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Irina Arkhipova
Marlene Belfort
Matthew Meselson
Bill Reznikoff
Irina Arkhipova
Marlene Belfort
Matthew Meselson
William Reznikoff


Overview

Cluster Activies


The Mobile Genetic Element Cluster at the MBL includes senior and junior investigators who have established international reputations in transposable element research and together share a vision of this exciting field. Our research teams explore the basic science questions of how mobile genetic elements accomplish their movement and how that movement affects genome evolution. The Cluster’s studies also impact medically relevant questions and provide improved tools for genome research. The cluster participants are:

Dr. Irina Arkhipova, Assistant Research Scientist at the MBL and Staff Scientist in the Department of Molecular and Cellular Biology at Harvard University.

Dr. Marlene Belfort, Distinguished Professor at the Wadsworth Center, and SUNY Albany (Member of the American Academy of Arts and Sciences and the National Academy of Sciences) and Adjunct Scientist at the MBL.

Dr. Matthew Meselson, Thomas Dudley Cabot Professor of Natural Sciences at Harvard University (Member of the American Academy of Arts and Sciences, the National Academy of Sciences, and the Institute of Medicine) and Adjunct Scientist at the MBL.

Dr. William Reznikoff, Senior Research Scientist at the MBL (Member of the American Academy of Arts and Sciences).



Overview

One of the most profound impacts on the biological sciences during the last half-century comes from new insights about genome architecture and underlying mechanisms of genome change. Two major contributions to this new genome understanding are the technical development of DNA sequencing / annotation procedures and the discovery of mobile genetic elements that have shaped genome structures and affected gene expression in important ways. Transposable genetic elements are specific gene sequences that can move or be copied from one site to another within a genome. Less often, they can move from one genome to another, a form of horizontal gene transfer.

Transposable element research originated in the 1940s with the ground-breaking work of Barbara McClintock on what she called “controlling” genetic elements in maize. However, it was not until the late 1960s that bacterial geneticists recognized the important role of insertion sequence elements as a major source of mutation in bacteria and their more general role as agents of genetic change. The next important milestones were the discovery of mobile antibiotic resistance genes and the elucidation of retroviral reverse transcriptase mechanisms in the 1970s. These latter discoveries demonstrated that transposable elements can have important medically relevant effects, led to the discoveries of multiple different transposition pathways, and stimulated an enormous output of transposable element research. Finally, the genome sequencing efforts have revealed the great impact of mobile elements on ever changing genome architecture. Almost all genomes contain some transposable elements (the rare exceptions are in fact one subject of the cluster’s research), and in some organisms transposable elements or their remnants account for as much as one-half of genomic DNA (for example, they represent more than 40% of the human genome). Thus, if one is to understand genome structure and its evolution, one must understand transposable elements.

Cluster Activities

Basic Science Questions


The cluster investigators are interested in two broad basic science questions: what are the molecular mechanisms that lead to genetic transposition and how do transposable elements impact an organism’s life style. In the process of addressing these questions we may also gain insights into related phenomena such as retroviral infection, antibody gene formation, RNA splicing, protein splicing, the nature of endosymbiotic relationships between bacteria and eukaryotic cells, the evolution of sexual reproduction, and the lateral dispersal of transposable elements in the biosphere.


Drs. Belfort and Reznikoff investigate molecular mechanisms of transposition and its regulation for two very different types of elements. Dr. Belfort studies mobile introns and inteins, elements that interrupt genes and that are removed by RNA and protein splicing, respectively. Intron- and intein-encoded proteins promote movement of the elements to new sites on DNA by both DNA- and RNA-based reactions.


Dr. Reznikoff studies DNA transposition, in which the DNA sequence of the transposable element is cut out of a donor DNA molecule and inserted into a new site. DNA transposition is catalyzed by element-encoded proteins called transposases that are structurally and mechanistically related to retroviral integrases and to the immune system RAG-1 protein.
Dr. Arkhipova studies eukaryotic retroelements, which transpose via an RNA intermediate that is reverse transcribed and integrated into new chromosomal locations. She recently described a widespread class of retroelements that have an unprecedented ability to retrain introns after transposition, and may also be the evolutionary precursors of eukaryotic telomerase reverse transcriptases. Her studies of mobile elements in bdelloid rotifers led to the discovery of massive horizontal transfer of foreign genetic material Into their genomes.
Dr. Meselson is investigating possible roles of mobile genetic elements in the evolution and maintenance of sexual reproduction in eukaryotes. Recently, he hypothesized that an important contributor to the maintenance of sexual lineages and to the early extinction of asexuals could be the operation of meiosis-dependent mechanisms that prevent the unchecked increase of deleterious transposable elements. He is interested in studying, in collaboration with Dr. Arkhipova, the extant and relict transposable elements in rotifers of the Class Bdelloidea, an anciently asexual taxon, in order to investigate possible links between their long-term asexuality and the presence, activity status, and role of transposable elements in their genomes.

