Haig H. Kazazian, Jr. (July 30, 1937 – January 19/20, 2022) was a professor in the Department of Genetic Medicine at

Johns Hopkins University School of Medicine The Johns Hopkins University School of Medicine (JHUSOM) is the medical school of Johns Hopkins University, a private research university in Baltimore, Maryland. Founded in 1893, the School of Medicine shares a campus with the Johns Hopkins Hospi ...

Baltimore, Maryland Baltimore ( , locally: or ) is the List of municipalities in Maryland, most populous city in the U.S. state of Maryland, fourth most populous city in the Mid-Atlantic (United States), Mid-Atlantic, and List of United States cities by popula ...

. Kazazian was an elected member of the

National Academy of Sciences The National Academy of Sciences (NAS) is a United States nonprofit, non-governmental organization. NAS is part of the National Academies of Sciences, Engineering, and Medicine, along with the National Academy of Engineering (NAE) and the Nati ...

and the

American Academy of Arts and Sciences The American Academy of Arts and Sciences (abbreviation: AAA&S) is one of the oldest learned societies in the United States. It was founded in 1780 during the American Revolution by John Adams, John Hancock, James Bowdoin, Andrew Oliver, and ...

. Kazazian determined the molecular basis of single-gene

genetic disorders A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

such as

hemoglobinopathies Hemoglobinopathy is the medical term for a group of inherited blood disorders and diseases that primarily affect red blood cells. They are single-gene disorders and, in most cases, they are inherited as autosomal co-dominant traits. There are t ...

and

hemophilia Haemophilia, or hemophilia (), is a mostly inherited genetic disorder that impairs the body's ability to make blood clots, a process needed to stop bleeding. This results in people bleeding for a longer time after an injury, easy bruising, ...

and introduced prenatal diagnosis for such disorders. His group was the first to identify a disease-causing mutation resulting from

jumping genes A transposable element (TE, transposon, or jumping gene) is a nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Trans ...

in humans. After this discovery, he focused on basic research into LINE

retrotransposition A transposable element (TE, transposon, or jumping gene) is a nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Trans ...

in humans and its implications for disease.

Early life and education

Kazazian's Armenian father (also Haig H. Kazazian) was from

Kayseri Kayseri (; el, Καισάρεια) is a large Industrialisation, industrialised List of cities in Turkey, city in Central Anatolia, Turkey, and the capital of Kayseri Province, Kayseri province. The Kayseri Metropolitan Municipality area is comp ...

, Turkey. He was sent to the Ras el Ain concentration camp in Syria as part of the

Armenian genocide The Armenian genocide was the systematic destruction of the Armenians in the Ottoman Empire, Armenian people and identity in the Ottoman Empire during World War I. Spearheaded by the ruling Committee of Union and Progress (CUP), it was ...

, but escaped in 1918 and arrived in the U.S. in 1923. Kazazian's mother Hermine left

Istanbul Istanbul ( , ; tr, İstanbul ), formerly known as Constantinople ( grc-gre, Κωνσταντινούπολις; la, Constantinopolis), is the List of largest cities and towns in Turkey, largest city in Turkey, serving as the country's economic, ...

and arrived in the U.S. in 1920. They married on January 1, 1929. Haig Hagop Kazazian, Jr. was born in

Toledo, Ohio Toledo ( ) is a city in and the county seat of Lucas County, Ohio, United States. A major Midwestern United States port city, Toledo is the fourth-most populous city in the state of Ohio, after Columbus, Cleveland, and Cincinnati, and according ...

, on July 30, 1937. He grew up speaking Armenian, Turkish and English. Kazazian attended

Dartmouth College Dartmouth College (; ) is a private research university in Hanover, New Hampshire. Established in 1769 by Eleazar Wheelock, it is one of the nine colonial colleges chartered before the American Revolution. Although founded to educate Native A ...

, receiving his A.B. degree from Dartmouth College in 1959, followed by a two-year program at

Dartmouth Medical School The Geisel School of Medicine at Dartmouth is the graduate medical school of Dartmouth College in Hanover, New Hampshire. The fourth oldest medical school in the United States, it was founded in 1797 by New England physician Nathan Smith. It is o ...

. He completed his M.D. degree at

in 1962 and interned in pediatrics at the

University of Minnesota The University of Minnesota, formally the University of Minnesota, Twin Cities, (UMN Twin Cities, the U of M, or Minnesota) is a public university, public Land-grant university, land-grant research university in the Minneapolis–Saint Paul, Tw ...

