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. 2022 Jul 8;13:3949. doi: 10.1038/s41467-022-31341-0

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 4 — a SBS mutation burden in peripheral blood per cell (x-axis) plotted against the age of the individual in years (y-axis). Dots are coloured according to the individual’s germline mutation; orange; MUTYH^{Y179C+/− G396D+/−}, yellow; MUTYH^Y179C+/+, green; MUTYH^Y104*+/+ and blue; MUTYH^G286E+/+. Whiskers represent the 95% confidence interval. Dashed line represents the mutation rate in wild-type (WT) normal control samples, dotted line represents the mutation rate in MUTYH samples (linear mixed-effects-model)⁵⁰. b Mutation rate of MUTYH associated mutational signatures; SBS18 and SBS36 per cell for peripheral blood (SBS/yr)(x-axis) against the SBS18 & SBS36 mutation rate of normal intestinal crypts (SBS/yr)(y-axis). Each dot represents one individual and they are coloured according to the individual’s germline mutation; orange; MUTYH^{Y179C+/− G396D+/−}, yellow; MUTYH^Y179C+/+, green; MUTYH^Y104*+/+ and blue; MUTYH^G286E+/+. The rate of MUTYH associated mutational processes is ~13x fold (linear model, 95% C.I.; 10-17) higher in intestine vs blood. Black line indicates the ratio, and dotted lines the 95% C.I.. Plot inset shows the mutation rate for n = 9 patients excluding the outlier, PD44890. c Stacked bar plot displaying the mutational signature contribution in each peripheral blood sample organised by patient. Coloured squares indicate the MUTYH germline mutation. Normal control data from granulocytes sequenced using the same method (data from Abascal et al 2021)⁵⁰. Significantly higher proportion of SBS18 and SBS36 is observed in individuals with MUTYH mutations vs normal healthy controls (two-sided Wilcoxon rank sum, P = 0.00004). d SBS mutation burden in intestinal lymphocyte cells from wild-type healthy individuals (grey) and individuals with MUTYH mutations (coloured according to the germline MUTYH genotype) plotted against age (years). Dots represent median values and whiskers represent the 95% confidence interval. Dashed line indicates the rate of increase of SBS burden in wild-type lymphocytes (40 SBS/yr, linear mixed-effects model, R² = 0.68, 95% C.I., 13-66, P = 0.01) and dotted line indicates the rate of increase in SBS burden in lymphocytes from individuals with MUTYH mutations (53 SBS/yr, linear mixed-effects model, R² = 0.68, 95% C.I., 21–85, P = 0.01). e Stacked bar plots showing the absolute (above) and relative (below) contributions of each mutational signature in tissue lymphocytes from wild-type healthy individuals and individuals with MUTYH mutations. Source data are provided as a Source Data file.