The Impact of the Nucleosome Code on Protein-Coding Sequence Evolution in Yeast

Abstract

Coding sequence evolution was once thought to be the result of selection on optimal protein function alone. Selection can, however, also act at the RNA level, for example, to facilitate rapid translation or ensure correct splicing. Here, we ask whether the way DNA works also imposes constraints on coding sequence evolution. We identify nucleosome positioning as a likely candidate to set up such a DNA-level selective regime and use high-resolution microarray data in yeast to compare the evolution of coding sequence bound to or free from nucleosomes. Controlling for gene expression and intra-gene location, we find a nucleosome-free “linker” sequence to evolve on average 5–6% slower at synonymous sites. A reduced rate of evolution in linker is especially evident at the 5′ end of genes, where the effect extends to non-synonymous substitution rates. This is consistent with regular nucleosome architecture in this region being important in the context of gene expression control. As predicted, codons likely to generate a sequence unfavourable to nucleosome formation are enriched in linker sequence. Amino acid content is likewise skewed as a function of nucleosome occupancy. We conclude that selection operating on DNA to maintain correct positioning of nucleosomes impacts codon choice, amino acid choice, and synonymous and non-synonymous rates of evolution in coding sequence. The results support the exclusion model for nucleosome positioning and provide an alternative interpretation for runs of rare codons. As the intimate association of histones and DNA is a universal characteristic of genic sequence in eukaryotes, selection on coding sequence composition imposed by nucleosome positioning should be phylogenetically widespread.

Fitness landscape for nucleosome positioning

“…About 70% of interspecific nucleosome architecture changes in yeast are caused by cis effects as opposed to trans-acting factors (23), which supports our inference of a local histone binding phenotype. At the level of sequence evolution, it has been shown that linker regions in yeast coding sequence are more conserved than regions of higher nucleosome occupancy (24,25), in agreement with a previous analysis of chromosome III promoters (15). More specifically, A:T-loss nucleotide changes are reduced in NDRs compared with high-occupancy regions (26), which is consistent with A:T-rich sequence disfavoring nucleosome formation.…”

Inverse relationship between genetic diversity and epigenetic complexity

“…Indeed, nucleosome code has been found to have a negative impact on protein sequence variations [45,46]. Fifth, complex organisms can eliminate reproductive cells carrying severe mutations [47].…”

“…Two predictions made in that version have now been confirmed by new papers or new knowledge that have since become known to the author. The first is about the restriction of genetic variation by the nucleosome code, which has now been shown by two recent papers [45,46]. The second is about natural death of mutant embryos prior to birth as a mechanism of epigenetic restriction of mutations.…”

Analysis of synonymous codon usage in FAD7 genes from different plant species

“…In previous studies, factors such as mutational bias, selection, intron splicing, gene conversion, protein secondary structures, and DNA replication were shown to be strongly related to synonymous codon usage biases (Birdsell, 2002;Kahali et al, 2007;Warnecke and Hurst, 2007;Drummond and Wilke, 2008;Warnecke et al, 2008). Codon usage is primarily determined by the balance between mutational bias and selection in prokaryotes or unicellular eukaryotes (Gouy and Gautier, 1982;Stenico et al, 1994;Sharp et al, 2005;Bragg et al, 2012).…”