Characterization of large structural genetic mosaicism in human autosomes.
Machiela MJ., Zhou W., Sampson JN., Dean MC., Jacobs KB., Black A., Brinton LA., Chang I-S., Chen C., Chen C., Chen K., Cook LS., Crous Bou M., De Vivo I., Doherty J., Friedenreich CM., Gaudet MM., Haiman CA., Hankinson SE., Hartge P., Henderson BE., Hong Y-C., Hosgood HD., Hsiung CA., Hu W., Hunter DJ., Jessop L., Kim HN., Kim YH., Kim YT., Klein R., Kraft P., Lan Q., Lin D., Liu J., Le Marchand L., Liang X., Lissowska J., Lu L., Magliocco AM., Matsuo K., Olson SH., Orlow I., Park JY., Pooler L., Prescott J., Rastogi R., Risch HA., Schumacher F., Seow A., Setiawan VW., Shen H., Sheng X., Shin M-H., Shu X-O., VanDen Berg D., Wang J-C., Wentzensen N., Wong MP., Wu C., Wu T., Wu Y-L., Xia L., Yang HP., Yang P-C., Zheng W., Zhou B., Abnet CC., Albanes D., Aldrich MC., Amos C., Amundadottir LT., Berndt SI., Blot WJ., Bock CH., Bracci PM., Burdett L., Buring JE., Butler MA., Carreón T., Chatterjee N., Chung CC., Cook MB., Cullen M., Davis FG., Ding T., Duell EJ., Epstein CG., Fan J-H., Figueroa JD., Fraumeni JF., Freedman ND., Fuchs CS., Gao Y-T., Gapstur SM., Patiño-Garcia A., Garcia-Closas M., Gaziano JM., Giles GG., Gillanders EM., Giovannucci EL., Goldin L., Goldstein AM., Greene MH., Hallmans G., Harris CC., Henriksson R., Holly EA., Hoover RN., Hu N., Hutchinson A., Jenab M., Johansen C., Khaw K-T., Koh W-P., Kolonel LN., Kooperberg C., Krogh V., Kurtz RC., LaCroix A., Landgren A., Landi MT., Li D., Liao LM., Malats N., McGlynn KA., McNeill LH., McWilliams RR., Melin BS., Mirabello L., Peplonska B., Peters U., Petersen GM., Prokunina-Olsson L., Purdue M., Qiao Y-L., Rabe KG., Rajaraman P., Real FX., Riboli E., Rodríguez-Santiago B., Rothman N., Ruder AM., Savage SA., Schwartz AG., Schwartz KL., Sesso HD., Severi G., Silverman DT., Spitz MR., Stevens VL., Stolzenberg-Solomon R., Stram D., Tang Z-Z., Taylor PR., Teras LR., Tobias GS., Viswanathan K., Wacholder S., Wang Z., Weinstein SJ., Wheeler W., White E., Wiencke JK., Wolpin BM., Wu X., Wunder JS., Yu K., Zanetti KA., Zeleniuch-Jacquotte A., Ziegler RG., de Andrade M., Barnes KC., Beaty TH., Bierut LJ., Desch KC., Doheny KF., Feenstra B., Ginsburg D., Heit JA., Kang JH., Laurie CA., Li JZ., Lowe WL., Marazita ML., Melbye M., Mirel DB., Murray JC., Nelson SC., Pasquale LR., Rice K., Wiggs JL., Wise A., Tucker M., Pérez-Jurado LA., Laurie CC., Caporaso NE., Yeager M., Chanock SJ.
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.