Characterization of large structural genetic mosaicism in human autosomes

Mitchell J. Machiela, Weiyin Zhou, Joshua N. Sampson, Michael C. Dean, Kevin B. Jacobs, Amanda Black, Louise A. Brinton, I. Shou Chang, Chu Chen, Constance Chen, Kexin Chen, Linda S. Cook, Marta Crous Bou, Immaculata De Vivo, Jennifer Doherty, Christine M. Friedenreich, Mia M. Gaudet, Christopher A. Haiman, Susan E. Hankinson, Patricia HartgeBrian E. Henderson, Yun Chul Hong, H. Dean Hosgood, Chao A. Hsiung, Wei Hu, David J. Hunter, Lea Jessop, Hee Nam Kim, Yeul Hong Kim, Young Tae Kim, Robert Klein, Peter Kraft, Qing Lan, Dongxin Lin, Jianjun Liu, Loic Le Marchand, Xiaolin Liang, Jolanta Lissowska, Lingeng Lu, Anthony M. Magliocco, Keitaro Matsuo, Sara H. Olson, Irene Orlow, Jae Yong Park, Loreall Pooler, Jennifer Prescott, Radhai Rastogi, Harvey A. Risch, Fredrick Schumacher, Adeline Seow, Veronica Wendy Setiawan, Hongbing Shen, Xin Sheng, Min Ho Shin, Xiao Ou Shu, David Vanden Berg, Jiu Cun Wang, Nicolas Wentzensen, Maria Pik Wong, Chen Wu, Tangchun Wu, Yi Long Wu, Lucy Xia, Hannah P. Yang, Pan Chyr Yang, Wei Zheng, Baosen Zhou, Christian C. Abnet, Demetrius Albanes, Melinda C. Aldrich, Christopher Amos, Laufey T. Amundadottir, Sonja I. Berndt, William J. Blot, Cathryn H. Bock, Paige M. Bracci, Laurie Burdett, Julie E. Buring, Mary A. Butler, Tania Carreón, Nilanjan Chatterjee, Charles C. Chung, Michael B. Cook, Michael Cullen, Faith G. Davis, Ti Ding, Eric J. Duell, Caroline G. Epstein, Jin Hu Fan, Jonine D. Figueroa, Joseph F. Fraumeni, Neal D. Freedman, Charles S. Fuchs, Yu Tang Gao, Susan M. Gapstur, Ana Patiño-Garcia, Montserrat Garcia-Closas, J. Michael Gaziano, Graham G. Giles, Elizabeth M. Gillanders, Edward L. Giovannucci, Lynn Goldin, Alisa M. Goldstein, Mark H. Greene, Goran Hallmans, Curtis C. Harris, Roger Henriksson, Elizabeth A. Holly, Robert N. Hoover, Nan Hu, Amy Hutchinson, Mazda Jenab, Christoffer Johansen, Kay Tee Khaw, Woon Puay Koh, Laurence N. Kolonel, Charles Kooperberg, Vittorio Krogh, Robert C. Kurtz, Andrea Lacroix, Annelie Landgren, Maria Teresa Landi, Donghui Li, Linda M. Liao, Nuria Malats, Katherine A. McGlynn, Lorna H. McNeill, Robert R. McWilliams, Beatrice S. Melin, Lisa Mirabello, Beata Peplonska, Ulrike Peters, Gloria M. Petersen, Ludmila Prokunina-Olsson, Mark Purdue, You Lin Qiao, Kari G. Rabe, Preetha Rajaraman, Francisco X. Real, Elio Riboli, Benjamín Rodríguez-Santiago, Nathaniel Rothman, Avima M. Ruder, Sharon A. Savage, Ann G. Schwartz, Kendra L. Schwartz, Howard D. Sesso, Gianluca Severi, Debra T. Silverman, Margaret R. Spitz, Victoria L. Stevens, Rachael Stolzenberg-Solomon, Daniel Stram, Ze Zhong Tang, Philip R. Taylor, Lauren R. Teras, Geoffrey S. Tobias, Kala Viswanathan, Sholom Wacholder, Zhaoming Wang, Stephanie J. Weinstein, William Wheeler, Emily White, John K. Wiencke, Brian M. Wolpin, Xifeng Wu, Jay S. Wunder, Kai Yu, Krista A. Zanetti, Anne Zeleniuch-Jacquotte, Regina G. Ziegler, Mariza De Andrade, Kathleen C. Barnes, Terri H. Beaty, Laura J. Bierut, Karl C. Desch, Kimberly F. Doheny, Bjarke Feenstra, David Ginsburg, John A. Heit, Jae H. Kang, Cecilia A. Laurie, Jun Z. Li, William L. Lowe, Mary L. Marazita, Mads Melbye, Daniel B. Mirel, Jeffrey C. Murray, Sarah C. Nelson, Louis R. Pasquale, Kenneth Rice, Janey L. Wiggs, Anastasia Wise, Margaret Tucker, Luis A. Pérez-Jurado, Cathy C. Laurie, Neil E. Caporaso, Meredith Yeager, Stephen J. Chanock

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)487-497
Number of pages11
JournalAmerican journal of human genetics
Issue number3
StatePublished - Mar 5 2015
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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