Hypermutability of ultraconserved histone genes and its contribution to human disease

Histone genes are among the most evolutionarily conserved sequences in eukaryotes, reflecting their essential role in nucleosome architecture. Intriguingly, our analysis reveals unexpectedly high germline mutation rates in replication-dependent histone genes across vertebrates. We provide multiple lines of evidence suggesting that this hypermutability is largely driven by off-target mutagenic effects of AID/APOBEC enzymes, representing an unintended fitness cost associated with vertebrate immune system innovation. To characterize the impact of these mutations, we develop HistMTR, a paralog-aware missense constraint framework that outperforms existing tools in predicting the pathogenicity of histone mutations. Applying this framework to large-scale human genomic data, we demonstrate that both coding and regulatory histone mutations contribute to a spectrum of diseases, including developmental disorders and reproductive failure. Analyses of allele transmission ratios and the distribution of fitness effects indicate intense ongoing negative selection against deleterious histone mutations in humans. Together, these findings uncover a hidden vulnerability of ultraconserved histone genes and establish HistMTR as an important framework for characterizing the underappreciated role of histone mutations in human disease.