Career

Kazazian returned to Baltimore, Maryland as a postdoctoral fellow, studying the genetics of

fruit flies Fruit fly may refer to: Organisms * Drosophilidae, a family of small flies, including: ** ''Drosophila'', the genus of small fruit flies and vinegar flies ** ''Drosophila melanogaster'' or common fruit fly ** ''Drosophila suzukii'' or Asian fruit ...

and X chromosome inactivation with

Barton Childs Barton Childs (February 29, 1916 – February 18, 2010)
was an American In 1966 he joined

Harvey Itano Harvey Akio Itano (November 3, 1920 – May 8, 2010) was an American biochemist best known for his work on the molecular basis of sickle cell anemia and other diseases. In collaboration with Linus Pauling, Itano used electrophoresis to demonstra ...

at the

National Institutes of Health The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...

, working as a staff associate for the

US Public Health Service The United States Public Health Service (USPHS or PHS) is a collection of agencies of the Department of Health and Human Services concerned with public health, containing nine out of the department's twelve operating divisions. The Assistant S ...

. In Itano's labotory, Kazazian worked on

hemoglobin Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...

regulation. Kazazian joined the faculty at Johns Hopkins in 1969. He became a full professor, heading the Pediatric Genetics Unit, in 1977. In 1979, he established one of the first DNA diagnostic laboratories, providing molecular detection facilities for identifying monogenic disorders. He introduced prenatal diagnosis for hemoglobin disorders. In 1988, Kazazian became Director of the Center for Medical Genetics at Johns Hopkins. From 1988 to 1994, he and

Maxine Singer Maxine Frank Singer (born February 15, 1931) is an American molecular biologist and science administrator. She is known for her contributions to solving the genetic code, her role in the ethical and regulatory debates on recombinant DNA techniq ...

at the National Institutes of Health (NIH) held joint quarterly lab meetings, sharing their knowledge of the biochemistry and genetics. Kazazian and Richard Cotton were founding co-editors of the journal ''

Human Mutation ''Human Mutation'' is a Peer review, peer-reviewed medical journal of human genetics published by Wiley-Liss on behalf of the Human Genome Variation Society. It first appeared in 1992. The founding editors-in-chief were Haig H. Kazazian and Richar ...

'', which appeared in 1992. Kazazian became a co-editor of the journal ''

Mobile DNA A transposable element (TE, transposon, or jumping gene) is a nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Trans ...

'' in 2015. In 1994 Kazazian became Chair of the Department of Genetics at the

University of Pennsylvania School of Medicine The Perelman School of Medicine, commonly known as Penn Med, is the medical school of the University of Pennsylvania, a private research university in Philadelphia, Pennsylvania. Founded in 1765, the Perelman School of Medicine is the oldest medi ...

, 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. In 1999, Kazazian and Arupa Ganguly joined the plaintiffs for ''

Association for Molecular Pathology v. Myriad Genetics, Inc. ''Association for Molecular Pathology v. Myriad Genetics, Inc.'', 569 U.S. 576 (2013), was a Supreme Court case that challenged the validity of gene patents in the United States, specifically questioning certain claims in issued patents owned or ...

'', after they were served with a cease-and-desist letter demanding that they stop

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...

screenings for the

BRCA1 Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a h ...

and

BRCA2 ''BRCA2'' and BRCA2 () are a human gene and its protein product, respectively. The official symbol (BRCA2, italic for the gene, nonitalic for the protein) and the official name (originally breast cancer 2; currently BRCA2, DNA repair associated) ...

genes. 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." In July 2010, Kazazian returned to Johns Hopkins, holding the position of a Professor in the Institute of Genetic Medicine. He closed his laboratory there in 2020. 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. 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". Kazazian died on January 19 or 20, 2022 in

Towson, Maryland Towson () is an unincorporated community and a census-designated place in Baltimore County, Maryland, United States. The population was 55,197 as of the 2010 census. It is the county seat of Baltimore County and the second-most populous unincorpo ...

Research

Kazazian made important contributions to

human genetics Human genetics is the study of inheritance as it occurs in human beings. Human genetics encompasses a variety of overlapping fields including: classical genetics, cytogenetics, molecular genetics, biochemical genetics, genomics, population gene ...

through his research into DNA

haplotypes A haplotype (haploid genotype) is a group of alleles in an organism that are inherited together from a single parent. Many organisms contain genetic material ( DNA) which is inherited from two parents. Normally these organisms have their DNA org ...

and the molecular basis of

beta thalassemia Beta thalassemias (β thalassemias) are a group of inherited blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to cli ...

and through his exploration of

retrotransposons Retrotransposons (also called Class I transposable elements or transposons via RNA intermediates) are a type of genetic component that copy and paste themselves into different genomic locations (transposon) by converting RNA back into DNA through ...

