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Characterization of large structural genetic mosaicism in human autosomes.

Autores: Machiela, M.J.; Zhou, W. ; Sampson, J.N.; Dean, M.C.; Jacobs, K.B. ; Black, A.; Brinton, L.A. ; Chang, I.S.; Chen, C. ; Chen, C.; Chen, K. ; Cook, L.S.; Crous Bou, M. ; De Vivo, I.; Doherty, J.; Friedenreich, C.M.; Gaudet, M.M.; Haiman, C.A. ; Hankinson, S.E. ; Hartge, P.; Henderson, B.E.; Hong, Y.C. ; Hosgood, H.D. 3rd.; Hsiung, C.A.; Hu, W.; Hunter, D.J.; Jessop, L.; Kim, H.N.; Kim, Y.H.; Kim, Y.T.; Klein, R. ; Kraft, P.; Lan, Q.; Lin, D. ; Liu, J. ; Le Marchand, L.; Liang, X.; Lissowska, J.; Lu, L.; Magliocco, A.M .; Matsuo, K.; Olson, S.H.; Orlow, I.; Park, J.Y. ; Pooler, L.; Prescott, J.; Rastogi, R. ; Risch, H.A. ; Schumacher, F.; Seow, A.
ISSN: 0002-9297
Volumen: 96
Número: 3
Páginas: 487-97
Fecha de publicación: 2015
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.