Widespread signatures of recent selection linked to nucleosome positioning in the human lineage

Abstract

In this study we investigated the strengths and modes of selection associated with nucleosome positioning in the human lineage through the comparison of interspecies and intraspecies rates of divergence. We identify significant evidence for both positive and negative selection linked to human nucleosome positioning for the first time, implicating a widespread and important role for DNA sequence in the location of well-positioned nucleosomes. Selection appears to be acting on particular base substitutions to maintain optimum GC compositions in core and linker regions, with, e.g., unexpectedly elevated rates of C→T substitutions during recent human evolution at linker regions 60-90 bp from the nucleosome dyad but significant depletion of the same substitutions within nucleosome core regions. These patterns are strikingly consistent with the known relationships between genomic sequence composition and nucleosome assembly. By stratifying nucleosomes according to the GC content of their genomic neighborhood, we also show that the strength and direction of selection detected is dictated by local GC content. Intriguingly these signatures of selection are not restricted to nucleosomes in close proximity to exons, suggesting the correct positioning of nucleosomes is not only important in and around coding regions. This analysis provides strong evidence that the genomic sequences associated with nucleosomes are not evolving neutrally, and suggests that underlying DNA sequence is an important factor in nucleosome positioning. Recent signatures of selection linked to genomic features as ubiquitous as the nucleosome have important implications for human genome evolution and disease.

Figure 1.

Human lineage-specific intra- and interspecies divergence rates around nucleosome dyads. Rates of intraspecies divergence are plotted on the secondary, right-hand y-axis, interspecies divergence on the primary, left-hand axis. Solid trend lines correspond to a sliding window size of 25 bp around each position. Nucleosome positioning data were derived independently from the Schones et al. (2008) and Barski et al. (2007) data sets.

Figure 2.

Interspecies rates of divergence around nucleosome dyads in the human lineage. Colored solid lines correspond to 25-bp sliding averages. Dotted vertical lines represent the estimated dyad position. Transversions are plotted on the secondary y-axis due to their substantially lower rates. Nucleosome positioning data were derived from the Schones et al. (2008) data set.

Figure 3.

Intraspecies rates of divergence around nucleosome dyads in the human lineage. Colored solid lines correspond to 25-bp sliding averages. Dotted vertical lines represent the estimated dyad position. Transversions are plotted on the secondary y-axis due to their substantially lower rates. Nucleosome positioning data were derived from the Schones et al. (2008) data set.

Figure 4.

Rates of selection in and around nucleosome dyads. Ratios of background corrected inter- and intraspecies divergence rates plotted against position from nucleosomal dyad (S_x→y scores). Dotted horizontal lines correspond to an uncorrected P-value of 0.004 (corrected P-value of 0.05). Nucleosome positioning data were derived from the Schones et al. (2008) data set.

Figure 5.

Deviation of interspecies divergence rates from flanking rates in and around nucleosomes and at different flanking GC compositions. The percentage of enrichment (or depletion) of flanking corrected interspecies rates of changes with respect to corresponding observed rates of intraspecies change. Significantly elevated or depleted levels are indicated by * (uncorrected P-value of 0.05) and ** (uncorrected P-value of 0.00046, corrected P-value of 0.05). Nucleosome positioning data were derived from the Schones et al. (2008) data set.

Figure 6.

Histone modification-specific mononucleotide biases (1). The ratio of a variety of histone modification–specific nucleotide frequencies versus the nucleotide frequencies observed in the total pool of nucleosomes (restricted to nucleosomes with a flanking GC percentage between 30% and 40%).

Figure 7.

Histone modification–specific mononucleotide biases (2). The ratio of a variety of histone modification–specific nucleotide frequencies versus the nucleotide frequencies observed in the total pool of nucleosomes (restricted to nucleosomes with a flanking GC percentage between 30% and 40%).