Ultra-sensitive Sequencing Identifies High Prevalence of Clonal Hematopoiesis- Associated Mutations throughout Adult Life Rocio Acuna-Hidalgo, Hilal Sengul,

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Ultra-sensitive Sequencing Identifies High Prevalence of Clonal Hematopoiesis- Associated Mutations throughout Adult Life Rocio Acuna-Hidalgo, Hilal Sengul, Marloes Steehouwer, Maartje van de Vorst, Sita H. Vermeulen, Lambertus A.L.M. Kiemeney, Joris A. Veltman, Christian Gilissen, Alexander Hoischen The American Journal of Human Genetics Volume 101, Issue 1, Pages 50-64 (July 2017) DOI: 10.1016/j.ajhg.2017.05.013 Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 1 Validation of Mutations by Restriction Digestion and Re-sequencing (A) Mutations identified in DNMT3A Arg882 selected for additional validation by non-sequencing-based method. (B) Scheme showing recognition site for restriction digestion enzyme TauI in the genomic sequence corresponding to DNMT3A Arg882. Mutations chr2:25457242C>T and chr2:25457243G>A (hg19) leading to p.Arg882His and p.Arg882Cys, respectively, are marked below with red arrows. (C) Size analysis of restriction digestion of DNMT3A PCR products. Lanes 1 to 5 represent samples with mutations with different VAFs. C1 is a control with false positive signal for a G>A mutation at chr2:25457243, as determined statistically. C2 is a control with no DNMT3A mutation. (D) Gel trace of size analysis of digestion, with sample 4 on the left and C2 on the right. The peak corresponding to the full-size product is marked with a red triangle for both samples. Note that C2 present a small peak at 577 bp, corresponding to undigested PCR products due to digestion enzyme saturation. (E) Sequencing results of digested PCR product for sample 5. We obtain a higher ratio of mutation to wild-type reads than in the original sample due to digestion of the wild-type product. The American Journal of Human Genetics 2017 101, 50-64DOI: (10.1016/j.ajhg.2017.05.013) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 Prevalence of Clonal Hematopoiesis-Driver Mutations (A) Prevalence and distribution of clonal hematopoiesis-driver mutations identified in healthy individuals aged between 20 and 69 years of age. (B) Prevalence of mutations in DNMT3A per age group. Hotspot in DNTM3A are defined as residues in which five or more mutations were identified in our cohort and include Arg326, Arg729, Tyr735, Arg736, Trp860, and Arg882. All other missense, loss-of-function, and indels are included in the non-hotspot mutations. The American Journal of Human Genetics 2017 101, 50-64DOI: (10.1016/j.ajhg.2017.05.013) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 3 Clonal Hematopoiesis-Driver Mutations per Age Group (A) Prevalence of clonal hematopoiesis per age group, defined as the frequency of individuals with one or more CHDMs per decade of age. (B) Proportion of the population per age group with CHDMs. (C) Mutation variant allele fraction per age of the individual in which the mutation was identified. The y axis is in logarithmic scale. No significant correlation is observed between the age of the individual and the VAF of the mutation identified. The American Journal of Human Genetics 2017 101, 50-64DOI: (10.1016/j.ajhg.2017.05.013) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 4 Type of Mutation Change per Age Group The American Journal of Human Genetics 2017 101, 50-64DOI: (10.1016/j.ajhg.2017.05.013) Copyright © 2017 American Society of Human Genetics Terms and Conditions