The identified mutations in all individuals were pooled into three groups: LSC cells/clones from young donors, hepatocytes from young and aged donors. The integrated spectra of six mutation types in each group were plotted using the R package “MutationalPatterns” (51). Using non-negative matrix factorization (NMF) decomposition in the same package, we revealed group-specific mutational signatures as well as de novo identified two signatures in normal human liver cells. To identify the potential origin of the mutational spectra, the group mutational signatures and newly revealed signatures to the published signatures associated with liver-specific organoids and various cancer tissues. Three tissue-specific organoid signatures were obtained from a recent study (8); 67 cancer mutation signatures were downloaded from the latest version 3 of the COSMIC database (https://cancer.sanger.ac.uk/cosmic/signatures/SBS/) (27, 28). The cosine similarity between newly identified and published signatures was calculated for comparisons (table S4).

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