Histone H2A variants generate diversity in chromatin structure and functions, as 
nucleosomes containing variant H2A histones have altered physical, chemical, and 
biological properties. H2A.Z is an evolutionarily ancient and highly conserved 
H2A variant that regulates processes ranging from gene expression to the DNA 
damage response. Here we find that the unstructured portion of the C-terminal 
tail of H2A.Z is required for the normal functions of this histone variant in 
budding yeast. We have also identified a novel splice isoform of the human 
H2A.Z-2 gene that encodes a C-terminally truncated H2A.Z protein that is similar 
to the truncation mutants we identified in yeast. The short forms of H2A.Z in 
both yeast and human cells are more loosely associated with chromatin than the 
full-length proteins, indicating a conserved function for the H2A.Z C-terminal 
tail in regulating the association of H2A.Z with nucleosomes.