a | From pan-cancer studies (The Cancer Genome Atlas cohorts used are listed in Supplementary Box 1), the mutational spectra of histone variant genes H2AFZ (encoding H2A.Z.1), H2AFV (encoding H2A.Z.2), H2AFY (encoding macroH2A1; both isoforms, macroH2A1.1 and macroH2A1.2, are included), H2AFY2 (encoding macroH2A2), H3F3A (encoding H3.3), H3F3B (encoding H3.3) and CENPA are shown. Most histone variants show a low frequency of mutation. H3F3A has hotspot mutations (denoted by flame symbol) that represent K27M/R and G34R/V mutations. While in adult cancers these mutations are diluted, cohorts of paediatric tumours (blue axis; right) have higher mutation frequency in these hotspots. Histones are not drawn to scale. Green dots represent missense somatic mutations, while black dots indicate truncations. b | Histone variant alterations across the human body by location; H2A.Z, centromeric protein A (CENP-A) and macroH2A display altered regulation in diverse adult cancers, while H3.3 alterations are restricted to paediatric tumours. aa, amino acids.