Self-assembling viral histones unravel early nucleosome evolution

Nucleosomes are a core-component of eukaryotic nuclei, forming the structural basis of chromatin and co-ordinating processes from gene expression to chromosome segregation. Composed of a DNA-protein complex consisting of the four individual histones, H2A, H2B, H3, and H4, the nucleosome and its associated functions were key innovations during eukaryotic evolution1,2. However, functional constraints and the extinction of stem-eukaryotes have concealed how these dynamic systems evolved from simpler histone homologues in Archaea3-5. Viral histones have also previously been identified and are thought to reflect an ancestral state as they often comprise multiple histone paralogues arranged within a single protein, termed histone repeats6-11. Here, using viruses as an alternative source of variation, we expand the known diversity of histones and develop an empirical hypothesis for the origin of the nucleosome. Our analysis identified hundreds of histones with variable domain repeat configurations including histone singlets, doublets, triplets, and quadruplets, the latter comprising the four core histones arranged in series. Viral histone repeats consistently branch between Archaea and eukaryotes in phylogenetic trees and display intermediate functions, self-assembling into eukaryotic-like nucleosomes that stack into archaeal-like oligomers capable of impacting genomic activity and condensing DNA. The linkers conjoining the histone repeats also facilitate nucleosome formation and can promote the assembly of eukaryotic nucleosomes in the bacterium, Escherichia coli. Combining these data, we hypothesize that viral histone repeats represent molecular relics acquired by viruses from stem-eukaryotes during eukaryogenesis and suggest that nucleosome evolution may have proceeded through histone repeat intermediates.