Evolutionary origins and diversification of testis-specific short histone H2A variants in mammals

Abstract

Eukaryotic genomes must accomplish both compact packaging for genome stability and inheritance, as well as accessibility for gene expression. They do so using post-translational modifications of four ancient canonical histone proteins (H2A, H2B, H3, and H4) and by deploying histone variants with specialized chromatin functions. Some histone variants are conserved across all eukaryotes, whereas others are lineage-specific. Here, we performed detailed phylogenomic analyses of "short H2A histone" variants found in mammalian genomes. We discovered a previously undescribed typically-sized H2A variant in monotremes and marsupials, , which may represent the common ancestor of the short H2As. We also discovered a novel class of short H2A histone variants in eutherian mammals, We show that short H2A variants arose on the X Chromosome in the common ancestor of all eutherian mammals and diverged into four evolutionarily distinct clades: ,, , and However, the repertoires of short histone H2A variants vary extensively among eutherian mammals due to lineage-specific gains and losses. Finally, we show that all four short H2As are subject to accelerated rates of protein evolution relative to both canonical and other variant H2A proteins including H2A.R. Our analyses reveal that short H2As are a unique class of testis-restricted histone variants displaying an unprecedented evolutionary dynamism. Based on their X-Chromosomal localization, genetic turnover, and testis-specific expression, we hypothesize that short H2A variants may participate in genetic conflicts involving sex chromosomes during reproduction.

Short Histone H2A Variants: Small in Stature but not in Function

“…Human H2A.B is encoded by three intronless non-allelic genes (H2AFB1, H2AFB2, and H2AFB3) and are all localised in the q28 locus of the human X chromosome [5,24]. The murine homolog H2A.B.3 (previously H2A.Lap1 for lack of an acidic patch) is also encoded by three X chromosome genes (Gm14920, H2afb2, and H2afb3) but are located at different syntenic locations compared to the human X chromosome [5,22].…”

“…Human H2A.B is encoded by three intronless non-allelic genes (H2AFB1, H2AFB2, and H2AFB3) and are all localised in the q28 locus of the human X chromosome [5,24]. The murine homolog H2A.B.3 (previously H2A.Lap1 for lack of an acidic patch) is also encoded by three X chromosome genes (Gm14920, H2afb2, and H2afb3) but are located at different syntenic locations compared to the human X chromosome [5,22]. Evolutionary, the four classes of short H2A variants H2A.B, H2A.L, H2A.P and H2A.Q genes appear to have resided (and still remain) on the X chromosome at least since the common ancestor of all eutherian mammals [5,22].…”

“…The murine homolog H2A.B.3 (previously H2A.Lap1 for lack of an acidic patch) is also encoded by three X chromosome genes (Gm14920, H2afb2, and H2afb3) but are located at different syntenic locations compared to the human X chromosome [5,22]. Evolutionary, the four classes of short H2A variants H2A.B, H2A.L, H2A.P and H2A.Q genes appear to have resided (and still remain) on the X chromosome at least since the common ancestor of all eutherian mammals [5,22]. However, rodents appear to be the exception for this X chromosome location.…”

“…On the other hand, nonallelic variants exist for all canonical histones that have major differences in their primary sequence, and have evolved at different rates [4][5][6]. For example, the ubiquitous histone H2A variant H2A.Z is evolutionarily conserved (from budding yeast to humans), while the short H2A histone variant class appeared later in evolution, in eutherian mammals, and is rapidly The structural features of the histone fold are annotated above the alignments.…”

“…The sequence identity is calculated by Clustal Omega. The short H2A histone variant family are the most divergent of the histone H2A variant family (<50% amino acid identity with canonical H2A; Figure 1) [5,13]. The best characterised of these variants are mice H2A.B.3 (involved in gene activation and splicing) [14] and H2A.L.2 (required for the histone-protamine exchange process) [20] (see below).…”