Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome
Authors: Machiela Mitchell J. , Zhou Weiyin , Karlins Eric , Sampson Joshua N. , Freedman Neal D. , Yang Qi , Hicks Belynda , Dagnall Casey , Hautman Christopher , Jacobs Kevin B. , Abnet Christian C. , Aldrich Melinda C. , Amos Christopher , Amundadottir Laufey T. , Arslan Alan A. , Beane-Freeman Laura E. , Berndt Sonja I. , Black Amanda , Blot William J. , Bock Cathryn H. , Bracci Paige M. , Brinton Louise A. , Bueno-de-Mesquita H Bas , Burdett Laurie , Buring Julie E. , Butler Mary A. , Canzian Federico , Carreón Tania , Chaffee Kari G. , Chang I-Shou , Chatterjee Nilanjan , Chen Chu , Chen Constance , Chen Kexin , Chung Charles C. , Cook Linda S. , Crous Bou Marta , Cullen Michael , Davis Faith G. , De Vivo Immaculata , Ding Ti , Doherty Jennifer , Duell Eric J. , Epstein Caroline G. , Fan Jin-Hu , Figueroa Jonine D. , Fraumeni Joseph F. , Friedenreich Christine M. , Fuchs Charles S. , Gallinger Steven , Gao Yu-Tang , Gapstur Susan M. , Garcia-Closas Montserrat , Gaudet Mia M. , Gaziano J. Michael , Giles Graham G. , Gillanders Elizabeth M. , Giovannucci Edward L. , Goldin Lynn , Goldstein Alisa M. , Haiman Christopher A. , Hallmans Goran , Hankinson Susan E. , Harris Curtis C. , Henriksson Roger , Holly Elizabeth A. , Hong Yun-Chul , Hoover Robert N. , Hsiung Chao A. , Hu Nan , Hu Wei , Hunter David J. , Hutchinson Amy , Jenab Mazda , Johansen Christoffer , Khaw Kay-Tee , Kim Hee Nam , Kim Yeul Hong , Kim Young Tae , Klein Alison P. , Klein Robert , Koh Woon-Puay , Kolonel Laurence N. , Kooperberg Charles , Kraft Peter , Krogh Vittorio , Kurtz Robert C. , LaCroix Andrea , Lan Qing , Landi Maria Teresa , Marchand Loic Le , Li Donghui , Liang Xiaolin , Liao Linda M. , Lin Dongxin , Liu Jianjun , Lissowska Jolanta , Lu Lingeng , Magliocco Anthony M. , Malats Nuria , Matsuo Keitaro , McNeill Lorna H. , McWilliams Robert R. , Melin Beatrice S. , Mirabello Lisa , Moore Lee , Olson Sara H. , Orlow Irene , Park Jae Yong , Patiño-Garcia Ana , Peplonska Beata , Peters Ulrike , Petersen Gloria M. , Pooler Loreall , Prescott Jennifer , Prokunina-Olsson Ludmila , Purdue Mark P. , Qiao You-Lin , Rajaraman Preetha , Real Francisco X. , Riboli Elio , Risch Harvey A. , Rodriguez-Santiago Benjamin , Ruder Avima M. , Savage Sharon A. , Schumacher Fredrick , Schwartz Ann G. , Schwartz Kendra L. , Seow Adeline , Wendy Setiawan Veronica , Severi Gianluca , Shen Hongbing , Sheng Xin , Shin Min-Ho , Shu Xiao-Ou , Silverman Debra T. , Spitz Margaret R. , Stevens Victoria L. , Stolzenberg-Solomon Rachael , Stram Daniel , Tang Ze-Zhong , Taylor Philip R. , Teras Lauren R. , Tobias Geoffrey S. , Van Den Berg David , Visvanathan Kala , Wacholder Sholom , Wang Jiu-Cun , Wang Zhaoming , Wentzensen Nicolas , Wheeler William , White Emily , Wiencke John K. , Wolpin Brian M. , Wong Maria Pik , Wu Chen , Wu Tangchun , Wu Xifeng , Wu Yi-Long , Wunder Jay S. , Xia Lucy , Yang Hannah P. , Yang Pan-Chyr , Yu Kai , Zanetti Krista A. , Zeleniuch-Jacquotte Anne , Zheng Wei , Zhou Baosen , Ziegler Regina G. , Perez-Jurado Luis A. , Caporaso Neil E. , Rothman Nathaniel , Tucker Margaret , Dean Michael C. , Yeager Meredith , Chanock Stephen J. 
Published: June 2016

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.