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. 2011 Feb;7(2):e1001316.
doi: 10.1371/journal.pgen.1001316. Epub 2011 Feb 24.

A genome-wide study of DNA methylation patterns and gene expression levels in multiple human and chimpanzee tissues

Athma A Pai  1 , Jordana T Bell, John C Marioni, Jonathan K Pritchard, Yoav Gilad
Affiliations

A genome-wide study of DNA methylation patterns and gene expression levels in multiple human and chimpanzee tissues

Athma A Pai et al. PLoS Genet. 2011 Feb.

Abstract

The modification of DNA by methylation is an important epigenetic mechanism that affects the spatial and temporal regulation of gene expression. Methylation patterns have been described in many contexts within and across a range of species. However, the extent to which changes in methylation might underlie inter-species differences in gene regulation, in particular between humans and other primates, has not yet been studied. To this end, we studied DNA methylation patterns in livers, hearts, and kidneys from multiple humans and chimpanzees, using tissue samples for which genome-wide gene expression data were also available. Using the multi-species gene expression and methylation data for 7,723 genes, we were able to study the role of promoter DNA methylation in the evolution of gene regulation across tissues and species. We found that inter-tissue methylation patterns are often conserved between humans and chimpanzees. However, we also found a large number of gene expression differences between species that might be explained, at least in part, by corresponding differences in methylation levels. In particular, we estimate that, in the tissues we studied, inter-species differences in promoter methylation might underlie as much as 12%-18% of differences in gene expression levels between humans and chimpanzees.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Genome-wide methylation patterns across all samples.
(A) Probability density functions (y-axis) of estimated promoter methylation levels (plotted as β-values on the x-axis) for genes whose expression levels are in the lowest (black) and highest (red) quartiles. (B) Principal components analysis of the methylation data from the 365 X-chromosome probes from all samples (PC1 is plotted on the y-axis, with sample indices on the x-axis). (C) Density (y-axes) histograms of β-values in humans (left) and chimpanzees (right) for 90 CpG-sites associated with 27 genes previously identified as imprinted in humans. The red lines indicate the β-value distributions in the genes with evidence for imprinting, while the grey lines are β-value distributions in ten sets of 90 randomly chosen probes.
Figure 2
Figure 2. Principal components analysis of the methylation profiles.
This analysis only considers the 9,911 autosomal CpG sites from all samples (PC1 and PC2 are plotted on the x-axis and y-axis, respectively).
Figure 3
Figure 3. Conservation of tissue-specific differentially methylated regions.
(A) Venn diagrams of the number of T-DMRs classified in each species per tissue. (B) Probability density functions (y-axis) of distributions of Pearson correlations (x-axis) between methylation and gene expression levels across tissues, in human (solid lines) and chimpanzee (broken lines), for all genes expressed in at least one tissue (black), genes associated with a T-DMR in only one species (blue), and genes associated with a conserved T-DMRs (red). See Figure S4 for plots of the tissue-specific data (C) A representative example of a heart-specific T-DMR associated with the CASQ1 gene. Plotted in the left panels are the methylation β-values (y-axis), and in the right panels are the normalized gene expression levels (y-axis) in liver, kidney, and heart samples from human (top) and chimpanzee (bottom).
Figure 4
Figure 4. Inter-species methylation and gene expression differences.
(A) Scatter-plots of the p-values obtained by testing the null hypothesis of no differences in gene expression levels between human and chimpanzee before (x-axis) and after (y-axis) regressing out methylation levels. The solid purple lines correspond to a 1% FDR threshold. (B) Boxplots of the distributions, based on 1000 permutations, of the percentage of genes for which the evidence for inter-species differences in gene expression levels is expected to be reduced following the correction for methylation levels, by chance alone. Yellow points indicate the percentages seen in the actual data. (C) A representative example of the ZBTB80S gene, which is associated with inter-species promoter methylation differences in the kidney. In the left and middle panels are the human and chimpanzee methylation β-values and normalized gene expression levels, respectively. In the right panel are the normalized gene expression levels for ZBTB80S, after correcting for the methylation β-values.
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