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Manolis Kellis, Ph.D.

Department of Electrical Engineering and Computer Science
Assistant professor of Computer Science.
Associate Member, Broad Institute for MIT and Harvard
Principal Investigator, Computer Science and Artificial Intelligence Laboratory

Room 32G-564
617-253-2419 (phone)

Biosketch

Assistant Professor, MIT Department of Electrical Engineering and Computer Science
Principal Investigator, Computer Science and Artificial Intelligence Laboratory
Associate Member, Broad Institute of MIT and Harvard

Research Summary

These are exciting times for computational biology. The completion of the human genome epitomizes the transformation of modern biology to a largely information-based, quantitative science. We are now faced with perhaps the greatest scientific challenge and opportunity: interpreting the code of our own biology. Our group is focused on the computational foundations of such a pursuit, developing new algorithms and machine learning techniques to understand complex biological systems.

Discovery of DNA signals
We have pioneered new computational methods for discovering biological DNA signals, and used these to analyze four related species of yeast with unprecedented success. This work led to (1) the most complete re-annotation of the yeast genome, with changes affecting more than 15% of genes, (2) the first systematic de-novo discovery of the regulatory motifs that govern gene expression, without requiring prior experimentation or biological knowledge, and (3) the first global view of eukaryotic genome evolution across multiple species.

More recently, we have applied similar methods to the comparative analysis of human, mouse, rat, and dog genomes. We showed that most previously known human transcription factor binding sites can be discovered solely on the basis of their genome-wide conservation. The work also led to the first systematic study of post-transcriptional regulatory motifs in human, including the discovery of many novel micro RNA genes.

Regulatory networks
Complementing our systematic discovery of functional elements, we are also studying the dynamic nature of regulatory networks in human and yeast. By integrating diverse datasets of gene expression, transcription factor binding, and protein interaction networks, we are interested in understanding the basis of the versatility of gene regulation. We have discovered significant motif co-occurrence patterns across multiple species, which lead to specific hypotheses of interacting transcription factors. We are using experimental interventions on these transcription factor pairs to dissect their specific mechanisms of co-operative, antagonistic or combinatorial effects.

Further, we are interested in understanding how these regulatory networks change across evolutionary time. We are modeling motif turnover rates in closely and distantly related species, and how these are affected by motif multiplicity and motif co-occurrence. Our aim is to correlate and predict observed regulatory changes across the different species, with genomic changes at the sequence level.

Evolutionary theory and genome duplication
We have also applied our comparative methods to much larger evolutionary distances, and studied the evidence and effects of genome duplication. We have conclusively showed that the yeast genome underwent complete duplication one hundred million years ago. More recently, we showed that a similar genome duplication event shaped the early vertebrate lineage of bony fish. In both vertebrates and fungi, genome duplication was followed by a period of massive gene loss, where 90% of duplicated genes returned to their single-copy state.

In the genes that were kept in two copies, we showed evidence of accelerated evolution by asymmetric gene divergence. The acceleration led to gene specialization and the emergence of new functions, often with striking examples. For these cases, we aim to understand more closely the mechanisms of gene duplication, by correlating the regulatory programs of duplicated genes with those of their non-duplicated counterparts.

