Figure 2.
Figure 2. Damage introduced by 5mC deamination is influenced by genetic and epigenetic features. (A) Observed relative mutation rates (RMRs) at different genomic features in whole genome sequencing from WEHI-AML-1 and WEHI-AML-2, calculated per Mb of CG dinucleotides (CG corrected), or corrected for methylation status in normal CD34+ cells (5mC corrected). (B) Abundance and methylation status for NCG trimers from whole genome bisulfite sequencing derived from normal CD34+ cells.37 An RMR value was calculated for WEHI-AML-1 and WEHI-AML-2 for each NCG trimer, accounting for differences in abundance and 5mC status in normal CD34+ cells and scaled to account for total mutation load (see supplemental Methods). Individual values are plotted (n = 2), and bars show the mean. (C) RMR values were calculated from exome data for the 5 MBD4-deficient cancers. There was a significant enrichment of mutations in the ACG context compared with TCG (P = .0079, Mann-Whitney U test). (D) RMR values were calculated from whole genome sequencing data generated from Mbd4 knockout (Mbd4-KO) murine blood cell progenitors at 4 months of age. Values from individual colonies are plotted (n = 3), and the bar shows the mean. There was a significant enrichment of mutations in the ACG context compared with TCG (P = .019, Welch’s t test). (E) RMR values were calculated for NCGN tetramers in WEHI-AML-1 and WEHI-AML-2, then separated by replication timing (n = 2).

Damage introduced by 5mC deamination is influenced by genetic and epigenetic features. (A) Observed relative mutation rates (RMRs) at different genomic features in whole genome sequencing from WEHI-AML-1 and WEHI-AML-2, calculated per Mb of CG dinucleotides (CG corrected), or corrected for methylation status in normal CD34+ cells (5mC corrected). (B) Abundance and methylation status for NCG trimers from whole genome bisulfite sequencing derived from normal CD34+ cells.37  An RMR value was calculated for WEHI-AML-1 and WEHI-AML-2 for each NCG trimer, accounting for differences in abundance and 5mC status in normal CD34+ cells and scaled to account for total mutation load (see supplemental Methods). Individual values are plotted (n = 2), and bars show the mean. (C) RMR values were calculated from exome data for the 5 MBD4-deficient cancers. There was a significant enrichment of mutations in the ACG context compared with TCG (P = .0079, Mann-Whitney U test). (D) RMR values were calculated from whole genome sequencing data generated from Mbd4 knockout (Mbd4-KO) murine blood cell progenitors at 4 months of age. Values from individual colonies are plotted (n = 3), and the bar shows the mean. There was a significant enrichment of mutations in the ACG context compared with TCG (P = .019, Welch’s t test). (E) RMR values were calculated for NCGN tetramers in WEHI-AML-1 and WEHI-AML-2, then separated by replication timing (n = 2).

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