D.M., Verjovski-Almeida, S., Reis, E.M., Neves, E.J., de Souza, S.J., Carvalho, A.F., Brentani, H., Reis, L.F.L. (2005)- Gene expression arrays in Cancer Research: Methods and Applications. Crit. Rev. in Oncol. Hematol. 54:95-105.
• Brentani, R.R., Camargo, A.A., Brentani, H., & de Souza, S.J. (2005). The FAPESP/LICR Human Cancer Genome Project: perspectives on integration. In: Cancer Bioinformatics, in press.
• Kirschbaum - Slager, N., Parmiggiani, R.B., Camargo, A.A. & de Souza, S.J. (2005) Identification of human exons over-expressed in tumors through the use of genome and expressed sequence data. Physiol. Genomics 21: 423-432.
• Vibranovski, M.D., Sakabe, N., & de Souza, S.J. (2006) A possible role of exon-shuffling in the evolution of signal peptides of human proteins. Elsevier Science B.V."FEBS Lett" 6;580(6):1621-1624.

Staff Members

• Ana Claudia Pereira Sanguin, secretary
• Daniel Takatori Ohara,
• Elza Helena Andrade Barbosa Durhan,
• Jorge Estefano Santana de Souza,
• Julio Cesar Nunes,
• Noboru Jô Sakabe,
• Patricia Marra de Carvalho,
• Pedro Alexandre Favoretto Galante,
• Robson Francisco de Souza