Characterization of large structural genetic mosaicism in human autosomes.

Authors:
Dr. Michael Dean, PhD
Dr. Michael Dean, PhD
National Cancer Institute
Sr. Scientist, LTG, DCEG
Human Genetics
Gaithersburg, MD | United States
Loreall Pooler
Loreall Pooler
University of Southern California
United States
Dr. Jonine Figueroa, PhD
Dr. Jonine Figueroa, PhD
Usher Institute of Population Health Sciences and Informatics
Chancellor's Fellow
Molecular epidemiology
Edinburgh, Scotland | United Kingdom
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 Hartge Brian 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 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

Am J Hum Genet 2015 Mar;96(3):487-97

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address:

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.

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http://dx.doi.org/10.1016/j.ajhg.2015.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375431PMC
March 2015
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25 Citations
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