Dataset Information

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

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.

SUBMITTER: Machiela MJ

PROVIDER: S-EPMC4909985 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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

Machiela Mitchell J MJ Zhou Weiyin W Karlins Eric E Sampson Joshua N JN Freedman Neal D ND Yang Qi Q Hicks Belynda B Dagnall Casey C Hautman Christopher C Jacobs Kevin B KB Abnet Christian C CC Aldrich Melinda C MC Amos Christopher C Amundadottir Laufey T LT Arslan Alan A AA Beane-Freeman Laura E LE Berndt Sonja I SI Black Amanda A Blot William J WJ Bock Cathryn H CH Bracci Paige M PM Brinton Louise A LA Bueno-de-Mesquita H Bas HB Burdett Laurie L Buring Julie E JE Butler Mary A MA Canzian Federico F Carreón Tania T Chaffee Kari G KG Chang I-Shou IS Chatterjee Nilanjan N Chen Chu C Chen Constance C Chen Kexin K Chung Charles C CC Cook Linda S LS Crous Bou Marta M Cullen Michael M Davis Faith G FG De Vivo Immaculata I Ding Ti T Doherty Jennifer J Duell Eric J EJ Epstein Caroline G CG Fan Jin-Hu JH Figueroa Jonine D JD Fraumeni Joseph F JF Friedenreich Christine M CM Fuchs Charles S CS Gallinger Steven S Gao Yu-Tang YT Gapstur Susan M SM Garcia-Closas Montserrat M Gaudet Mia M MM Gaziano J Michael JM Giles Graham G GG Gillanders Elizabeth M EM Giovannucci Edward L EL Goldin Lynn L Goldstein Alisa M AM Haiman Christopher A CA Hallmans Goran G Hankinson Susan E SE Harris Curtis C CC Henriksson Roger R Holly Elizabeth A EA Hong Yun-Chul YC Hoover Robert N RN Hsiung Chao A CA Hu Nan N Hu Wei W Hunter David J DJ Hutchinson Amy A Jenab Mazda M Johansen Christoffer C Khaw Kay-Tee KT Kim Hee Nam HN Kim Yeul Hong YH Kim Young Tae YT Klein Alison P AP Klein Robert R Koh Woon-Puay WP Kolonel Laurence N LN Kooperberg Charles C Kraft Peter P Krogh Vittorio V Kurtz Robert C RC LaCroix Andrea A Lan Qing Q Landi Maria Teresa MT Marchand Loic Le LL Li Donghui D Liang Xiaolin X Liao Linda M LM Lin Dongxin D Liu Jianjun J Lissowska Jolanta J Lu Lingeng L Magliocco Anthony M AM Malats Nuria N Matsuo Keitaro K McNeill Lorna H LH McWilliams Robert R RR Melin Beatrice S BS Mirabello Lisa L Moore Lee L Olson Sara H SH Orlow Irene I Park Jae Yong JY Patiño-Garcia Ana A Peplonska Beata B Peters Ulrike U Petersen Gloria M GM Pooler Loreall L Prescott Jennifer J Prokunina-Olsson Ludmila L Purdue Mark P MP Qiao You-Lin YL Rajaraman Preetha P Real Francisco X FX Riboli Elio E Risch Harvey A HA Rodriguez-Santiago Benjamin B Ruder Avima M AM Savage Sharon A SA Schumacher Fredrick F Schwartz Ann G AG Schwartz Kendra L KL Seow Adeline A Wendy Setiawan Veronica V Severi Gianluca G Shen Hongbing H Sheng Xin X Shin Min-Ho MH Shu Xiao-Ou XO Silverman Debra T DT Spitz Margaret R MR Stevens Victoria L VL Stolzenberg-Solomon Rachael R Stram Daniel D Tang Ze-Zhong ZZ Taylor Philip R PR Teras Lauren R LR Tobias Geoffrey S GS Van Den Berg David D Visvanathan Kala K Wacholder Sholom S Wang Jiu-Cun JC Wang Zhaoming Z Wentzensen Nicolas N Wheeler William W White Emily E Wiencke John K JK Wolpin Brian M BM Wong Maria Pik MP Wu Chen C Wu Tangchun T Wu Xifeng X Wu Yi-Long YL Wunder Jay S JS Xia Lucy L Yang Hannah P HP Yang Pan-Chyr PC Yu Kai K Zanetti Krista A KA Zeleniuch-Jacquotte Anne A Zheng Wei W Zhou Baosen B Ziegler Regina G RG Perez-Jurado Luis A LA Caporaso Neil E NE Rothman Nathaniel N Tucker Margaret M Dean Michael C MC Yeager Meredith M Chanock Stephen J SJ

Nature communications 20160613

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 mos ...[more]

PMID: 27291797

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Project description:Primary biliary cirrhosis (PBC) is an autoimmune chronic cholestatic liver disease with a strong genetic susceptibility due to the high concordance in monozygotic (MZ) twins and a striking female predominance. Women with PBC manifest an enhanced X monosomy rate in peripheral lymphocytes and we thus hypothesized an X chromosome epigenetic component to explain PBC female prevalence. While most genes on the female inactive X chromosome are silenced by promoter methylation following X chromosome inactivation (XCI), approximately 10% of X- linked genes exhibit variable escape from XCI in healthy females. This study was designed to test the hypothesis that susceptibility to PBC is modified by one or more X-linked gene with variable XCI status. Peripheral blood mRNA and DNA samples were obtained from a unique cohort of MZ twin sets discordant and concordant for PBC. Transcript levels of the 125 variable XCI status genes was determined by quantitative RT-PCR analysis and two genes (CLIC2 and PIN4) were identified as consistently downregulated in the affected twin of discordant pairs. Both CLIC2 and PIN4 demonstrated partial and variable methylation of CpG sites within 300 bp of the transcription start site that did not predict the XCI status. Promoter methylation of CLIC2 manifested no significant difference between samples and no significant correlation with transcript levels. PIN4 methylation showed a positive trend with transcription in all samples but no differential methylation was observed between discordant twins. A genetic polymorphism affecting the number of CpG sites in the PIN4 promoter did not impact methylation or transcript levels in a heterozygous twin pair and showed a similar frequency in independent series of unrelated PBC cases and controls. Our results suggest that epigenetic factors influencing PBC onset are more complex than methylation differences at X-linked promoters and variably 3 inactivated X-linked genes may be characterized by partial promoter methylation and biallelic transcription.

Dataset Information

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

Publications

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

Similar Datasets

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