Haig Kazazian

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Haig H. Kazazian
Born(1937-07-30)July 30, 1937[1]
Toledo, Ohio
DiedJanuary 20, 2022(2022-01-20) (aged 84)
Towson, Maryland.
Alma materDartmouth College, Johns Hopkins University School of Medicine
Scientific career
FieldsGenetics
InstitutionsJohns Hopkins University School of Medicine, University of Pennsylvania

Haig H. Kazazian (July 30, 1937-January 19/20, 2022) was a professor in the Department of Genetic Medicine at Johns Hopkins University School of Medicine, Baltimore, Maryland. [2] Kazazian was an elected member of the National Academy of Sciences[3] and the American Academy of Arts and Sciences.[4]

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

Kazazian's Armenian father (also Haig H. Kazazian) 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. They married on January 1, 1929. Haig Hagop Kazazian, Jr. was born in Toledo, Ohio[7][8][9] on July 30, 1937.[1] He grew up speaking Armenian, Turkish and English.[8]

Kazazian attended Dartmouth College, receiving his A.B. degree from Dartmouth College in 1959, followed by a two-year program at Dartmouth Medical School. He completed his M.D. degree at Johns Hopkins University School of Medicine[11] in 1962[8] and interned in pediatrics at the University of Minnesota.[8]

Career

Kazazian returned to Baltimore, Maryland as a postdoctoral fellow, studying the genetics of fruit flies and X chromosome inactivation with Barton Childs at Johns Hopkins (1964–1966)[12][8][9] In 1966 he joined Harvey Itano at the National Institutes of Health,[11] working as a staff associate for the US Public Health Service.[7] In Itano's labotory, Kazazian worked on hemoglobin regulation.[9]

Kazazian joined the faculty at Johns Hopkins in 1969, became head of the Pediatric Genetics Unit and a full professor in 1977. 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, pooling their knowledge of the biochemistry and genetics.[13]

Kazazian and Richard Cotton were founding co-editors of the journal Human Mutation, which appeared in 1992.[14] Kazazian became a co-editor of the journal Mobile DNA in 2015.[15]

In 1994 Kazazian 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 2006-2010.[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]

Kazazian's 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]

Kazazian died on January 19[2] or 20, 2022 in Towson, Maryland.[12]

Research

Kazazian made important contributions to human genetics through his research into DNA haplotypes and the molecular basis of beta thalassemia and through his exploration of retrotransposons (jumping genes).[7]

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, 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. A small number of LINE-1 (L1) insertions, 80–100 young LINEs, are active in humans.[6][22] In addition to understanding diseases, studying L1 insertions enables researchers to learn about human diversity.[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 L1 retrotransposons, a handful of which are very active. Kazazian's lab also discovered SVA, a short interspersed nuclear element (SINE) and active jumping gene.[9]

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 has also 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]

