The rate and spectrum of mosaic mutations during embryogenesis revealed by RNA sequencing of 49 tissues [article]

Francesc Muyas, Luis Zapata, Roderic Guigó, Stephan Ossowski
2019 biorxiv/medrxiv   pre-print
Mosaic mutations acquired during early embryogenesis can lead to severe early-onset genetic disorders and cancer predisposition, but are often undetectable in blood samples. The rate and mutational spectrum of embryonic mosaic mutations (EMMs) have only been studied in few selected tissues and their contribution to genetic disorders is unknown. For this reason, we investigated how frequent mosaic mutations occur during embryogenesis across all germ layers and tissues. Using RNA sequencing
more » ... eq) data from the Genotype-Tissue Expression (GTEx) cohort comprising 49 tissues and 570 individuals, we found that new-borns on average harbour 0.5 - 1 post-zygotic and early embryonic mosaic mutations in coding exons affecting multiple tissues and organs (rate of 1.3225x 10-8 per nucleotide per individual). We further observed that EMMs are dominated by a mutational signature associated with spontaneous deamination of methylated cytosines and the number of cell divisions. Our findings suggest that EMMs are as frequent as germline de novo mutations, could therefore explain a substantial fraction of unsolved sporadic disease entities, and might play a previously under-appreciated role in cancer predisposition. After birth, cells continue to accumulate somatic mutations, which can lead to the development of cancer if key functions such as cell cycle control are affected. Investigation of the mutational spectrum of the gastrointestinal tract revealed a mutational pattern associated with the food-borne carcinogen aflatoxin, a signature that has so far only been reported in liver cancer. In summary, the analysis of multiple tissues per individual allowed us to distinguish mosaic mutations acquired during different stages of embryogenesis and life. Our results show that embryonic mosaic mutations are frequent and likely play a role in many unsolved genetic disease cases. Hence, their detection needs to be an indispensable part of clinical diagnostics.
doi:10.1101/687822 fatcat:aj7kxdy4g5abhkrc5xfovlo5uq