Haig H. Kazazian, Jr., M.D.,
Professor, Dept of Genetics

Genetics and Gene Regulation Program

Address

564 Clinical Research Building
415 Curie Boulevard
Philadelphia, Pennsylvania 19104-6145

Office tel.: 215 898-3582
Fax: 215 573-7760
E-mail:kazazian@mail.med.upenn.edu

Link(s)

Dr Kazazian at the Dept of Genetics

Education

Dartmouth College, A.B. (Biology ), 1959.

Johns Hopkins University, M.D., 1962.

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.

Search PubMed for articles

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 3´ 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.

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.

Recent Publications

Kazazian HH, Jr. L1 retrotransposons shape the human genome. Science 289:1152-1154, 2000.

Ostertag EM and Kazazian HH, Jr. Twin priming: a proposed mechanism for the creation of inversions in L1 retrotransposition. Genome Research 11:2059-2065, 2001.

Ostertag EM, DeBerardinis RJ, Goodier JL, Zhang Y, Yang, N, Gerton G, and Kazazian HH, Jr. A mouse model of human L1 retrotransposition. Nature Genetics 32:655-660, 2002.

Brouha B, Shustak J, Badge RM, Lutz-Prigge S, Farley AH, Moran JV, and Kazazian HH, Jr. Hot L1s account for the bulk of retrotransposition in the human population. Proc. Natl. Acad. Sci. U.S.A. 100:5280-5285, 2003.

Yang N, Zhang L, Zhang Y, and Kazazian HH, Jr. An important role for RUNX3 in human L1 transcription and retrotransposition. Nucleic Acids Research 31:4929-4940, 2003.

Lab

Rotation Projects

Please see Dr. Kazazian for current lab rotation projects.

Lab personnel:

Adam D. Ewing University of Pennsylvania Graduate Student
Irene Godoy Research Specialist
John L. Goodier Senior Research Investigator
Dustin Carl Hancks University of Pennsylvania Graduate Student
Hiroki Kano Postdoctoral Researcher
Amy Marie Lange Research Specialist
Blair B. Madison Postdoctoral Fellow
Prabhat K. Mandal Postdoctoral Researcher
Sanjida H. Rangwala Postdoctoral Fellow
Denise E. Sabatino Senior Research Investigator
Samuel Vidal Haverford College Undergraduate Student
Lili Zhang Research Specialist