Characterization of large structural genetic mosaicism in human autosomes.

Machiela MJ1, Zhou W2, Sampson JN1, Dean MC3, Jacobs KB4, Black A1, Brinton LA1, Chang IS5, Chen C6, Chen C7, Chen K8, Cook LS9, Crous Bou M10, De Vivo I10, Doherty J11, Friedenreich CM12, Gaudet MM13, Haiman CA14, Hankinson SE15, Hartge P1, Henderson BE14, Hong YC16, Hosgood HD 3rd17, Hsiung CA18, Hu W1, Hunter DJ19, Jessop L1, Kim HN20, Kim YH21, Kim YT22, Klein R23, Kraft P7, Lan Q1, Lin D24, Liu J25, Le Marchand L26, Liang X27, Lissowska J28, Lu L29, Magliocco AM30, Matsuo K31, Olson SH27, Orlow I27, Park JY32, Pooler L33, Prescott J10, Rastogi R27, Risch HA29, Schumacher F14, Seow A34,Setiawan VW14, Shen H35, Sheng X33, Shin MH36, Shu XO37, VanDen Berg D14, Wang JC38, Wentzensen N1, Wong MP39, Wu C24, Wu T40, Wu YL41, Xia L33, Yang HP1, Yang PC42, Zheng W43, Zhou B44, Abnet CC1, Albanes D1, Aldrich MC45, Amos C46, Amundadottir LT1, Berndt SI1, Blot WJ47, Bock CH48,Bracci PM49, Burdett L2, Buring JE50, Butler MA51, Carreón T51, Chatterjee N1, Chung CC2, Cook MB1, Cullen M2, Davis FG52, Ding T53, Duell EJ54, Epstein CG1, Fan JH55, Figueroa JD1, Fraumeni JF Jr1, Freedman ND1, Fuchs CS56, Gao YT57, Gapstur SM13, Patiño-Garcia A58, Garcia-Closas M59, Gaziano JM60,Giles GG61, Gillanders EM62, Giovannucci EL63, Goldin L1, Goldstein AM1, Greene MH1, Hallmans G64, Harris CC65, Henriksson R66, Holly EA49, Hoover RN1, Hu N1, Hutchinson A2, Jenab M67, Johansen C68, Khaw KT69, Koh WP70, Kolonel LN26, Kooperberg C6, Krogh V71, Kurtz RC72, LaCroix A6, Landgren A1, Landi MT1, Li D73, Liao LM1, Malats N74, McGlynn KA1, McNeill LH75, McWilliams RR76, Melin BS66, Mirabello L1, Peplonska B77, Peters U6, Petersen GM78, Prokunina-Olsson L1, Purdue M1, Qiao YL79, Rabe KG78, Rajaraman P1, Real FX80, Riboli E81, Rodríguez-Santiago B82, Rothman N1, Ruder AM51,Savage SA1, Schwartz AG48, Schwartz KL83, Sesso HD50, Severi G84, Silverman DT1, Spitz MR85, Stevens VL13, Stolzenberg-Solomon R1, Stram D14, Tang ZZ53, Taylor PR1, Teras LR13, Tobias GS1, Viswanathan K86, Wacholder S1, Wang Z2, Weinstein SJ1, Wheeler W87, White E6, Wiencke JK88, Wolpin BM56, Wu X89, Wunder JS90, Yu K1, Zanetti KA62, Zeleniuch-Jacquotte A91, Ziegler RG1, de Andrade M78, Barnes KC92, Beaty TH86, Bierut LJ93, Desch KC94, Doheny KF95, Feenstra B96, Ginsburg D97, Heit JA98, Kang JH99, Laurie CA100, Li JZ101, Lowe WL102, Marazita ML103, Melbye M104, Mirel DB105, Murray JC106,Nelson SC100, Pasquale LR107, Rice K100, Wiggs JL108, Wise A109, Tucker M1, Pérez-Jurado LA110, Laurie CC100, Caporaso NE1, Yeager M2, Chanock SJ111.

Author information

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.