Haig Kazazian Explained

Haig Kazazian
Birth Date:30 July 1937[1]
Birth Name:Haig Hagop Kazazian Jr.
Birth Place:Toledo, Ohio
Death Place:Towson, Maryland
Workplaces:Johns Hopkins University School of Medicine, University of Pennsylvania
Field:Genetics
Alma Mater:Dartmouth College, Johns Hopkins University School of Medicine

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

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. After this discovery, he focused on basic research into LINE retrotransposition in humans and its implications for disease.

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. Kazazian's mother, Hermine,[3] left Istanbul and arrived in the U.S. in 1920. They married on January 1, 1929.

Haig Jr. was born in Toledo, Ohio, on July 30, 1937.[1] He grew up speaking Armenian, Turkish and English. He 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 in 1962, and interned in pediatrics at the University of Minnesota.

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) In 1966, he joined Harvey Itano at the National Institutes of Health,[4] working as a staff associate for the US Public Health Service.[5] In Itano's labotory, Kazazian worked on hemoglobin regulation.

Kazazian joined the faculty at Johns Hopkins in 1969.[2] He became a full professor, heading the Pediatric Genetics Unit, in 1977.[4] In 1979,[5] 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.[4] 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.[6]

Kazazian and Richard Cotton were founding co-editors of the journal Human Mutation, which appeared in 1992.[7] Kazazian became a co-editor of the journal Mobile DNA in 2015.[8]

In 1994, he became Chair of the Department of Genetics at the University of Pennsylvania School of Medicine, holding the position until 2006. He remained at the University of Pennsylvaniaf as the Seymour Gray Professor of Molecular Medicine in Genetics from 2006 to 2010.[4]

In 1999, Kazazian and Arupa Ganguly joined the plaintiffs for Association for Molecular Pathology v. Myriad Genetics, Inc.,[2] [9] after they were served with a cease-and-desist letter demanding that they stop breast cancer screenings for the BRCA1 and BRCA2 genes.[5] 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."[10] [11] [12] In July 2010, Kazazian returned to Johns Hopkins, holding the position of a Professor in the Institute of Genetic Medicine.[4] He closed his laboratory there in 2020.

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.[13] 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".[14]

Kazazian died on January 19[2] or 20, 2022 in Towson, Maryland.[15]

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).[5]

Much of his early research focused on the regulation of hemoglobin synthesis and its implications for the human blood disorder β-thalassemia. 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.[2] He used haplotypes to classify β-thalassemia mutations in patients from around the world and to prenatally identify β-thalassemia.[15]

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. 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.[16] [2] Kazazian expanded this work to mouse models, providing evidence that active retrotransposons occur in other mammals.

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.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.[17] In addition to understanding diseases, studying L1 insertions enables researchers to learn about human diversity.[18]

Kazazian's studies with rodents suggest that retrotransposition tends to occur during early embryonic development. Kazazian found that retrotransposon mobility causes shuffling of exons and their flanking sequences, a discovery with important implications for the understanding of evolution.

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.[19]

