PT - JOURNAL ARTICLE AU - Francesc Muyas AU - Luis Zapata AU - Roderic Guigó AU - Stephan Ossowski TI - The rate and spectrum of mosaic mutations during embryogenesis revealed by RNA sequencing of 49 tissues AID - 10.1101/687822 DP - 2019 Jan 01 TA - bioRxiv PG - 687822 4099 - http://biorxiv.org/content/early/2019/10/08/687822.short 4100 - http://biorxiv.org/content/early/2019/10/08/687822.full AB - Background 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 tissues and their contribution to genetic disorders is unknown. Therefore, we investigated how frequent mosaic mutations occur during embryogenesis across all germ layers and tissues.Results Using RNA sequencing data from the Genotype-Tissue Expression (GTEx) cohort comprising 49 normal tissues and 570 individuals, we found that new-borns on average harbour 0.5 - 1 EMMs in the exome affecting multiple organs (1.3230 × 10−8 per nucleotide per individual), a similar frequency as reported for germline de novo mutations. Our multi-tissue, multi-individual study design allowed us to distinguish mosaic mutations acquired during different stages of embryogenesis and adult life, as well as to provide insights into the rate and spectrum of mosaic mutations. We observed that EMMs are dominated by a mutational signature associated with spontaneous deamination of methylated cytosines and the number of cell divisions. After birth, cells continue to accumulate somatic mutations, which can lead to the development of cancer. 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.Conclusion In summary, our multi-tissue, multi-individual study reveals a surprisingly high number of embryonic mosaic mutations in coding regions, implying novel hypotheses and diagnostic procedures for investigating genetic causes of disease and cancer predisposition.