Characterization of large structural genetic mosaicism in human autosomes.

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

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.
Year of Publication
2015
Journal
Am J Hum Genet
Volume
96
Issue
3
Pages
487-97
Date Published
2015 Mar 05
ISSN
1537-6605
URL
http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(15)00019-1
DOI
10.1016/j.ajhg.2015.01.011
PubMed ID
25748358
PubMed Central ID
PMC4375431
Links
Grant list
P30 CA016672 / CA / NCI NIH HHS / United States
P01 CA087969 / CA / NCI NIH HHS / United States
K05 CA154337 / CA / NCI NIH HHS / United States
R01 CA092447 / CA / NCI NIH HHS / United States
UM1 CA182934 / CA / NCI NIH HHS / United States
G1000143 / Medical Research Council / United Kingdom
K07 CA172294 / CA / NCI NIH HHS / United States
R01 HL039693 / HL / NHLBI NIH HHS / United States
P30 CA023108 / CA / NCI NIH HHS / United States
R25 CA174664 / CA / NCI NIH HHS / United States
R01 CA124908 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 DE016148 / DE / NIDCR NIH HHS / United States
G0401527 / Medical Research Council / United Kingdom
R01 EY022305 / EY / NEI NIH HHS / United States
R01 EY015473 / EY / NEI NIH HHS / United States
P30 EY014104 / EY / NEI NIH HHS / United States
R01 HL112642 / HL / NHLBI NIH HHS / United States

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