Awards

Papers

  • Kazazian, H. H.; Young, W. J.; Childs, B. (17 December 1965). "X-Linked 6-Phosphogluconate Dehydrogenase in Drosophila : Subunit Associations". Science. 150 (3703): 1601–1602. doi:10.1126/science.150.3703.1601.
  • Phillips, J. A.; Snyder, P. G.; Kazazian, H. H. (September 1977). "Ratios of α-to β-globin mRNA and regulation of globin synthesis in reticulocytes". Nature. 269 (5627): 442–445. doi:10.1038/269442a0.
  • Antonarakis, Stylianos E.; Boehm, Corinne D.; Giardina, Patricia J. V.; Kazazian, Haig H. (January 1982). "Nonrandom association of polymorphic restriction sites in the β-globin gene cluster". Proceedings of the National Academy of Sciences of the United States of America. 79 (1): 137–141. ISSN 0027-8424.
  • Orkin, Stuart H.; Kazazian, Haig H.; Antonarakis, Stylianos E.; Goff, Sabra C.; Boehm, Corinne D.; Sexton, Julianne P.; Waber, Pamela G.; Giardina, Patricia J. V. (April 1982). "Linkage of β-thalassaemia mutations and β-globin gene polymorphisms with DNA polymorphisms in human β-globin gene cluster". Nature. 296 (5858): 627–631. doi:10.1038/296627a0.
  • Chakravarti, A; Buetow, K H; Antonarakis, S E; Waber, P G; Boehm, C D; Kazazian, H H (November 1984). "Nonuniform recombination within the human beta-globin gene cluster". American Journal of Human Genetics. 36 (6): 1239–1258. ISSN 0002-9297.
  • Orkin, Stuart H.; Kazazian, Haig H. (1 December 1984). "The mutation and polymorphism of the human β-globin gene and its surrounding DNA". Annual Review of Genetics. 18 (1): 131–171. doi:10.1146/annurev.ge.18.120184.001023. ISSN 0066-4197.
  • Francomano, C A; Kazazian, H H (1 February 1986). "DNA Analysis in Genetic Disorders". Annual Review of Medicine. 37 (1): 377–395. doi:10.1146/annurev.me.37.020186.002113. ISSN 0066-4219.
  • 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. doi:10.1038/332164a0.
  • Dombroski, Beth A.; Mathias, Stephen L.; Nanthakumar, Elizabeth; Scott, Alan F.; Kazazian, Haig H. (20 December 1991). "Isolation of an Active Human Transposable Element". Science. 254 (5039): 1805–1808. doi:10.1126/science.1662412.
  • 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.
  • Moran, John V; Holmes, Susan E; Naas, Thierry P; DeBerardinis, Ralph J; Boeke, Jef D; Kazazian, Haig H (November 1996). "High Frequency Retrotransposition in Cultured Mammalian Cells". Cell. 87 (5): 917–927. doi:10.1016/s0092-8674(00)81998-4.
  • Moran, John V.; DeBerardinis, Ralph J.; Kazazian, Haig H. (5 March 1999). "Exon Shuffling by L1 Retrotransposition". Science. 283 (5407): 1530–1534. doi:10.1126/science.283.5407.1530.
  • Kazazian, Haig H. (18 August 2000). "L1 Retrotransposons Shape the Mammalian Genome". Science. 289 (5482): 1152–1153. doi:10.1126/science.289.5482.1152.
  • Ostertag, Eric M.; Kazazian Jr, Haig H. (1 December 2001). "Biology of Mammalian L1 Retrotransposons". Annual Review of Genetics. 35 (1): 501–538. doi:10.1146/annurev.genet.35.102401.091032. ISSN 0066-4197.
  • 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.
  • Hancks, Dustin C.; Goodier, John L.; Mandal, Prabhat K.; Cheung, Ling E.; Kazazian, Haig H. (1 September 2011). "Retrotransposition of marked SVA elements by human L1s in cultured cells". Human Molecular Genetics. 20 (17): 3386–3400. doi:10.1093/hmg/ddr245.

