1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Genomics and Human Genetics
  4. Volume 22, 2021
  5. Article

Annual Review of Genomics and Human Genetics

Volume 22, 2021

A Long, Fulfilling Career in Human Genetics

Abstract

I have been fortunate and privileged to have participated in amazing breakthroughs in human genetics since the 1960s. I was lucky to have trained in medical school at Dartmouth and Johns Hopkins, in pediatrics at the University of Minnesota and Johns Hopkins, and in genetics and molecular biology with Dr. Barton Childs at Johns Hopkins and Dr. Harvey Itano at the National Institutes of Health. Later, the collaborative spirit at Johns Hopkins and the University of Pennsylvania were important to my career. Here, I describe the thrill of scientific discovery in two diverse areas of human genetics: DNA haplotypes and their role in solving the molecular basis of beta thalassemia and the role of retrotransposons (jumping genes) in human biology. I hope that this article may inspire others who love human genetics as much as I do.

Keyword(s): autobiography, haplotypes, retrotransposons, thalassemia
Loading

Article metrics loading...

/content/journals/10.1146/annurev-genom-111620-095614
2021-08-31
2024-04-23
Loading full text...

Full text loading...

/deliver/fulltext/genom/22/1/annurev-genom-111620-095614.html?itemId=/content/journals/10.1146/annurev-genom-111620-095614&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Antonarakis SE, Boehm CD, Giardina PJV, Kazazian HH Jr 1982. Non-random association of polymorphic restriction sites in the β-globin gene cluster. PNAS 79:137–41
     [Google Scholar]
  2. 2. 
    Antonarakis SE, Orkin SH, Cheng T-C, Scott AF, Sexton JP et al. 1984. β-Thalassemia in American Blacks: novel mutations in the TATA box and IVS-2 acceptor splice site. PNAS 81:1154–58
     [Google Scholar]
  3. 3. 
    Baillie JK, Barnett MW, Upton KR, Gerhardt DJ, Richmond TA et al. 2011. Somatic retrotransposition alters the genetic landscape of the human brain. Nature 479:534–37
     [Google Scholar]
  4. 4. 
    Beck CR, Collier P, Macfarlane C, Malig M, Kidd JM et al. 2010. LINE-1 retrotransposition activity in human genomes. Cell 141:1159–70
     [Google Scholar]
  5. 5. 
    Boeke JD, Garfinkel DJ, Styles CA, Fink GR. 1985. Ty elements transpose through an RNA intermediate. Cell 40:491–500
     [Google Scholar]
  6. 6. 
    Boissinot S, Entezam A, Young L, Munson PJ, Furano AV. 2004. The insertional history of an active family of L1 retrotransposons in humans. Genome Res 14:1221–31
     [Google Scholar]
  7. 7. 
    Brouha B, Schustak J, Badge RM, Lutz-Prigge S, Farley AH et al. 2003. Hot L1s account for the bulk of retrotransposition in the human population. PNAS 100:5280–85
     [Google Scholar]
  8. 8. 
    Chakravarti A, Buetow KH, Antonarakis SE, Waber PG, Boehm CD, Kazazian HH Jr. 1984. Non-uniform recombination within the human β-globin gene cluster. Am. J. Hum. Genet. 36:1239–84
     [Google Scholar]
  9. 9. 
    Cheng T-C, Orkin SH, Antonarakis SE, Potter MJ, Sexton JP et al. 1984. β-Thalassemia in Chinese: use of in vivo RNA analysis and oligonucleotide hybridization in systematic characterization of molecular defects. PNAS 81:2821–25
     [Google Scholar]
  10. 10. 
    Coufal NG, Garcia-Perez JL, Peng GE, Yeo GW, Mu Y et al. 2009. L1 retrotransposition in human neural progenitor cells. Nature 460:1127–31
     [Google Scholar]
  11. 11. 
    Davidson RG, Nitowsky HM, Childs B. 1963. Demonstration of two populations of cells in the human female heterozygous for glucose-6-phosphate dehydrogenase variants. PNAS 50:481–85
