Article open access publication

Characterization of Large Structural Genetic Mosaicism in Human Autosomes

American Journal of Human Genetics, Elsevier, ISSN 1537-6605

Volume 96, 3, 2015

DOI:10.1016/j.ajhg.2015.01.011, Dimensions: pub.1048500652, PMC: PMC4375431, PMID: 25748358,

Authors

Jacobs, Kevin B (1) (3)
Chen, Chu (5)
Hosgood, H. Dean (1) (16)
Hu, Wei (1)
Hunter, David J. (6) (9) (17)
Lan, Qing (1)
Liu, Jianjun (22) (23)
Sheng, Xin (13)
Wu, Chen (21)
Xia, Lucy (13)
Zheng, Wei (32)
Aldrich, Melinda C (32) (39)
Blot, William J. (32) (41)
Ding, Ti (46)
Hu, Nan (1)
Koh, Woon-Puay (30) (60)
Real, Francisco X. (62) (65)
Severi, Gianluca (54) (69)
Wolpin, Brian M. (9) (49)
Wu, Xifeng (40)
Yu, Kai (1)
Li, Jun Z (75)
Melbye, Mads (76) (80)
Pérez-Jurado, Luis A. (65) (68) (83)

* Corresponding author

Affiliations

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  1. (1) National Institute of Arthritis and Musculoskeletal and Skin Diseases, grid.420086.8
  2. (2) National Center for Advancing Translational Sciences, grid.429651.d
  3. (3) BioInformed LLC, Gaithersburg, MD 20877, USA
  4. (4) National Health Research Institutes, grid.59784.37
  5. (5) Fred Hutchinson Cancer Research Center, grid.270240.3
  6. (6) Harvard University, grid.38142.3c
  7. (7) Tianjin Medical University Cancer Institute and Hospital, grid.411918.4
  8. (8) University of New Mexico, grid.266832.b
  9. (9) Brigham and Women's Hospital, grid.62560.37
  10. (10) Dartmouth College, grid.254880.3
  11. (11) Alberta Health Services, grid.413574.0
  12. (12) American Cancer Society, grid.422418.9
  13. (13) University of Southern California, grid.42505.36
  14. (14) University of Massachusetts Amherst, grid.266683.f
  15. (15) Seoul National University, grid.31501.36
  16. (16) Albert Einstein College of Medicine, grid.251993.5
  17. (17) Broad Institute, grid.66859.34
  18. (18) Chonnam National University, grid.14005.30
  19. (19) Korea University Medical Center, grid.411134.2
  20. (20) Memorial Sloan Kettering Cancer Center, grid.51462.34
  21. (21) Chinese Academy of Medical Sciences & Peking Union Medical College, grid.506261.6
  22. (22) Anhui Medical University, grid.186775.a
  23. (23) Genome Institute of Singapore, grid.418377.e
  24. (24) University of Hawaii at Manoa, grid.410445.0
  25. (25) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
  26. (26) Yale University, grid.47100.32
  27. (27) Moffitt Cancer Center, grid.468198.a
  28. (28) Kyushu University, grid.177174.3
  29. (29) Kyungpook National University Medical Center, grid.477473.4
  30. (30) National University of Singapore, grid.4280.e
  31. (31) Nanjing Medical University, grid.89957.3a
  32. (32) Vanderbilt University Medical Center, grid.412807.8
  33. (33) Fudan University, grid.8547.e
  34. (34) University of Hong Kong, grid.194645.b
  35. (35) Huazhong University of Science and Technology, grid.33199.31
  36. (36) Guangdong Academy of Medical Sciences, grid.410643.4
  37. (37) National Taiwan University, grid.19188.39
  38. (38) China Medical University, grid.412449.e
  39. (39) Vanderbilt University, grid.152326.1
  40. (40) The University of Texas MD Anderson Cancer Center, grid.240145.6
  41. (41) International Epidemiology Institute, grid.419344.f
  42. (42) Wayne State University, grid.254444.7
  43. (43) University of California, San Francisco, grid.266102.1
  44. (44) National Institute for Occupational Safety and Health, grid.416809.2
  45. (45) University of Alberta, grid.17089.37
  46. (46) Shanxi Tumor Hospital, grid.440201.3
  47. (47) Unit of Nutrition, Environment, and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute,, Barcelona 08908, Spain
  48. (48) Shanghai Cancer Institute, grid.419087.3
  49. (49) Dana-Farber Cancer Institute, grid.65499.37
  50. (50) Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiaotaong University Shanghai 200032, People’s Republic of China
  51. (51) Department of Pediatrics, University Clinic of Navarra, Universidad de Navarra, Pamplona 31080, Spain
  52. (52) Institute of Cancer Research, grid.18886.3f
  53. (53) VA Boston Healthcare System, grid.410370.1
  54. (54) University of Melbourne, grid.1008.9
  55. (55) Umeå University, grid.12650.30
  56. (56) International Agency For Research On Cancer, grid.17703.32
  57. (57) Rigshospitalet, grid.475435.4, Capital Region
  58. (58) Unit of Survivorship Research, Danish Cancer Society Research Centre, Copenhagen 2100, Denmark
  59. (59) University of Cambridge, grid.5335.0
  60. (60) Duke NUS Graduate Medical School, grid.428397.3
  61. (61) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  62. (62) Spanish National Cancer Research Centre, grid.7719.8
  63. (63) Mayo Clinic, grid.66875.3a
  64. (64) Nofer Institute of Occupational Medicine, grid.418868.b
  65. (65) Pompeu Fabra University, grid.5612.0
  66. (66) Imperial College London, grid.7445.2
  67. (67) Quantitative Genomic Medicine Laboratory, qGenomics, Barcelona 08003, Spain
  68. (68) Centre for Biomedical Network Research on Rare Diseases, grid.452372.5
  69. (69) Human Genetics Foundation, grid.428948.b
  70. (70) Baylor College of Medicine, grid.39382.33
  71. (71) Johns Hopkins University, grid.21107.35
  72. (72) Information Management Services, grid.280929.8
  73. (73) Washington University in St. Louis, grid.4367.6
  74. (74) New York University, grid.137628.9
  75. (75) University of Michigan, grid.214458.e
  76. (76) State Serum Institute, grid.6203.7
  77. (77) University of Washington, grid.34477.33
  78. (78) Northwestern University, grid.16753.36
  79. (79) University of Pittsburgh, grid.21925.3d
  80. (80) Stanford University, grid.168010.e
  81. (81) University of Iowa, grid.214572.7
  82. (82) Office of Population Genomics, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
  83. (83) Hospital Del Mar, grid.411142.3

Description

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

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Times Cited: 52

Field Citation Ratio (FCR): 7

Relative Citation ratio (RCR): 2.08

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