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Different Mutational Processes Affect Accumulation of Somatic Variants In Fetal Tissues

NEW YORK (GenomeWeb) – Different mutational mechanisms are at work in different human fetal tissues, a new study has found.

While researchers have examined the contribution of mutations within human adult stem cells to somatic mosaicism, a team of Dutch researchers noted that the contribution of fetal mutations has been less widely studied. They have now cataloged genome-wide somatic mutations within stem cells isolated from fetal livers and intestines, finding that mutation mechanisms like oxidative stress and spontaneous deamination of methylated cytosines have varying influences on mutation accumulation in these cells.

"[O]ur results show that fetal growth comes at the cost of elevated mutation rates. Furthermore, distinct mutational mechanisms shape the mutational landscapes of the fetal liver and the fetal intestine," Utrecht University's Edwin Cuppen and his colleagues wrote in their paper, which appeared today in Science Advances.

Cuppen and his team isolated stem cells from the liver and intestines of four fetuses at 15, 17, and 22 weeks' gestational age. They expanded these stem cells in vitro as organioids and, prior to performing whole-genome sequencing, filtered them for clonal variants. In all, they sequenced 14 clonal lines — eight intestinal lines and six liver lines — to a minimum 30X average coverage.

Overall, they found that each stem cell accumulated an average 67 base substitutions, though they noted that fetal age influenced the number of alterations present. Fetal tissues, they added, accumulated five-fold more somatic variants per week than adult tissues.

The pattern of mutations varied by tissue, though. The researchers found that fetal intestinal stem cells commonly contained C-to-T changes, particularly at CpG sites. This suggested to the researchers that the mutations could be due to the deamination of methylated cytosines. This, they noted, is similar to the mutation spectrum found in adult intestinal stem cells.

Fetal liver stem cells, though, exhibited a mutational pattern that differed from that of fetal intestinal stem cells as well as from that of adult liver stem cells.

Using nonnegative matrix factorization, the researchers extracted mutational signatures from within their samples, uncovering three, which they dubbed signature A, signature B, and signature C. These signatures broadly correlated to various cancer-derived COSMIC signatures, the researchers noted.

The mutational signature found among fetal and adult intestinal stem cells was similar to COSMIC signature 1.

COSMIC signature 1, though, contributed little to the fetal liver mutational profile. Instead, fetal liver stem cells harbored a mutation profile more similar to COSMIC signatures 8 and 18, which the researchers noted are both marked by C-to-A changes and have been linked to oxidative stress-related mechanisms. Adult liver stem cells, meanwhile, have mutational patterns similar to COSMIC signatures 5 and 16, suggesting to the researchers that different mutational mechanism are at work in fetal versus adult liver stem cells.

The researchers speculated that the difference in mutation accumulation between the different fetal tissues is likely due to cellular or tissue processes that are differentially regulated in the developing organs. They found that the expression of MUTYH and OGG1 — which identify oxidized base pairs and initiate base excision repair — are both lower in the fetal liver than the fetal intestine, while the expression of MBD4 and TDG — which catalyze the removal of thymines opposite of guanines at CpG sites — is higher in fetal intestine stem cells than in fetal liver stem cells.

This suggested to the researchers that cell-intrinsic processes lead to tissue-specific mutation accumulation in fetal stem cells.