     [Google Scholar]
  12. 12. 
    Dewannieux M, Esnault C, Heidmann T. 2003. LINE-1 mediated retrotransposition of marked Alu sequences. Nat. Genet. 35:41–48
     [Google Scholar]
  13. 13. 
    Dombroski BA, Mathias SL, Nanthakumar E, Scott AF, Kazazian HH Jr. 1991. Isolation of an active human transposable element. Science 254:1805–8
     [Google Scholar]
  14. 14. 
    Doucet AJ, Wilusz JE, Miyoshi T, Liu Y, Moran JV. 2015. A 3′ poly(A) tract is required for LINE-1 retrotransposition. Mol. Cell 60:728–41
     [Google Scholar]
  15. 15. 
    Doucet-O’ Hare TT, Rodić N, Sharma R, Darbari I, Abril G et al. 2015. LINE-1 expression and retrotransposition in Barrett's esophagus and esophageal carcinoma. PNAS 112:E4894–900
     [Google Scholar]
  16. 16. 
    Doucet-O’ Hare TT, Sharma R, Rodić N, Anders RA, Burns KH, Kazazian HH Jr. 2016. Somatically acquired LINE-1 insertions in normal esophagus undergo clonal expansion in esophageal squamous cell carcinoma. Hum. Mutat. 37:942–54
     [Google Scholar]
  17. 17. 
    Economou EP, Antonarakis SE, Dowling CC, Ibarra B, de la Mora E, Kazazian HH Jr. 1991. Molecular heterogeneity of β-thalassemia in Mestizo Mexicans. Genomics 11:474
     [Google Scholar]
  18. 18. 
    Erwin JA, Paquola AC, Singer T, Gallina I, Novotny M et al. 2016. L1-associated regions are deleted in somatic cells of the healthy human brain. Nat. Neurosci. 19:1583–91
     [Google Scholar]
  19. 19. 
    Evrony GD, Cai X, Lee E, Hills LB, Elhosary PC et al. 2012. Single neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain. Cell 151:483–96
     [Google Scholar]
  20. 20. 
    Evrony GD, Lee E, Mehta BK, Benjamini Y, Johnson RM et al. 2015. Cell lineage analysis in human brain using endogenous retroelements. Neuron 85:49–59
     [Google Scholar]
  21. 21. 
    Ewing AD, Kazazian HH Jr. 2010. High-throughput sequencing reveals extensive variation in human-specific L1 content in individual human genomes. Genome Res 20:1262–70
     [Google Scholar]
  22. 22. 
    Feng Q, Moran JV, Kazazian HH Jr., Boeke JD. 1996. Human L1 retrotransposon encodes a conserved endonuclease required for retrotransposition. Cell 87:905–916
     [Google Scholar]
  23. 23. 
    Flasch DA, Macia Á, Sánchez L, Ljungman M, Heras SR et al. 2019. Genome-wide de novo 1 retrotransposition connects endonuclease activity with replication. Cell 177:837–51
     [Google Scholar]
  24. 24. 
    Ganguly A, Prockop DJ. 1995. Detection of mismatched bases in double stranded DNA by gel electrophoresis. Electrophoresis 16:1830–35
     [Google Scholar]
  25. 25. 
    Goodier JL, Ostertag EM, Du K, Kazazian HH Jr. 2001. Characterization of a novel active L1 retrotransposon subfamily in the mouse. Genome Res 11:1677–85
     [Google Scholar]
  26. 26. 
    Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA et al. 1990. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250:1684–89
     [Google Scholar]
  27. 27. 
    Hancks DC, Ewing AD, Chen JE, Tokunaga K, Kazazian HH Jr. 2009. Exon-trapping mediated by the human retrotransposon SVA. Genome Res 19:1983–91
     [Google Scholar]
  28. 28. 
    Hancks DC, Goodier JL, Mandal PK, Cheung LE, Kazazian HH Jr. 2011. Retrotransposition of marked SVA elements by human L1s in cultured cells. Hum. Mol. Genet. 20:3386–400
     [Google Scholar]
  29. 29. 
    Hattori M, Kuhara S, Takenaka O, Sakaki Y. 1986. L1 family of repetitive DNA sequences in primates may be derived from a sequence encoding a reverse transcriptase-related protein. Nature 321:625–28
