Kazazian determined the molecular basis of single-gene genetic disorders such as hemoglobinopathies and hemophilia and introduced prenatal diagnosis for such disorders. His group was the first to identify a disease-causing mutation resulting from jumping genes in humans.[5] After this discovery, he focused on basic research into LINE retrotransposition in humans and its implications for disease.[6]
Early life and education
Haig Hagop Kazazian Jr.'s Armenian father was from Kayseri, Turkey. He was sent to the Ras el Ain concentration camp in Syria as part of the Armenian genocide, but escaped in 1918 and arrived in the U.S. in 1923.[7][8][9] Kazazian's mother, Hermine,[10] left Istanbul and arrived in the U.S. in 1920.[7][8][9] They married on January 1, 1929.[7]
Kazazian joined the faculty at Johns Hopkins in 1969.[2] He became a full professor, heading the Pediatric Genetics Unit, in 1977.[11] In 1979,[7] he established one of the first DNA diagnostic laboratories, providing molecular detection facilities for identifying monogenic disorders. He introduced prenatal diagnosis for hemoglobin disorders.[2] In 1988, Kazazian became Director of the Center for Medical Genetics at Johns Hopkins.[11] From 1988 to 1994, he and Maxine Singer at the National Institutes of Health (NIH) held joint quarterly lab meetings, sharing their knowledge of the biochemistry and genetics.[13]
In 1994, he became Chair of the Department of Genetics at the University of Pennsylvania School of Medicine, holding the position until 2006.[12] He remained at the University of Pennsylvaniaf as the Seymour Gray Professor of Molecular Medicine in Genetics from 2006 to 2010.[11]
In 1999, Kazazian and Arupa Ganguly joined the plaintiffs for Association for Molecular Pathology v. Myriad Genetics, Inc.,[2][16] after they were served with a cease-and-desist letter demanding that they stop breast cancer screenings for the BRCA1 and BRCA2 genes.[7]
In a unanimous ruling in 2013, the Supreme Court ruled that companies cannot patent parts of naturally occurring human genes. The Court stated that "a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but manmade cDNA is patent eligible because it is not naturally occurring."[17][18][19] In July 2010, Kazazian returned to Johns Hopkins, holding the position of a Professor in the Institute of Genetic Medicine.[11] He closed his laboratory there in 2020.[3]
His book Mobile DNA: Finding Treasure in Junk (2011) gives an overview of research on transposable elements. It does a "remarkable job" of discussing early contributors, the development of computational biology, and the field of mobile DNA and retrotransposable elements.[20] Although the initial chapters of background information on the field have been criticized as less interesting than later and more personal chapters, the account is credited with vividly illustrating "both the destructive and constructive facets of transposition in the genome".[21]
Much of his early research focused on the regulation of hemoglobin synthesis and its implications for the human blood disorder β-thalassemia.[9]
Using information on β-globin DNA polymorphisms from Stylianos Antonarakis and others, Kazazian helped develop methods for prenatal diagnosis of sickle cell anemia. Coining the term haplotypes for certain types of polymorphisms, Kazazian collaborated with Stuart Orkin to characterize the mutations causing beta-thalassemia.[9][2] He used haplotypes to classify β-thalassemia mutations in patients from around the world and to prenatally identify β-thalassemia.[12]
In the 1980s, Kazazian began to study the factor 8 blood-clotting gene, which was known to be defective in hemophilia A. Lab member Hagop Youssoufian found a long interspersed nuclear element (LINE) insertion, a mobile DNA element or transposon colloquially known as a “jumping gene”. Jumping genes were discovered in maize by Barbara McClintock.[9] The Kazazian lab was the first to discover a jumping gene in humans, and to demonstrate that a transposable element caused disease in man via insertional mutagenesis.[4][5][2] Kazazian expanded this work to mouse models, providing evidence that active retrotransposons occur in other mammals.[4]
Since then Kazazian has focused on basic research into LINE retrotransposition in humans, and the role of jumping genes in human disease. Retrotransposons copy and insert themselves into new locations in the genome.[6]
As a postdoctoral fellow with Kazazian, John Moran developed a cell culture assay to detect retrotransposition. They determined that the average human genome has 80–100 active LINE-1 (L1) retrotransposons, a handful of which are very active.[9][6][22]
In addition to understanding diseases, studying L1 insertions enables researchers to learn about human diversity.[6]
Kazazian's studies with rodents suggest that retrotransposition tends to occur during early embryonic development.[9] Kazazian found that retrotransposon mobility causes shuffling of exons and their flanking sequences, a discovery with important implications for the understanding of evolution.[4]
Kazazian investigated the possibility that LINE-1 jumping genes play a role in cancer. He and others have observed instances of new insertions of jumping genes in some cancers, but he could not determine whether LINE-1 genes drive cancer development or are a side effect of cancer.[23]
Kazazian, Haig H.; Wong, Corinne; Youssoufian, Hagop; Scott, Alan F.; Phillips, Deborah G.; Antonarakis, Stylianos E. (March 1988). "Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man". Nature. 332 (6160): 164–166. Bibcode:1988Natur.332..164K. doi:10.1038/332164a0. PMID2831458. S2CID4259071.
Dombroski, Beth A.; Mathias, Stephen L.; Nanthakumar, Elizabeth; Scott, Alan F.; Kazazian, Haig H. (December 20, 1991). "Isolation of an Active Human Transposable Element". Science. 254 (5039): 1805–1808. Bibcode:1991Sci...254.1805D. doi:10.1126/science.1662412. PMID1662412.
Bi, L.; Lawler, A.M.; Antonarakis, S.E.; High, K.A.; Gearhart, J.D.; Kazazian, H.H. (May 1995). "Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A". Nature Genetics. 10 (1): 119–121. doi:10.1038/ng0595-119. PMID7647782. S2CID27366245.
Ostertag, Eric M.; DeBerardinis, Ralph J.; Goodier, John L.; Zhang, Yue; Yang, Nuo; Gerton, George L.; Kazazian, Haig H. (December 2002). "A mouse model of human L1 retrotransposition". Nature Genetics. 32 (4): 655–660. doi:10.1038/ng1022. PMID12415270. S2CID22004980.
