In the case of TP53, most sites under significant selection are in the p53 DNA-binding domain48 (Fig. 5c), and are observed more frequently across tumours24,49,50 (Extended Data Fig. 10b), more likely to be identified as cancer drivers46 (Extended Data Fig. 10b) and tend to score higher on an experimental saturation mutagenesis assay51 (Fig. 5d), as described previously in duplex sequencing analysis of TP53 in other normal tissues52–54. Here, TP53 is linked to cancer.