     [Google Scholar]
  30. 30. 
    Helman E, Lawrence MS, Stewart C, Sougnez C, Getz G, Meyerson M. 2014. Somatic retrotransposition in human cancer revealed by whole genome and exome sequencing. Genome Res 24:1053–63
     [Google Scholar]
  31. 31. 
    Hobbins JC, Mahoney MJ. 1976. Fetoscopy and fetal blood sampling: the present state of the method. Clin. Obstet. Gynecol. 19:341–52
     [Google Scholar]
  32. 32. 
    Hollenberg MD, Kaback MM, Kazazian HH Jr. 1972. Adult hemoglobin synthesis by reticulocytes from the human fetus at midtrimester. Science 174:698–702
     [Google Scholar]
  33. 33. 
    Holmes SE, Dombroski BA, Krebs CM, Boehm CD, Kazazian HH Jr. 1994. A new retrotransposable human L1 element from the LRE 2 locus on chromosome 1q produces a chimeric insertion. Nat. Genet. 7:143–48
     [Google Scholar]
  34. 34. 
    Hussein IR, Temtamy SA, El-Beshlawy A, Fearon C, Shalaby Z et al. 1993. Molecular characterization of β-thalassemia in Egyptians. Hum. Mutat. 2:48–52
     [Google Scholar]
  35. 35. 
    Iskow RC, McCabe MT, Mills RE, Torene S, Pittard WS et al. 2010. Natural mutagenesis of human genomes by endogenous retrotransposons. Cell 141:1253–61
     [Google Scholar]
  36. 36. 
    Itakura K, Rossi JJ, Wallace RB. 1984. Synthesis and use of synthetic oligonucleotides. Annu. Rev. Biochem. 53:323–56
     [Google Scholar]
  37. 37. 
    Itano HA, Robinson EA. 1960. Genetic control of the α- and β-chains of hemoglobin. PNAS 46:1492–501
     [Google Scholar]
  38. 38. 
    Jeffreys AJ. 1979. DNA sequence variants in the Gγ-, Aγ-, δ- and β-globin genes of man. Cell 18:1–10
     [Google Scholar]
  39. 39. 
    Kan YW, Dozy AM. 1978. Polymorphism of DNA sequence adjacent to β-globin structural gene: relationship to sickle mutation. PNAS 75:5631–35
     [Google Scholar]
  40. 40. 
    Kazazian HH Jr. 2009. Allan Award Lecture: on jumping fields and “jumping genes. .” Am. J. Hum. Genet. 84:105–14
     [Google Scholar]
  41. 41. 
    Kazazian HH Jr., Boehm CD. 1988. Molecular basis and prenatal diagnosis of β-thalassemia. Blood 72:1107–16
     [Google Scholar]
  42. 42. 
    Kazazian HH Jr., Itano HA. 1968. Studies on the quantitative control of polypeptide synthesis in human reticulocytes. J. Biol. Chem. 243:2048–55
     [Google Scholar]
  43. 43. 
    Kazazian HH Jr., Orkin SH, Antonarakis SE, Sexton JP, Boehm CD et al. 1984. Molecular characterization of seven β-thalassemia mutations in Asian Indians. EMBO J 3:593–96
     [Google Scholar]
  44. 44. 
    Kazazian HH Jr., Wong C, Youssoufian H, Scott AF, Phillips D, Antonarakis SE. 1988. A novel mechanism of mutation in man: hemophilia A due to de novo insertion of L1 sequences. Nature 332:164–66
     [Google Scholar]
  45. 45. 
    Kazazian HH Jr., Young WJ, Childs B. 1965. X-linked 6-phosphogluconate dehydrogenase in Drosophila: subunit associations. Science 150:1601–2
     [Google Scholar]
  46. 46. 
    Lander ES, Linton LM, Birren B, Nusbaum C, Zody ML et al. 2001. Initial sequencing and analysis of the human genome. Nature 409:860–921
     [Google Scholar]
  47. 47. 
    Lee E, Iskow R, Yang L, Gokcumen O, Haseley P et al. 2012. Landscape of somatic retrotransposition in human cancers. Science 337:967–71
     [Google Scholar]
  48. 48. 
    Luan DD, Korman MH, Jakubczak JL, Eickbush TH. 1993. Reverse transcription of R2Bm RNA is primed by a nick at the chromosomal target site: a mechanism for non-LTR retrotransposition. Cell 72:595–605
     [Google Scholar]
