Histone proteins cannot tolerate much change

Histones are proteins which serve as the hubs about which DNA is wrapped. They are highly similar across vastly different species which means they must have evolved early in evolutionary history. As one textbook explains, “The amino acid sequences of four histones are remarkably similar among distantly related species. … The similarity in sequence among histones from all eukaryotes indicates that they fold into very similar three-dimensional conformations, which were optimized for histone function early in evolution in a common ancestor of all modern eukaryotes.” (Lodish et. al., Section 9.5) And this high similarity among the histones also means they must not tolerate change very well, as another textbook explains: “Changes in amino acid sequence are evidently much more harmful for some proteins than for others. … virtually all amino acid changes are harmful in histone H4. We assume that individuals who carried such harmful mutations have been eliminated from the population by natural selection.” (Alberts et. al. 1994, 243)

So the evolutionary prediction is that in these histone proteins practically all changes are deleterious: “As might be expected from their fundamental role in DNA packaging, the histones are among the most highly conserved eucaryotic proteins. For example, the amino acid sequence of histone H4 from a pea and a cow differ at only at 2 of the 102 positions. This strong evolutionary conservation suggests that the functions of histones involve nearly all of their amino acids, so that a change in any position is deleterious to the cell.” (Alberts et. al. 2002, Chapter 4)

This prediction has also been given in popular presentations of the theory: “Virtually all mutations impair histone’s function, so almost none get through the filter of natural selection. The 103 amino acids in this protein are identical for nearly all plants and animals.” (Molecular Clocks: Proteins That Evolve at Different Rates)

But this prediction has turned out to be false. An early study suggested that one of the histone proteins could well tolerate many changes. (Agarwal and Behe) And later studies confirmed and expanded this finding: “despite the extremely well conserved nature of histone residues throughout different organisms, only a few mutations on the individual residues (including nonmodifiable sites) bring about prominent phenotypic defects.” (Kim et. al.)

Similarly another paper documented these contradictory results: “It is remarkable how many residues in these highly conserved proteins can be mutated and retain basic nucleosomal function. … The high level of sequence conservation of histone proteins across phyla suggests a fitness advantage of these particular amino acid sequences during evolution. Yet comprehensive analysis indicates that many histone mutations have no recognized phenotype.” (Dai et. al.) In fact, even more surprising, many mutations actually raised the fitness level. (Dai et. al.)

References

Agarwal, S., M. Behe. 1996. “Non-conservative mutations are well tolerated in the globular region of yeast histone H4.” J Molecular Biology 255:401-411.

Alberts, Bruce., D. Bray, J. Lewis, M. Raff, K. Roberts, J. Watson. 1994. Molecular Biology of the Cell. 3d ed. New York: Garland Publishing.

Alberts, Bruce., A. Johnson, J. Lewis, et. al. 2002. Molecular Biology of the Cell. 4th ed. New York: Garland Publishing. http://www.ncbi.nlm.nih.gov/books/NBK26834/

Dai, J., E. Hyland, D. Yuan, H. Huang, J. Bader, J. Boeke. 2008. “Probing nucleosome function: a highly versatile library of synthetic histone H3 and H4 mutants.” Cell 134:1066-1078.

Kim, J., J. Hsu, M. Smith, C. Allis. 2012. “Mutagenesis of pairwise combinations of histone amino-terminal tails reveals functional redundancy in budding yeast.” Proceedings of the National Academy of Sciences 109:5779-5784.

Lodish H., A. Berk, S. Zipursky, et. al. 2000. Molecular Cell Biology. 4th ed. New York: W. H. Freeman. http://www.ncbi.nlm.nih.gov/books/NBK21500/

“Molecular Clocks: Proteins That Evolve at Different Rates.” 2001. WGBH Educational Foundation and Clear Blue Sky Productions.