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Am J Hum Genet. 2015 Mar 5;96(3):487-97. doi: 10.1016/j.ajhg.2015.01.011.

Characterization of large structural genetic mosaicism in human autosomes.

Machiela MJ1, Zhou W2, Sampson JN1, Dean MC3, Jacobs KB4, Black A1, Brinton LA1, Chang IS5, Chen C6, Chen C7, Chen K8, Cook LS9, Crous Bou M10, De Vivo I10, Doherty J11, Friedenreich CM12, Gaudet MM13, Haiman CA14, Hankinson SE15, Hartge P1, Henderson BE14, Hong YC16, Hosgood HD 3rd17, Hsiung CA18, Hu W1, Hunter DJ19, Jessop L1, Kim HN20, Kim YH21, Kim YT22, Klein R23, Kraft P7, Lan Q1, Lin D24, Liu J25, Le Marchand L26, Liang X27, Lissowska J28, Lu L29, Magliocco AM30, Matsuo K31, Olson SH27, Orlow I27, Park JY32, Pooler L33, Prescott J10, Rastogi R27, Risch HA29, Schumacher F14, Seow A34, Setiawan VW14, Shen H35, Sheng X33, Shin MH36, Shu XO37, VanDen Berg D14, Wang JC38, Wentzensen N1, Wong MP39, Wu C24, Wu T40, Wu YL41, Xia L33, Yang HP1, Yang PC42, Zheng W43, Zhou B44, Abnet CC1, Albanes D1, Aldrich MC45, Amos C46, Amundadottir LT1, Berndt SI1, Blot WJ47, Bock CH48, Bracci PM49, Burdett L2, Buring JE50, Butler MA51, Carreón T51, Chatterjee N1, Chung CC2, Cook MB1, Cullen M2, Davis FG52, Ding T53, Duell EJ54, Epstein CG1, Fan JH55, Figueroa JD1, Fraumeni JF Jr1, Freedman ND1, Fuchs CS56, Gao YT57, Gapstur SM13, Patiño-Garcia A58, Garcia-Closas M59, Gaziano JM60, Giles GG61, Gillanders EM62, Giovannucci EL63, Goldin L1, Goldstein AM1, Greene MH1, Hallmans G64, Harris CC65, Henriksson R66, Holly EA49, Hoover RN1, Hu N1, Hutchinson A2, Jenab M67, Johansen C68, Khaw KT69, Koh WP70, Kolonel LN26, Kooperberg C6, Krogh V71, Kurtz RC72, LaCroix A6, Landgren A1, Landi MT1, Li D73, Liao LM1, Malats N74, McGlynn KA1, McNeill LH75, McWilliams RR76, Melin BS66, Mirabello L1, Peplonska B77, Peters U6, Petersen GM78, Prokunina-Olsson L1, Purdue M1, Qiao YL79, Rabe KG78, Rajaraman P1, Real FX80, Riboli E81, Rodríguez-Santiago B82, Rothman N1, Ruder AM51, Savage SA1, Schwartz AG48, Schwartz KL83, Sesso HD50, Severi G84, Silverman DT1, Spitz MR85, Stevens VL13, Stolzenberg-Solomon R1, Stram D14, Tang ZZ53, Taylor PR1, Teras LR13, Tobias GS1, Viswanathan K86, Wacholder S1, Wang Z2, Weinstein SJ1, Wheeler W87, White E6, Wiencke JK88, Wolpin BM56, Wu X89, Wunder JS90, Yu K1, Zanetti KA62, Zeleniuch-Jacquotte A91, Ziegler RG1, de Andrade M78, Barnes KC92, Beaty TH86, Bierut LJ93, Desch KC94, Doheny KF95, Feenstra B96, Ginsburg D97, Heit JA98, Kang JH99, Laurie CA100, Li JZ101, Lowe WL102, Marazita ML103, Melbye M104, Mirel DB105, Murray JC106, Nelson SC100, Pasquale LR107, Rice K100, Wiggs JL108, Wise A109, Tucker M1, Pérez-Jurado LA110, Laurie CC100, Caporaso NE1, Yeager M2, Chanock SJ111.