  49. 49. 
    Mathias SL, Scott AF, Kazazian HH Jr., Boeke JD, Gabriel A. 1991. Reverse transcriptase encoded by a human transposable element. Science 254:1808–10
     [Google Scholar]
  50. 50. 
    McClintock B. 1950. The origin and behavior of mutable loci in maize. PNAS 36:344–55
     [Google Scholar]
  51. 51. 
    Mears JG, Ramirez F, Leibowitz D, Nakamura F, Bloom A et al. 1978. Changes in restricted human cellular DNA fragments containing globin gene sequences in thalassemias and related disorders. PNAS 75:1222–28
     [Google Scholar]
  52. 52. 
    Miki Y, Nishisho I, Horii A, Miyoshi Y, Utsunomiya J et al. 1992. Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer. Cancer Res 52:643–45
     [Google Scholar]
  53. 53. 
    Moran JV, DeBerardinis RJ, Kazazian HH Jr. 1999. Exon shuffling by L1 retro-transposition. Science 283:1530–34
     [Google Scholar]
  54. 54. 
    Moran JV, Holmes SE, Naas TP, DeBerardinis RJ, Boeke JD, Kazazian HH Jr. 1996. High frequency retrotransposition in cultured mammalian cells. Cell 87:917–27
     [Google Scholar]
  55. 55. 
    Muotri AR, Chu VT, Marchetto MC, Deng W, Moran JV, Gage FH. 2005. Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature 435:903–10
     [Google Scholar]
  56. 56. 
    Orkin SH, Alter BP, Altay C. 1979. Deletion of the Aγ-globin gene in Gγ-δβ-thalassemia. J. Clin. Investig. 64:866–69
     [Google Scholar]
  57. 57. 
    Orkin SH, Kazazian HH Jr., Antonarakis SE, Goff SC, Boehm CD et al. 1982. Linkage of β-thalassemia mutations and β-globin gene polymorphisms with DNA polymorphisms in the human β-globin gene cluster. Nature 296:627–31
     [Google Scholar]
  58. 58. 
    Orkin SH, Little PF, Kazazian HH Jr., Boehm CD. 1982. Improved detection of the sickle mutation by DNA analysis: application to prenatal diagnosis. N. Engl. J. Med. 307:32–36
     [Google Scholar]
  59. 59. 
    Ostertag EM, Goodier JL, Zhang Y, Kazazian HH Jr. 2003. SVA elements are nonautonomous retrotransposons that cause disease in humans. Am. J. Hum. Genet. 73:1444–51
     [Google Scholar]
  60. 60. 
    Ostertag EM, Luning Prak ET, Deberardinis RJ, Moran JV, Kazazian HH Jr. 2000. Determination of L1 retrotransposition kinetics in cultured cells. Nucleic Acids Res 28:1418–23
     [Google Scholar]
  61. 61. 
    Ovchinnikov I, Rubin A, Swergold GD. 2002. Tracing the LINEs of human evolution. PNAS 99:10522–27
     [Google Scholar]
  62. 62. 
    Pauling L, Itano HA, Singer SJ, Wells IC. 1949. Sickle cell anemia, a molecular disease. Science 110:543–48
     [Google Scholar]
  63. 63. 
    Phillips JA III, Panny SR, Kazazian HH Jr., Boehm CD, Scott AF, Smith KD. 1980. Prenatal diagnosis of sickle cell anemia by restriction and endonuclease analysis: HindIII polymorphisms in γ-globin genes extend test applicability. PNAS 77:2853–56
     [Google Scholar]
  64. 64. 
    Phillips JA III, Parks JS, Hjelle BL, Herd JE, Plotnick LP et al. 1982. Genetic analysis of familial isolated growth hormone deficiency type I. J. Clin. Investig. 70:489–95
     [Google Scholar]
  65. 65. 
    Pitkanen E, Cajuso T, Katainen R, Kaasinen E, Valimaki N et al. 2014. Frequent retrotranspositions originating from TTC28 in colorectal cancer. Oncotarget 5:853–59
     [Google Scholar]
  66. 66. 
    Raiz J, Damert A, Chira S, Held U, Klawitter S et al. 2012. The non-autonomous retrotransposon SVA is trans-mobilized by the L1 protein machinery. Nucleic Acids Res 40:1666–83
     [Google Scholar]
  67. 67. 