Selected Publications

  • Systematic discovery of regulatory motifs in human promoters and 3` UTRs by comparison of several mammals Xiaohui Xie, Jun Lu, EJ. Kulbokas, Todd Golub, Vamsi Mootha, Kerstin Lindblad-Toh, Eric Lander, Manolis Kellis Nature 2005 Feb 27, doi:10.1038/nature03441 (pdf) (Nature website)
  • Proof and evolutionary analysis of ancient genome duplication in the yeast Saccharomyces cerevisiae Manolis Kellis, Bruce Birren, Eric Lander Nature 2004 Apr 8; 428 pp. 617-24 (pdf) (Nature website)
  • Sequencing and comparison of yeast species to identify genes and regulatory motifs Manolis Kellis, Nick Patterson, Matt Endrizzi, Bruce Birren, Eric Lander Nature 2003 May 15; 423 pp. 241-254 (pdf) (Nature website)
  • Transcriptional regulatory code of a eukaryotic genome Chris Harbison et al., Ben Gordon, Tony Lee, Nicola Rinaldi, Macisaac, Danford, Hannett, Tagne, Reynolds, Yoo, Jennings, Zeitlinger, Pokholok, Kellis, Rolfe, Takusagawa, Lander, Gifford, Fraenkel, Young. Nature 2004 Sep 2; 431 pp. 99-104 (pdf) (Nature website)
  • Genome duplication in the teleost fish Tetraodon nigrovidridis reveals the early vertebrate proto-karyotype Olivier Jaillon et al., Aury, Brunet, Petit, Stange-Thomann, Mauceli, Bouneau, Fischer, Ozouf-Costaz, Bernot, Nicaud, Jaffe, Fisher, Lutfalla, Dossat, Segurens, Dasilva, Salanoubat, Levy, Boudet, Castellano, Anthouard, Jubin, Castelli, Katinka, Vacherie, Biemont, Skalli, Cattolico, Poulain, Berardinis, Cruaud, Duprat, Brottier, Coutanceau, Gouzy, Parra, Lardier, Chapple, McKernan, McEwan, Bosak, Kellis, Volff, Guigo, Zody, Mesirov, Lindblad-Toh, Birren, Nusbaum, Kahn, Robinson-Rechavi, Laudet, Schachter, Quetier, Saurin, Scarpelli, Wincker, Lander, Weissenbach, Hugues Roest Crollius. Nature 2004 Oct 21; 431 pp. 946-957 (pdf) (Nature website)
  • Methods in comparative genomics: genome correspondence, gene identification, regulatory motif discovery Manolis Kellis, Nick Patterson, Bruce Birren, Bonnie Berger, Eric Lander Journal of Computational Biology 2004; 11 pp. 319-55. (pdf).
  • Whole-genome comparative annotation and motif discovery in yeast Manolis Kellis (Kamvysselis), Nick Patterson, Bruce Birren, Bonnie Berger, Eric Lander ACM Recomb `03 Proceedings (pdf).
  • Phylogenetically and spatially conserved word pairs associated with gene-expression changes in yeasts Derek Chiang, Alan Moses, Manolis Kellis, Eric Lander, Mike Eisen ACM Recomb `03 Proceedings. (pdf)
  • Gene finding using multiple related species: a classification approach. Manolis Kellis Encyclopedia of Genetics, Genomics, Proteomics, John Wiley & Sons, special review, 2005 (in press) (pdf).
  • What`s in the human genome? Large-scale discovery and validation of functional elements Bradley E Bernstein and Manolis Kellis Genome Biology 2005 Mar 1; 6:312 (pdf)
  • The changing face of genomics Manolis Kellis Genome Biology 2004 Apr 30; 5(5): p. 324 (pdf)
  • Computational Comparative Genomics: Genes, Regulation, Evolution Manolis Kellis (Kamvysselis) MIT Ph.D. Thesis `03 (pdf)
  • Position specific variation in the rate of evolution in transcription factor binding sites Alan Moses, Derek Chiang, Manolis Kellis, Eric Lander, Mike Eisen BMC Evolutionary Biology 2003, 3:19, Aug 28, 2003 (pdf)
  • The Genome Sequence of the filamentous fungus Neurospora crassa James Galagan, Sarah Calvo, Borkovich, Selker, Read, Jaffe, FitzHugh, Ma, Smirnov, Purcell, Rehman, Elkins, Engels, Wang, Nielsen, Butler, Endrizzi, Qui, Ianakiev, Bell-Pedersen, Nelson, Werner-Washburne, Selitrennikoff, Kinsey, Braun, Zelter, Schulte, Kothe, Jedd, Mewes, Staben, Marcotte, Greenberg, Roy, Foley, Naylor, Stange-Thomann, Barrett, Gnerre, Kamal, Kamvysselis, Mauceli, Bielke, Rudd,, Frishman, Krystofova, Rasmussen, Metzenberg, Perkins, Kroken, Cogoni, Macino, Catcheside, Li, Pratt,, Osmani, DeSouza, Glass, Orbach, Berglund, Voelker, Yarden, Plamann, Seiler, Dunlap, Radford, Aramayo, Natvig, Alex, Mannhaupt, Ebbole, Freitag, Paulsen, Sachs, Lander, Nusbaum, Birren Nature, 2003 Apr 24; 422 pp 859-868. (pdf) (Nature website)
  • Phylogenetically and spatially conserved word pairs associated with gene-expression changes in yeasts Derek Chiang, Alan Moses, Manolis Kellis, Eric Lander, Mike Eisen Genome Biology, 4(7):R43, Jun 26, 2003. (pdf)
  • Biological Signal Discovery: The Power of Multiple Genomes Manolis Kellis Fungal comparative genomics, Springer Verlag, invited book chapter, 2004 (in preparation).

Last Updated: April 16, 2008