Awards

Papers

Notes and References

  1. Web site: Kazazian, Haig H., Jr., 1937- . Library of Congress Authorities . 7 February 2022.
  2. News: Wasta . Vanessa . Butch . Rachel . Haig Kazazian, pioneer in genetic medicine, dies at 84 . 6 February 2022 . The Hub . 2 February 2022 . en.
  3. News: Hermine A. Kazazian Obituary . 2007 . The Detroit News . 7 February 2022.
  4. Web site: Haig H. Kazazian . InformIT . 5 February 2022.
  5. Kazazian . Haig H. . A Long, Fulfilling Career in Human Genetics . Annual Review of Genomics and Human Genetics . 31 August 2021 . 22 . 1 . 27–53 . 10.1146/annurev-genom-111620-095614 . 33945751 . 233744364 . 1527-8204. free .
  6. Book: Kazazian . Haig H. . Mobile DNA: Finding Treasure in Junk . March 18, 2011 . FT Press . Upper Saddle River, NJ . 978-0-13-257525-6 . February 7, 2022 . en.
  7. Infectious Enthusiasm! Larger than Life! That Laugh! That Smile! In Loving Memory of Richard G.H. (Dick) Cotton . 10.1002/humu.22990 . 27030029 . 37. 6. Human Mutation. 598–615. 2016. 205923182 . free.
  8. Rose . Sam . Mobile DNA welcomes new Editors-in-Chief, Marlene Belfort and Haig Kazazian . On Biology . 17 April 2015 . 7 February 2022.
  9. News: Butanis . Benjamin . Supreme Court Rules on Gene Patent Case . 6 February 2022 . Johns Hopkins Medicine . en.
  10. News: Goldstein . Tom . Details on Association for Molecular Pathology v. Myriad Genetics, Inc. . 6 February 2022 . SCOTUSblog . 13 June 2013.
  11. News: Brandom . Russell . After Supreme Court ruling, don't count out gene patenting quite yet . 6 February 2022 . The Verge . 14 June 2013 . en.
  12. News: Marbella . Jean . Ban on patenting DNA cheers researchers . 6 February 2022 . The Baltimore Sun . June 13, 2013.
  13. Batzer . Mark A. . Mobile DNA: Finding Treasure in Junk . American Journal of Human Genetics . 11 July 2013 . 93 . 1 . 5 . 10.1016/j.ajhg.2013.06.001 . 3710766 . 0002-9297.
  14. Feschotte . Cédric . Review of Mobile DNA - finding treasure in junk by Haig H Kazazian . Mobile DNA . 3 October 2012 . 3 . 1 . 16 . 10.1186/1759-8753-3-16 . 1024114 . 1759-8753. free . 3517452 .
  15. News: Rader . Daniel J. . Announcement from Dr. Rader: Death of Haig H Kazazian, Jr, MD . 7 February 2022 . Penn Genetics . 25 January 2022.
  16. Singer . Maxine F. . From Genomic Junk to Human Disease . Proceedings of the American Philosophical Society . 1994 . 138 . 1 . 11–24 . 986702 . 7 February 2022 . 0003-049X.
  17. Ishak . Charles A. . De Carvalho . Daniel D. . Reactivation of Endogenous Retroelements in Cancer Development and Therapy . Annual Review of Cancer Biology . 9 March 2020 . 4 . 1 . 159–176 . 10.1146/annurev-cancerbio-030419-033525 . 213919601 . 2472-3428. free .
  18. News: Johns Hopkins Researchers Capture Jumping Genes . 6 February 2022 . Johns Hopkins Medicine . February 4, 2011 . en.
  19. News: Ives . James . Jumping genes: a marker for early cancer diagnosis? An interview with Dr Kazazian . 7 February 2022 . News-Medical.net . 6 October 2015 . en.
  20. Azar . Beth . Profile of Haig H. Kazazian Jr. . Proceedings of the National Academy of Sciences . 22 December 2020 . 117 . 51 . 32185–32188 . 10.1073/pnas.2023398117 . 33273116 . 7768710 . 2020PNAS..11732185A . en . 0027-8424. free .
  21. Web site: Haig H. Kazazian . National Academy of Sciences . 7 February 2022.
  22. Antonarakis . Stylianos E. . William Allan Award Introduction: Haig H. Kazazian, Jr. . American Journal of Human Genetics . 13 February 2009 . 84 . 2 . 103–104 . 10.1016/j.ajhg.2009.01.002 . 2667997 . 0002-9297.
  23. Web site: Haig H. Kazazian . American Academy of Arts & Sciences . 6 February 2022 . en.
  24. Web site: Past Award Recipients - Society for Pediatric Research Award in honor of E. Mead Johnson . Society for Pediatric Research . 7 February 2022.

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