(jumping genes). Much of his early research focused on the regulation of hemoglobin synthesis and its implications for the human blood disorder

β-thalassemia Beta thalassemias (β thalassemias) are a group of genetic disorder, inherited hemoglobinopathy, blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the HBB, beta chains of hemoglobin that result in variable out ...

. Using information on β-globin DNA polymorphisms from Stylianos Antonarakis and others, Kazazian helped develop methods for prenatal diagnosis of

sickle cell anemia Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blo ...

. Coining the term

for certain types of polymorphisms, Kazazian collaborated with

Stuart Orkin Stuart Holland Orkin is an American physician, stem cell biologist and researcher in pediatric hematology-oncology. He is the David G. Nathan Distinguished Professor of Pediatrics at Harvard Medical School. Orkin's research has focused on the gen ...

to characterize the mutations causing

beta-thalassemia Beta thalassemias (β thalassemias) are a group of inherited blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to cl ...

. He used haplotypes to classify β-thalassemia mutations in patients from around the world and to prenatally identify β-thalassemia. In the 1980s, Kazazian began to study the

factor 8 Factor VIII (FVIII) is an essential blood-clotting protein, also known as anti-hemophilic factor (AHF). In humans, factor VIII is encoded by the ''F8'' gene. Defects in this gene result in hemophilia A, a recessive X-linked coagulation disorder. ...

blood-clotting gene, which was known to be defective in

hemophilia A Haemophilia A (or hemophilia A) is a genetic deficiency in clotting factor VIII, which causes increased bleeding and usually affects males. In the majority of cases it is inherited as an X-linked recessive trait, though there are cases which arise ...

. Lab member Hagop Youssoufian found a

long interspersed nuclear element Long interspersed nuclear elements (LINEs) (also known as long interspersed nucleotide elements or long interspersed elements) are a group of non-LTR (long terminal repeat) retrotransposons that are widespread in the genome of many eukaryotes. The ...

(LINE) insertion, a

mobile DNA A transposable element (TE, transposon, or jumping gene) is a nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Trans ...

element or transposon colloquially known as a “jumping gene”. Jumping genes were discovered in

maize Maize ( ; ''Zea mays'' subsp. ''mays'', from es, maíz after tnq, mahiz), also known as corn (North American and Australian English), is a cereal grain first domesticated by indigenous peoples in southern Mexico about 10,000 years ago. Th ...

Barbara McClintock Barbara McClintock (June 16, 1902 – September 2, 1992) was an American scientist and cytogeneticist who was awarded the 1983 Nobel Prize in Physiology or Medicine. McClintock received her PhD in botany from Cornell University in 1927. There s ...

. 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 In molecular biology, insertional mutagenesis is the creation of mutations of DNA by addition of one or more base pairs. Such insertional mutations can occur naturally, mediated by viruses or transposons, or can be artificially created for researc ...

. 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

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. In addition to understanding diseases, studying L1 insertions enables researchers to learn about human diversity. Kazazian's studies with rodents suggest that retrotransposition tends to occur during early embryonic development. Kazazian found that retrotransposon mobility causes shuffling of

exons An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

and their flanking sequences, a discovery with important implications for the understanding of

evolution Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...

. Kazazian has also investigated the possibility that LINE-1 jumping genes play a role in

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

. 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.

Awards

* 2018, Member,

* 2008,

William Allan Award The William Allan Award, given by the American Society of Human Genetics, was established in 1961 in memory of William Allan (1881–1943), one of the first American physicians to conduct extensive research in human genetics. The William Allan ...

American Society of Human Genetics The American Society of Human Genetics (ASHG), founded in 1948, is a professional membership organization for specialists in human genetics. As of 2009, the organization had approximately 8,000 members. The Society's members include researchers, a ...

* 2007, Member,

* 1976, E. Mead Johnson Award for Pediatric Research,

Society for Pediatric Research A society is a group of individuals involved in persistent social interaction, or a large social group sharing the same spatial or social territory, typically subject to the same political authority and dominant cultural expectations. Socie ...

Papers

* * * * * * * * * * * * * * * *

References

{{DEFAULTSORT:Kazazian, Haig H. 1937 births 2022 deaths American geneticists American molecular biologists Dartmouth College alumni Johns Hopkins University alumni Johns Hopkins University people University of Pennsylvania staff Writers from Toledo, Ohio Members of the National Academy of Medicine