In Memoriam

Haig H. Kazazian Jr., M.D.

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Department: Genetics

Contact information
Haig H. Kazazian, Jr., M.D.
Department of Genetics
University of Pennsylvania
564 Clinical Research Building
415 Curie Boulevard
Philadelphia, PA 19104-6145
Office: 215-898-3582
Fax: 215-573-7760
A.B. (Medical Science)
Dartmouth College (magna cum laude), 1959.
Dartmouth Medical School, 1960.
M.D. (Medicine)
The Johns Hopkins University School of Medicine, 1962.
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Description of Research Expertise

Research Interests
  • Population genetics of active L1 retrotransposons in humans.
  • Individual differences in retrotransposition capability have global effects on genome diversity and human evolution.
  • A mouse model of human L1 retrotransposition as a tool for insertional mutagenesis and discovery of gene function.
  • The SVA element is a non-autonomous retrotransposon that can cause disease
  • Preclinical trials of AAV-mediated gene therapy of hemophilia A in mice and dogs.
Key words: hemophilia, retrotransposon, gene therapy.

Description of Research

Dr. Kazazian has had a long interest in the nature of retrotransposable elements in humans. These L1 elements are present in 500,000 inactive copies and 80-100 active copies in the average human genome. The active elements encode a reverse transcriptase, an endonuclease, and other protein functions that help them retrotranspose. Retrotransposition is characterized by transcription of the L1 DNA into L1 RNA, reverse transcription to L1 cDNA, and integration into a new site in the genome. Some retrotranspositions produce disease, such as hemophilia A, muscular dystrophy, and breast and colon cancer. The lab has developed an assay for retrotransposition in human and rodent cells in culture and has used this assay to elucidate important L1 protein sequences for retrotransposition and the number of human L1 elements capable of retrotransposition. It has also used the assay to demonstrate the existence of 3 distinct subfamilies of mouse L1 elements and shown that mice have up to 3,000 active L1s or 40 times the number present in the human genome. We have also shown that L1 retrotransposition is a likely source of exon shuffling via transduction of sequences 3ยด to active L1s into new genomic sites. This shuffling of DNA sequences from one place to another suggests a major evolutionary benefit of retrotransposons to their mammalian hosts. Recently, we have successfully created a mouse model of human L1 retrotransposition. These mice demonstrate retrotransposition of marked L1s in male germ cells at frequencies as high as 1 in 20 sperm. In addition, the events are indistinguishable from natural endogenous insertions. We plan to use this model of insertional mutagenesis to characterize phenotypic effects of various mouse genes.

A most exiting recent project uses computational and wet bench skills along with high-throughput sequencing. In this work we find essentially all of the L1 insertion sites in any genome using PCR reactions off the 3' end of L1 and Solexa sequencing of the products. With this approach we have already found 600 L1s that are polymorphic as to presence in human genomes. We are using the approach to discover the frequency of new insertions in the population, the frequency of somatic insertions, the frequency of new insertions in clonal stem cell lines,and the frequency of insertions in cancers, other diseases, and aborted fetuses. We have obtained a Challenge Grant to augment Genome Wide Association studies with L1 and Alu insertional polymorphisms.

The lab has long studied the molecular diagnosis and treatment of hemophilia A. The lab has made a knockout mouse model of hemophilia A for studies of factor VIII biology and gene therapy. We are now working on treatment of the mice by factor VIII derived from skin and liver. We have shown that factor VIII transgenes expressed in the outer layers of skin will correct factor VIII deficiency in knockout mice. We have also obtained correction of factor VIII deficiency in the mice using adenoviral vectors and transient immune suppression. Presently, we are using gene therapy with adeno-associated virus vectors to correct hemophilia A in these mice and hemophilia A dogs, and have obtained 100% correction of the mice over 1 year.

Rotation Projects

Please see Dr. Kazazian for current lab rotation projects.

Lab personnel:

Katie Altynova, Research Specialist
Jessie Chen, Research Specialist
Julie Crudele, University of Pennsylvania Graduate Student
Adam Ewing, University of Pennsylvania Graduate Student
John Goodier, M.Sc., Ph.D., Research Assistant Professor
Dustin Hancks, University of Pennsylvania Graduate Student
Blair Madison, Ph.D., Postdoctoral Fellow
Prabhat Mandel, Ph.D., Postdoctoral Researcher
Sanjida Rangwala, Ph.D., Postdoctoral Fellow
Denise Sabatino, Ph.D., Research Assistant Professor
Lu Zheng, Research Specialist

Selected Publications

Hancks, D., Ewing, A., Chen, J. E., Tokunaga, K., Kazazian, H.: Exon-trapping mediated by the human retrotransposon SVA. Genome Res 2009.

Rangwala, S. H., Zhang, L., Kazazian, H. H., Jr.: Many LINE1 elements contribute to the transcriptome of human somatic cells. Genome Biol 10(9): R100, 2009.

Kano, H., Godoy, I., Courtney, C., Vetter, M. R., Gerton, G. L., Ostertag, E. M., Kazazian, H. H., Jr.: L1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicism. Genes Dev 23(11): 1303-12, 2009.

Goodier, J. L., Kazazian, H. H., Jr.: Retrotransposons revisited: the restraint and rehabilitation of parasites. Cell 135(1): 23-35, 2008.

Goodier, J. L., Zhang, L., Vetter, M. R., Kazazian, H. H., Jr.: LINE-1 ORF1 protein localizes in stress granules with other RNA-binding proteins, including components of RNA interference RNA-induced silencing complex. Mol Cell Biol 27(18): 6469-83, 2007.

Babushok, D. V., Ohshima, K., Ostertag, E. M., Chen, X., Wang, Y., Mandal, P. K., Okada, N., Abrams, C. S., Kazazian, H. H., Jr.: A novel testis ubiquitin-binding protein gene arose by exon shuffling in hominoids. Genome Res 17(8): 1129-38, 2007.

Babushok, D. V., Ostertag, E. M., Kazazian, H. H., Jr.: Current topics in genome evolution: molecular mechanisms of new gene formation. Cell Mol Life Sci 64(5): 542-54, 2007.

Babushok, D. V., Kazazian, H. H., Jr.: Progress in understanding the biology of the human mutagen LINE-1. Hum Mutat 28(6): 527-39, 2007.

Babushok, D. V., Ostertag, E. M., Courtney, C. E., Choi, J. M., Kazazian, H. H., Jr.: L1 integration in a transgenic mouse model. Genome Res 16(2): 240-50, 2006.

Seleme, M. C., Vetter, M. R., Cordaux, R., Bastone, L., Batzer, M. A., Kazazian, H. H., Jr.: Extensive individual variation in L1 retrotransposition capability contributes to human genetic diversity. Proc Natl Acad Sci U S A 103(17): 6611-6, 2006.

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Last updated: 01/26/2010
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