The eutherian-specific histone H3.4 promotes germ cell development and reproductive fitness

ABSTRACT: Many genes encoding chromatin proteins are subject to evolutionary selection driving reproductive fitness. In mice and men, the H3f4 (H3-4) gene encoding the histone H3.4 variant (formerly known as H3t) is essential to spermatogenesis. Here we define the evolutionary origin and molecular-physiological roles of sequence variation in H3f4 for male germ cell development in mice. Our phylogenetic analyses indicate that eutherian H3f4 orthologs originate from an ancestral H3.2 gene existing prior to the divergence of eutherian and marsupial mammals over 100 million years ago. Positioned in small histone gene clusters, eutherian H3f4 orthologs show increased non-synonymous and synonymous substitution rates compared to orthologous marsupial H3.2 loci located in prototypal large histone clusters. To determine the impact of sequence divergence on reproductive fitness, we revert non-synonymously substituted residues in H3.4 to those present in canonical H3.1 (H3f4V24A, H3f4H42R, H3f4S98A). Expression of such a triply reverted H3f4H3.1 allele on a H3f4-deficiency background causes an >40% reduction in testis weight associated with impaired meiotic progression, death of pachytene spermatocytes, impaired differentiation of spermatids and aberrant expression of thousands of genes during spermatid elongation. Hemizygous expression of individual residue substitution alleles reveals residues V24 and H42 of H3.4 to promote spermatogenesis, while residue S98 is neutral. Together, our study shows that H3f4 has been subject to positive evolutionary selection, promoting male reproductive fitness.

ORGANISM(S): Mus musculus (mouse)

SUBMITTER: Antoine Peters 

PROVIDER: S-BSST2851 | biostudies-other |

REPOSITORIES: biostudies-other