Author information

1
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
2
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Leidos Biomedical Research Inc., Bethesda, MD 20892, USA.
3
Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, MD 21702, USA.
4
Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Leidos Biomedical Research Inc., Bethesda, MD 20892, USA; BioInformed LLC, Gaithersburg, MD 20877, USA.
5
National Institute of Cancer Research, National Health Research Institutes, Zhunan 35053, Taiwan, ROC.
6
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
7
Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, MA 02115, USA.
8
Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300040, People's Republic of China.
9
University of New Mexico, Albuquerque, NM 87131, USA.
10
Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, MA 02115, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
11
Geisel School of Medicine, Dartmouth College, Lebanon, NH 03755, USA.
12
Department of Population Health Research, CancerControl Alberta, Alberta Health Services, Calgary, AB T2N 2T9, Canada.
13
Epidemiology Research Program, American Cancer Society, Atlanta, GA 30303, USA.
14
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
15
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, MA 01003, USA.
16
Department of Preventive Medicine, College of Medicine, Seoul National University, Seoul 151-742, Republic of Korea.
17
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
18
Institute of Population Health Sciences, National Health Research Institutes, Zhunan 35053, Taiwan, ROC.
19
Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, MA 02115, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
20
Center for Creative Biomedical Scientists, Chonnam National University, Gwangju 500-757, Republic of Korea.
21
Division of Oncology/Hematology, Department of Internal Medicine, College of Medicine, Korea University Anam Hospital, Seoul 151-742, Republic of Korea.
22
Department of Thoracic and Cardiovascular Surgery, Cancer Research Institute, College of Medicine, Seoul National University, Seoul 151-742, Republic of Korea.
23
Program in Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
24
Department of Etiology & Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People's Republic of China; State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People's Republic of China.
25
Department of Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore; School of Life Sciences, Anhui Medical University, Hefei 230032, People's Republic of China.
26
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
27
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
28
Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw 02-781, Poland.
29
Yale School of Public Health, New Haven, CT 06510, USA.
30
H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
31
Department of Preventive Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka 819-0395, Japan.
32
Lung Cancer Center, Kyungpook National University Medical Center, Daegu 101, Republic of Korea.
33
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90007, USA.
34
Saw Swee Hock School of Public Health, National University of Singapore, Singapore 119077, Singapore.
35
Jiangsu Key Laboratory of Cancer Biomarkers, Prevention, and Treatment, Nanjing Medical University, Nanjing 210029, People's Republic of China; Ministry of Education Key Laboratory of Modern Toxicology, Nanjing Medical University, Nanjing 210029, People's Republic of China.
36
Department of Preventive Medicine, Chonnam National University Medical School, Gwanju 501-746, Republic of Korea.
37
Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
38
Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, People's Republic of China; State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, People's Republic of China.
39
Department of Pathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, People's Republic of China.
40
Institute of Occupational Medicine and Ministry of Education Key Laboratory for Environment and Health, School of Public Health, Huazhong University of Science and Technology, Wuhan 430400, People's Republic of China.
41
Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou 515200, People's Republic of China.
42
Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 10617, Taiwan, ROC.
43
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
44
Department of Epidemiology, School of Public Health, China Medical University, Shenyang 110001, People's Republic of China.
45
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Thoracic Surgery, School of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
46
Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
47
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; International Epidemiology Institute, Rockville, MD 20850, USA.
48
Karmanos Cancer Institute and Department of Oncology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
49
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94143, USA.
50
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
51
National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Cincinnati, OH 45226, USA.
52
Department of Public Health Sciences, School of Public Health, University of Alberta, Edmonton, AB T6G 2R3, Canada.
53
Shanxi Cancer Hospital, Taiyuan, Shanxi 030013, People's Republic of China.
54
Unit of Nutrition, Environment, and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute,, Barcelona 08908, Spain.
55
Shanghai Cancer Institute, Shanghai 200032, People's Republic of China.
56
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
57
Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiaotaong University Shanghai 200032, People's Republic of China.
