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

Abstract

Background: Mosaic mutations acquired during early embryogenesis can lead to severe earlyonset 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 x 10 -8 per nucleotide per individual), a similar frequency as reported for germline de novo mutations. Our multi-tissue, multiindividual 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.

Rates and Patterns of Clonal Oncogenic Mutations in the Normal Human Brain

“…Nonetheless, all the evaluated brain regions do not achieve a high level of statistical support (showing a FDR>0.1) and hence are not inconsistent with a lack of age-related increase. In the second study (45), they report negative values of age-correlation with brain mutations, but these are also insignificant, supporting a lack of age-related increase and a trend consistent with our findings. The relative stability of oncogenic brain mutations with age, combined with the ability of RNAseq analysis to detect only those clonal mutations with high mosaic fraction, suggests that some oncogenic mutations at a young age may be congenital.…”

“…Normal brain sSNVs statistically decomposed into several signatures (SBS 39, 5, 23, 1, 30, and 2), each reported in COSMIC as present in brain tumors (Fig. 6) and consistent with previous findings (45). Our analysis confirmed that the mutational signatures found in normal brains are indeed enriched for brain cancer signatures (Permutation test, p=0.00018).…”

Likely foregut endoderm origin for a postzygotic mutation affecting the RNase IIIb domain of DICER1

“…In such patients, the mutation is presumed to have occurred before gastrulation (day 16 after fertilisation) 6. In the current case, however, the limited number of affected organs reflects a highly restricted mutation distribution,7 8 suggesting that the c.5425G>A, p.Gly1809Arg mutation occurred later than gastrulation. We hypothesise that the hotspot mutation arose after the primitive foregut is established on day 18 of embryonic development and before bifurcation of the lung bud on day 26 (figure 2).…”

dN/dS dynamics quantify tumour immunogenicity and predict response to immunotherapy

“…While some studies have shown evidence of an association between immune activity and selective pressures 8,34,51,55,59 , others have claimed that there is a lack of evidence to prove this relationship 16 . Given that several studies have applied dN/dS as a metric of selection in cancer and in normal tissue 7,8,[60][61][62][63] , we aimed to prove the use of hypothesis, a recent study of longitudinal recurrence of metastasis reported a more aggressive phenotype in metastatic deposits that had higher levels of immune-selection 55 . However, whether tumor cells growing in immunecompetent tissues are more likely to colonize new niches and how long it takes those tumor cells to readapt or to find a novel escape mechanism, as has been previously observed in mice models 31,64 , remains a challenging question.…”