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. 2023 Aug 23;3(9):100389. doi: 10.1016/j.xgen.2023.100389

Figure 3.

Figure 3

PTATO detects normal single base substitution burdens in most human FA HSPCs

(A) Correlation of the number of somatic single base substitutions per HSPC genome of healthy donors (gray points) and patients with FA. Linear mixed modeling showed that healthy HSPCs accumulate base substitutions in a linear fashion with age.27,28 The 95% confidence interval and the prediction interval of the model are indicated by the dark gray and light gray shading, respectively.

(B) Ratios between the observed and expected number of base substitutions per genome (sorted on age) based on extrapolation of the age linear mixed model. To match the ages of the patients with FA, only 12 HSPCs of four healthy donors (HSCT1–4, ages 7 to 14) are included in this and following panels. Adjusted p values indicate multiple testing corrected significant differences (padj < 0.05) between three FA patients and the age-matched healthy donors (Bonferroni-corrected Wilcoxon Mann-Whitney test).

(C) Mutation spectra showing the relative contribution of each base substitution type in the genomes of the donors. Numbers above the bar indicate the total number of base substitutions found in the samples from each individual.

(D) The averaged 96-trinucleotide mutational profiles of the HSPCs of the four healthy individuals (HSCT1–4), the patients with mutations in FANCA or FANCC (PMCFANC01, PMCFANC03, PMCFANC06, PMCFANC08), and the patient with mutations in BRCA2 (PMCFANC02).

(E) Contribution of base substitution mutational signatures commonly found in blood cells27,28 to each FA sample or healthy individual (averaged). Horizontal black lines indicate the expected number of base substitutions based on age. Non-PTA samples sequenced with bulk WGS are indicated by an asterisk. For donors HSCT1 to HSCT4, the mean contributions over all samples per donor is shown.

(F) Cosine similarities between the mean 96-trinucleotide mutational profiles of the HSPCs of FA patients with the profiles of the healthy HSPCs from the four age-matched donors and the mutational signatures.