    Rodriguez-Martin B, Alvarez EG, Baez-Ortega A, Zamora J, Supek F et al. 2020. Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition. Nat. Genet. 52:306–19
     [Google Scholar]
  68. 68. 
    Rund D, Cohen T, Filon D, Dowling CE, Warren TC et al. 1991. Evolution of a genetic disease in an ethnic isolate: β-thalassemia in the Jews of Kurdistan. PNAS 88:310–14
     [Google Scholar]
  69. 69. 
    Sassaman DM, Dombroski BA, Moran JV, Kimberland ML, Naas TP et al. 1997. Many human L1 elements are capable of retrotransposition. Nat. Genet. 16:37–43
     [Google Scholar]
  70. 70. 
    Scott AF, Schmeckpeper BJ, Abdelrazik M, Comey CT, O'Hara B et al. 1987. Origin of the human L1 elements: proposed progenitor genes deduced from a consensus DNA sequence. Genomics 1:113–25
     [Google Scholar]
  71. 71. 
    Scott EC, Gardner EJ, Masood A, Chuang NT, Vertino PM, Devine SE. 2016. The Mobile Element Locator Tool (MELT): population scale mobile element discovery and biology. Genome Res 26:745–55
     [Google Scholar]
  72. 72. 
    Seleme MDC, Vetter MR, Cordaux R, Bastone L, Batzer MA, Kazazian HH Jr. 2006. Extensive individual variation in L1 retrotransposition capability contributes to human genetic diversity. PNAS 103:6611–16
     [Google Scholar]
  73. 73. 
    Singer MF. 1982. SINEs and LINEs: highly repeated short and long interspersed sequences in mammalian genomes. Cell 28:433–34
     [Google Scholar]
  74. 74. 
    Skowronski J, Fanning TG, Singer MF. 1988. Unit length line-1 transcripts in human teratocarcinoma cells. Mol. Cell. Biol. 4:1385–97
     [Google Scholar]
  75. 75. 
    Solyom S, Ewing AD, Rahrmann EP, Doucet T, Nelson HH et al. 2012. Extensive somatic L1 retrotransposition in colorectal tumors. Genome Res 22:2328–38
     [Google Scholar]
  76. 76. 
    Toole JJ, Knopf JL, Wozney JM, Sultzman LA, Buecker JL et al. 1984. Molecular cloning of a cDNA encoding human antihaemophilic factor. Nature 312:342–47
     [Google Scholar]
  77. 77. 
    Tubio JMC, Li Y, Ju YS, Martincorena I, Cooke SL et al. 2014. Mobile DNA in cancer: extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes. Science 345:1251343
     [Google Scholar]
  78. 78. 
    Upton KR, Gerhardt DJ, Jesuadian JS, Richardson SR, Sánchez-Luque FJ et al. 2015. Ubiquitous L1 mosaicism in hippocampal neurons. Cell 161:228–39
     [Google Scholar]
  79. 79. 
    Wong C, Dowling CE, Saiki RK, Higuchi RG, Erlich HA, Kazazian HH Jr. 1987. Characterization of β-thalassemia mutations using direct genomic sequencing of amplified single copy DNA. Nature 330:384–86
     [Google Scholar]
  80. 80. 
    Wooster R, Bignell G, Lancaster J, Swift S, Seal S et al. 1995. Identification of the breast cancer susceptibility gene BRCA2. Nature 378:789–92
     [Google Scholar]
  81. 81. 
    Yamaguchi K, Soares AO, Goff LA, Talasila A, Choi JA et al. 2020. Striking heterogeneity of somatic L1 retrotransposition in single normal and cancerous gastrointestinal cells. PNAS 117:32215–22
     [Google Scholar]
  82. 82. 
    Youssoufian H, Kazazian HH Jr., Phillips DG, Aronis S, Tsiftis G et al. 1986. Recurrent mutations in hemophilia A: evidence for CpG dinucleotides as mutation hotspots. Nature 324:380–82
     [Google Scholar]
/content/journals/10.1146/annurev-genom-111620-095614
Loading
A Long, Fulfilling Career in Human Genetics
Annual Review of Genomics and Human Genetics 22, 27 (2021); https://doi.org/10.1146/annurev-genom-111620-095614
/content/journals/10.1146/annurev-genom-111620-095614
/content/journals/10.1146/annurev-genom-111620-095614
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error