Fig. 3: Signature analysis of sSNV reveals mutational processes in cardiomyocytes during aging.
a, Substitution type for the age-accumulated sSNVs (the ‘net increase’ in sSNVs between infant and aged cardiomyocytes). C > T and T > C substitutions are predominant. b, Cardiac mutational signatures identified by NMF based on the trinucleotide context of sSNVs. Each signature is displayed according to the 96 trinucleotide contexts, defined by the six substitution types and sequence context immediately 5′ and 3′ to the mutated base. Although both Signatures A and D predominate with C > T and T > C substitutions, they differ in trinucleotide contexts at C > T and T > C substitutions. c, Signature-specific sSNV density in cardiomyocytes, neurons, hepatocytes and lymphocytes. Signature D specifically accumulated in aged cardiomyocytes, whereas Signature A accumulated with age in all cell types but at different rates. d, NMF-based decomposition of cardiac signatures into COSMIC cancer signatures. The relative contribution of each cancer signature is shown as heatmaps. e, Transcription bias of age-accumulated sSNVs. Asterisks mark significant difference between transcribed and untranscribed strands (two-tailed Poisson test) in cardiomyocytes (C > G, P = 4.7 × 10−3; T > A, P = 1.2 × 10−6; T > C, P < 2.2 × 10−16; T > G, P < 2.2 × 10−16) and in neurons (C > T, P = 7.3 × 10−4; T > C, P = 8.9 × 10−7; T > G, P = 1.6 × 10−2). Notably, T > C substitution is enriched in the untranscribed strand in cardiomyocytes, whereas it is enriched in the transcribed strand in neurons, suggesting different mutation mechanisms in these two nondividing cells.
