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Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome

2016; Nature Portfolio; Volume: 7; Issue: 1 Linguagem: Inglês

10.1038/ncomms11843

2041-1723

Mitchell J. Machiela, Weiyin Zhou, Eric Karlins, Joshua N. Sampson, Neal D. Freedman, Qi Yang, Belynda Hicks, Casey Dagnall, Christopher Hautman, Kevin B. Jacobs, Christian C. Abnet, Melinda C. Aldrich, Christopher I. Amos, Laufey T. Ámundadóttir, Alan A. Arslan, Laura E. Beane Freeman, Sonja I. Berndt, Amanda Black, William J. Blot, Cathryn H. Bock, Paige M. Bracci, Louise A. Brinton, H. Bas Bueno‐de‐Mesquita, Laurie Burdett, Julie E. Buring, Mary Ann Butler, Federico Canzian, Tania Carreón, Kari G. Chaffee, I‐Shou Chang, Nilanjan Chatterjee, Chu Chen, Constance Chen, Kexin Chen, Charles C. Chung, Linda S. Cook, Marta Crous‐Bou, Michael Cullen, Faith G. Davis, Immaculata De Vivo, Ti Ding, Jennifer A. Doherty, Eric J. Duell, Caroline G. Epstein, Jin‐Hu Fan, Jonine D. Figueroa, Joseph F. Fraumeni, Christine M. Friedenreich, Charles S. Fuchs, Steven Gallinger, Yu‐Tang Gao, Susan M. Gapstur, Montserrat García‐Closas, Mia M. Gaudet, J. Michael Gaziano, Graham G. Giles, Elizabeth M. Gillanders, Edward L. Giovannucci, Lynn R. Goldin, Alisa M. Goldstein, Christopher A. Haiman, Göran Hallmans, Susan E. Hankinson, Curtis C. Harris, Roger Henriksson, Elizabeth A. Holly, Yun‐Chul Hong, Robert N. Hoover, Chao A. Hsiung, Nan Hu, Wei Hu, David J. Hunter, Amy Hutchinson, Mazda Jenab, Christoffer Johansen, Kay‐Tee Khaw, Hee Nam Kim, Yeul Hong Kim, Young Tae Kim, Alison P. Klein, Robert J. Klein, Woon‐Puay Koh, Laurence N. Kolonel, Charles Kooperberg, Peter Kraft, Vittorio Krogh, Robert C. Kurtz, Andrea Z. LaCroix, Qing Lan, Maria Teresa Landi, Loı̈c Le Marchand, Donghui Li, Xiaolin Liang, Linda M. Liao, Dongxin Lin, Jianjun Liu, Jolanta Lissowska, Lingeng Lu, Anthony Magliocco, Núria Malats, Keitaro Matsuo, Lorna H. McNeill, Robert R. McWilliams, Beatrice Melin, Kari G. Rabe, Lee E. Moore, Sara H. Olson, Irene Orlow, Jae Yong Park, Ana Patiño-Garcı́a, Beata Pepłońska, Ulrike Peters, Gloria M. Petersen, Loreall Pooler, Jennifer Prescott, Ludmila Prokunina‐Olsson, Mark P. Purdue, You‐Lin Qiao, Preetha Rajaraman, Francisco X. Real, Elio Ríboli, Harvey A. Risch, Benjamín Rodríguez‐Santiago, Avima M. Ruder, Sharon A. Savage, Fredrick R. Schumacher, Ann G. Schwartz, Kendra Schwartz, Adeline Seow, Veronica Wendy Setiawan, Gianluca Severi, Hongbing Shen, Xin Sheng, Min‐Ho Shin, Xiao‐Ou Shu, Debra T. Silverman, Margaret R. Spitz, Victoria L. Stevens, Rachael Z. Stolzenberg‐Solomon, Daniel O. Stram, Ze‐Zhong Tang, Philip R. Taylor, Lauren R. Teras, Geoffrey S. Tobias, David Van Den Berg, Kala Visvanathan, Sholom Wacholder, Jiucun Wang, Zhaoming Wang, Nicolas Wentzensen, William Wheeler, Emily White, John K. Wiencke, Brian M. Wolpin, Maria Pik Wong, Chen Wu, Tangchun Wu, Xifeng Wu, Yi‐Long Wu, Jay S. Wunder, Lucy Xia, Hannah Yang, Pan‐Chyr Yang, Kai Yu, Krista A. Zanetti, Anne Zeleniuch‐Jacquotte, Wei Zheng, Baosen Zhou, Regina G. Ziegler, Luis A. Pérez‐Jurado, Neil E. Caporaso, Nathaniel Rothman, Margaret A. Tucker, Michael Dean, Meredith Yeager, Stephen J. Chanock,

Genomics and Chromatin Dynamics

Abstract To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.