58
Department of Pediatrics, University Clinic of Navarra, Universidad de Navarra, Pamplona 31080, Spain.
59
Division of Genetics and Epidemiology and Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, Surrey SM2 5NG, UK.
60
Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Massachusetts Veterans Epidemiology Research and Information Center and Cooperative Studies Programs, Veterans Affairs Boston Healthcare System, Boston, MA 02130, USA.
61
Cancer Epidemiology Centre, Cancer Council Victoria and Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia.
62
Division of Cancer Control and Population Sciences, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
63
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
64
Nutritional Research Unit, Department of Public Health and Clinical Medicine, Umeå University, Umeå 901 87, Sweden.
65
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
66
Department of Oncology, Department of Radiation Sciences, Umeå University, Umeå 901 87, Sweden.
67
International Agency for Research on Cancer, Lyon 69372, France.
68
Department of Oncology, Finsen Centre, Rigshospitalet, Copenhagen 2100, Denmark; Unit of Survivorship Research, Danish Cancer Society Research Centre, Copenhagen 2100, Denmark.
69
School of Clinical Medicine, University of Cambridge, Cambridge CB2 1TN, UK.
70
Saw Swee Hock School of Public Health, National University of Singapore, Singapore 119077, Singapore; Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
71
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano 20133, Italy.
72
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
73
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
74
Spanish National Cancer Research Centre, Madrid 28029, Spain.
75
Department of Health Disparities Research, Division of OVP, Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Community-Engaged Translational Research, Duncan Family Institute, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
76
Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
77
Nofer Institute of Occupational Medicine, Lodz 91-348, Poland.
78
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
79
Department of Epidemiology, Cancer Institute, Chinese Academy of Medical Sciences, Beijing 100730, People's Republic of China.
80
Spanish National Cancer Research Centre, Madrid 28029, Spain; Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona 08003, Spain.
81
Division of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London SW7 2AZ, UK.
82
Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona 08003, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona 08003, Spain; Quantitative Genomic Medicine Laboratory, qGenomics, Barcelona 08003, Spain.
83
Karmanos Cancer Institute and Department of Family Medicine and Public Health Sciences, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
84
Cancer Epidemiology Centre, Cancer Council Victoria and Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia; Human Genetics Foundation, Torino 10126, Italy.
85
Baylor College of Medicine, Houston, TX 77030, USA.
86
Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21218, USA.
87
Information Management Services Inc., Calverton, MD 20904, USA.
88
University of California, San Francisco, San Francisco, CA 94143, USA.
89
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
90
Division of Urologic Surgery, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
91
Department of Population Health, School of Medicine, New York University, New York, NY 10016, USA; Perlmutter Cancer Institute, New York University, New York, NY 10016, USA.
92
School of Medicine, Johns Hopkins University, Baltimore, MD 21218, USA.
93
Department of Psychiatry, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
94
Department of Pediatrics and Communicable Diseases, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, MI 48109, USA.
95
Center for Inherited Disease Research, Institute of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21218, USA.
96
Department of Epidemiology Research, Statens Serum Institut, Copenhagen 2300, Denmark.
97
Howard Hughes Medical Institute and Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
98
Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
99
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
100
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
101
Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
102
Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60208, USA.
103
Center for Craniofacial and Dental Genetics, Department of Oral Biology School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15260, USA.
104
Department of Epidemiology Research, Statens Serum Institut, Copenhagen 2300, Denmark; Department of Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA.
105
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
106
Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.
107
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard University, Boston, MA 02114, USA.
108
Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard University, Boston, MA 02114, USA.
109
Office of Population Genomics, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
110
Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona 08003, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona 08003, Spain; Hospital del Mar Research Institute, Barcelona 08003, Spain.
111
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: chanocks@mail.nih.gov.

Abstract

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.

PMID:
25748358
PMCID:
PMC4375431
DOI:
10.1016/j.ajhg.2015.01.011
[Indexed for MEDLINE]
Free PMC Article
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