Medical Science Questions

Transposable elements are relevant to important medical issues. One example of this relevance can be found in Dr. Reznikoff’s work. The transposase protein is structurally and mechanistically related to HIV-1 integrase, but the transposase is easier to work with and has better structural information available. Therefore, the transposase can be used as a surrogate for isolating and analyzing small molecule inhibitors of the integrase, with the eventual hope that one might serve as a lead compound for anti-HIV-1 therapy. Likewise, the reverse transcriptases encoded by the mobile group II introns studied by Dr. Belfort can be used as surrogates for developing drug targets against retroviral reverse transcriptases. The research of Dr. Arkhipova will help to evaluate the potential of retrotransposable elements to serve as replicative vectors for genetic transformation of invertebrates. These vectors could become invaluable for health-related purposes such as the control of insect populations that are carriers for important diseases. Similar long-term goals are contemplated by Dr. Bordenstein, whose studies on mobile elements in Wolbachia could lead to extension studies in related pathogens (Rickettsia, Ehrlichia, or Anaplasma) or alternative therapies to combat Wolbachia-assisted pathologies in humans, including River Blindness and Elephantiasis.

Transposable Elements as Tools

Transposable elements are powerful research tools for scientists interested in genomics, protein structure/function studies, etc. For instance, transposable elements can provide insertion mutation libraries that facilitate genetic function analyses. There are novel strategies based upon transposon biology that can map protein secondary structures and determine protein cellular locations. In addition, transposable elements can function as mobile primer binding sites for large-scale DNA sequencing operations. We have already seen transposons used in DNA sequencing at the Bay Paul Center of the MBL (Dr. Hillary Morrison, personal communication), and two of the cluster investigators have plans for other applied transposition projects at the MBL. Dr. Reznikoff is planning a project with Dr. Anton Post to use transposable elements for a large scale Synechococcus mutation project which, if successful, will provide the worldwide cyanobacteria research community with a powerful set of tools. Dr. Bordenstein is considering using DNA transposable elements to generate mutations in the obligate endosymbiont Wolbachia. It is likely that this is one of only a few ways in which genetic studies can be performed in Wolbachia. An alternative is to use group II introns as gene-specific gene targeting agents in Wolbachia. Because group II introns integrate into DNA sites in a programmable, sequence-specific manner, and because their splicing can be rendered conditional, they may prove to be highly suitable for functional genomic studies in Wolbachia, as well as in many other microorganisms.

Synergistic Activities

It is a given in research that forming interactive scientific communities always generates synergy of efforts and exciting prospects for new research. The cluster represents a mix of investigators who are in complementary overlapping areas of research, work well together, and have a commitment to the MBL. Members of the cluster share expertise and methodologies and support each other’s work through the inevitable scientific exchanges. The long-term synergies are likely to include joint research grants and projects and to provide unique focused training opportunities for young investigators, including graduate students from the joint Brown University – MBL graduate program. In addition, the cluster can serve as a resource for the MBL summer courses and for other MBL resident and visiting investigators who wish to use transposable genetic elements as research tools.

There is no institution comparable to the MBL for facilitating collaborative biological investigation. This is because of its unique ability of attracting and housing short-term research projects. The cluster welcomes researchers working in the field to become associate members and to participate in any and all of the cluster activities. We also hope that the cluster will attract investigators from around the world to come to the MBL to pursue research related to mobile genetic elements.

Finally, one of the key scientific functions of the MBL is to act as an internationally recognized venue for research meetings. A workshop on transposition and site-specific recombination has been meeting at the MBL on a four year-cycle, bringing in a constant influx of new ideas and research initiatives. Plans are underway to host the MBL-based annual Northeast regional transposition meeting, which would facilitate contacts between transposon researchers in the area and provide an opportunity for graduate students and postdoctoral scientists to present their results in a series of informal talks. Regular meetings of the cluster will feature research seminars presented by members, associate members from nearby universities and research institutions, and visiting scientists throughout the year (biweekly in summer, bimonthly during the rest of the year).

Meeting Schedule

Northeast Mobile DNA Meeting Schedule, April 13-15, 2007, Woods Hole, MA

Northeast Mobile DNA Meeting Schedule, September 2-4, 2009, Woods Hole, MA

Northeast Mobile DNA Meeting Schedule, September 1-3, 2011, Woods Hole, MA

Related meetings at the MBL:

Site-specific Recombination Meeting, September 14-19, Woods Hole, MA

3rd International Conference on Retroviral Integrase, September 14-18, Woods Hole, MA

All of the above activities will result in broader dissemination of knowledge on the subject, and will help to transform the MBL into an international venue for transposable element science. We hope that all members of the cluster will be able to provide exciting contributions to Mobile DNA III by 2012!

       
Supported by NIH, NSF, NASA, The Josephine Bay Paul and C. Michael Paul Foundation, W.M. Keck Foundation, G. Unger Vetlesen Foundation, and Ellison Medical Foundation.
Unless otherwise stated, all material © 2004 Bay Paul Center, MBL.