Lander Lab Research Summary

With the successful completion of the Human Genome Project, the challenge now is to decipher the information encoded within the human genetic code - including genes, regulatory controls and cellular circuitry. Understanding these components, controls and circuits is fundamental to the study of physiology in both health and disease.

The Broad Institute brings together a community focused on the comprehensive understanding of genomes through genome comparison to reveal functional elements through evolutionary conservation, studies of regulatory control by proteins and chromatin structure, and characterization of cell circuitry through monitoring and modulation of cellular states.

The Institute is home to the research laboratories that were previously known as the Whitehead Institute/MIT Center for Genome Research (WICGR). Founded in 1990, the WICGR served as a flagship for the international collaborations to produce a draft sequence of the human and mouse genomes.

Using a variety of techniques and a multi-disciplinary approach, the Lander laboratory and others at the Broad Institute are currently working on the following projects:

Genome Analysis

Mammalian Genomes:
One of the most powerful ways to understand the human genome is by directly comparing it with other mammalian genomes. Evolution tends to conserve the sequence of functional elements, allowing them stand out above background. Broad scientists are leading a national program to sequence the genomes of 16 mammalian species, with the goal of obtaining enough comparative information to recognize those functional elements that are conserved across all mammals. Comparing these sequences also reveals information about the evolutionary constraints and innovations in the class Mammalia.

Genome Regulation:
One of the great frontiers of genomics is identifying and understanding the regulatory elements that control the expression of genes. Deciphering this regulatory code involves both experimental and computational approaches. Current projects include: techniques for identifying conserved regulatory elements in promoters, UTRs and other genomic regions; large-scale discovery of the binding sites of regulatory proteins through chromatin immunoprecipitation; analysis of microRNAs and their target sites; and mass-spectrometric identification of proteins binding to particular DNA elements.

Microbial and Fungal Genomes:
Microorganisms (including fungi, bacteria and viruses) are both key model systems for genomics and important organisms for clinical medicine. Scientists in the Broad community are sequencing and analyzing the genomes of a wide range of microorganisms to understand their genetic regulation, population variation and specialized genomic mechanisms.

Cell Circuits Connectivity Map:
The Connectivity Map project seeks to connect diseases, genes and drugs by characterizing their interactions through the common language of gene expression. The project is assembling a database of 'cellular signatures', consisting of the genome-wide pattern of mRNAs induced by the actions of specific drugs, the inhibition of specific genes and the presence of specific diseases. Initial work has already identified several striking similarities that reveal surprising connections and validate this approach to understanding cellular physiology.

RNAi Consortium:
The recently discovered phenomenon of RNA inhibition (RNAi) provides a general technique to studying the function of any gene by creating a RNAi inhibitor specific for that gene. The Broad is the home of a public-private partnership, called The RNAi Consortium (TRC), which aims to create and disseminate validated RNAi against all human and mouse genes.

Last updated 2007.

SELECTED PUBLICATIONS

T.S. Mikkelsen, et al. Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequences. Nature 447:167-77 (2007).

J. Lamb, E.D. Crawford, D. Peck, J.W. Modell, I.C. Blat, M.J. Wrobel, J. Lerner, J.P. Brunet, A. Subramanian, K.N. Ross, M. Reich, H. Hieronymous, G. Wei, S.A. Armstrong, S.J. Haggarty, P.A. Clemons, R. Wei, S.A. Carr, E.S. Lander, and T.R. Golub. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313: 1929–1935 (2006).

B.E. Bernstein, T.S. Mikkelsen, X. Xie, M. Kamal, D.J. Huebert, J. Cuff, B. Fry, A. Meissner, M. Wernig, K. Plath, R. Jaenisch, A. Wagschal, R. Feil, S.L. Schreiber, and E.S. Lander. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125: 315–326 (2006).

N. Houstis, E.D. Rosen, and E.S. Lander. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440: 944–948 (2006).

T.S. Mikkelsen, et al. Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437: 69–87 (2005).

International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature 431: 931 - 945 (2004)

Kellis M, Birren BW, and Lander ES. Proof and evolutionary analysis of ancient genome duplication in the yeast Saccharomyces cerevisiae. Nature 428: 617‚624 (2004).

Mootha VK, Handschin C, Arlow D, Xie X, St Pierre J, Sihag S, Yang W, Altshuler D, Puigserver P, Patterson N, Willy PJ, Schulman IG, Heyman RA, Lander ES, Spiegelman BM.. Erra and Gabpa/b specify PGC-1a-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6570-5.

M. Kellis, N. Patterson, M. Endrizzi, B. Birren, and E.S. Lander. Sequencing and comparison of yeast species to identify genes and regulatory elements. Nature 423: 241–254 (2003).

Mootha VK, Bunkenborg J, Olsen JV, Hjerrild M, Wisniewski JR, Stahl E, Bolouri MS, Ray HN, Sihag S, Kamal M, Patterson N, Lander ES, Mann M. Integrated analysis of protein composition, tissue diversity, and gene regulation in mouse mitochondria. Cell 115(5):629–640 (2003).

Mootha VK, Lepage P, Miller K, Bunkenborg J, Reich M, Hjerrild M, Delmonte T, Villeneuve A, Sladek R, Xu F, Mitchell GA, Morin C, Mann M, Hudson TJ, Robinson B, Rioux JD, Lander ES. Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics. Proc Natl Acad Sci USA 100(2):605–610 (2003).

Ramaswamy S, Ross KN, Lander ES, Golub TR. A molecular signature of metastasis in primary solid tumors. Nat Genet 33(1):49–54 (2003).

Waterston RH, Lindblad-Toh K, Birney E, et al; Mouse Genome Sequencing Consortium. Initial sequencing and comparative analysis of the mouse genome. Nature 420(6915):520–562 (2002).

Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D. The structure of haplotype blocks in the human genome. Science 296(5576):2225–2229 (2002).

International Human Genome Sequencing Consortium., Lander, E.S., Patrinos, A., Morgan, J.J. Initial sequencing and analysis of the human genome Nature 409, 813-958 (2001).

For additional publications, visit the PubMed database.