References

  1. ^ a b "Kazazian, Haig H., Jr., 1937-". Library of Congress Authorities. Retrieved 7 February 2022.
  2. ^ a b c d e f Wasta, Vanessa; Butch, Rachel (2 February 2022). "Haig Kazazian, pioneer in genetic medicine, dies at 84". The Hub. Retrieved 6 February 2022.
  3. ^ a b c "Haig H. Kazazian". National Academy of Sciences. Retrieved 7 February 2022.
  4. ^ a b c d e "Haig H. Kazazian". American Academy of Arts & Sciences. Retrieved 6 February 2022.
  5. ^ a b Singer, Maxine F. (1994). "From Genomic Junk to Human Disease". Proceedings of the American Philosophical Society. 138 (1): 11–24. ISSN 0003-049X. Retrieved 7 February 2022.
  6. ^ a b c "Johns Hopkins Researchers Capture Jumping Genes". Johns Hopkins Medicine. February 4, 2011. Retrieved 6 February 2022.
  7. ^ a b c d e f Kazazian, Haig H. (31 August 2021). "A Long, Fulfilling Career in Human Genetics". Annual Review of Genomics and Human Genetics. 22 (1): 27–53. doi:10.1146/annurev-genom-111620-095614. ISSN 1527-8204. Retrieved 5 February 2022.
  8. ^ a b c d e f g Antonarakis, Stylianos E. (13 February 2009). "William Allan Award Introduction: Haig H. Kazazian, Jr". American Journal of Human Genetics. 84 (2): 103–104. doi:10.1016/j.ajhg.2009.01.002. ISSN 0002-9297. Retrieved 6 February 2022.
  9. ^ a b c d e f g h i j Azar, Beth (22 December 2020). "Profile of Haig H. Kazazian Jr". Proceedings of the National Academy of Sciences. 117 (51): 32185–32188. doi:10.1073/pnas.2023398117. ISSN 0027-8424. Retrieved 6 February 2022.
  10. ^ "Hermine A. Kazazian Obituary". The Detroit News. 2007. Retrieved 7 February 2022.
  11. ^ a b c d e "Haig H. Kazazian". InformIT. Retrieved 5 February 2022.
  12. ^ a b c d Rader, Daniel J. (25 January 2022). "Announcement from Dr. Rader: Death of Haig H Kazazian, Jr, MD". Penn Genetics. Retrieved 7 February 2022.
  13. ^ Kazazian, Haig H. (18 March 2011). Mobile DNA: Finding Treasure in Junk. Upper Saddle River, NJ: FT Press. ISBN 978-0-13-257525-6. Retrieved 7 February 2022.
  14. ^ "Infectious Enthusiasm! Larger than Life! That Laugh! That Smile! In Loving Memory of Richard G.H. (Dick) Cotton". Human Mutation. 37 (6): 598–615. 2016. doi:10.1002/humu.22990. PMID 27030029. S2CID 205923182.
  15. ^ Rose, Sam (17 April 2015). "Mobile DNA welcomes new Editors-in-Chief, Marlene Belfort and Haig Kazazian". On Biology. Retrieved 7 February 2022.
  16. ^ Butanis, Benjamin. "Supreme Court Rules on Gene Patent Case". Johns Hopkins Medicine. Retrieved 6 February 2022.
  17. ^ Goldstein, Tom (13 June 2013). "Details on Association for Molecular Pathology v. Myriad Genetics, Inc". SCOTUSblog. Retrieved 6 February 2022.
  18. ^ Brandom, Russell (14 June 2013). "After Supreme Court ruling, don't count out gene patenting quite yet". The Verge. Retrieved 6 February 2022.
  19. ^ Marbella, Jean (June 13, 2013). "Ban on patenting DNA cheers researchers". The Baltimore Sun. Retrieved 6 February 2022.
  20. ^ Batzer, Mark A. (11 July 2013). "Mobile DNA: Finding Treasure in Junk". American Journal of Human Genetics. 93 (1): 5. doi:10.1016/j.ajhg.2013.06.001. ISSN 0002-9297. Retrieved 6 February 2022.
  21. ^ Feschotte, Cédric (3 October 2012). "Review of Mobile DNA - finding treasure in junk by Haig H Kazazian". Mobile DNA. 3 (1): 16. doi:10.1186/1759-8753-3-16. ISSN 1759-8753. Retrieved 7 February 2022.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  22. ^ Ishak, Charles A.; De Carvalho, Daniel D. (9 March 2020). "Reactivation of Endogenous Retroelements in Cancer Development and Therapy". Annual Review of Cancer Biology. 4 (1): 159–176. doi:10.1146/annurev-cancerbio-030419-033525. ISSN 2472-3428. Retrieved 7 February 2022.
  23. ^ Ives, James (6 October 2015). "Jumping genes: a marker for early cancer diagnosis? An interview with Dr Kazazian". News-Medical.net. Retrieved 7 February 2022.
  24. ^ "Past Award Recipients - Society for Pediatric Research Award in honor of E. Mead Johnson". Society for Pediatric Research. Retrieved 7 February 2022.
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