The genetic changes that underlie human-specific traits remain largely obscure, although changes in gene regulation are known to play an important part. A comparative genomics study now catalogues gene expression and DNA methylation profiles of multiple tissues sampled from the same individuals across humans and two non-human primate species.

Catalogues that map similarities and differences in gene expression and its regulation between primate species have been useful to elucidate evolutionary adaptations. However, a confounding factor arises if multiple tissues are not sampled from the same individuals, as differences between tissues can be mistaken for differences between individuals. Blake, Roux et al. set to address this problem by using a balanced study design to compare gene expression and DNA methylation levels of heart, kidney, liver and lung tissue obtained from four humans, four chimpanzees and four rhesus macaques.

Gene expression levels were determined using RNA sequencing and estimated using an approach that was designed to minimize technical confounders and “biases driven by sequence divergence across species”. Confirming previous findings, gene expression variation was greater across tissues than species, as determined by principal component analysis (PCA) and clustering analysis. The team then classified genes with tissue-specific expression patterns that were conserved across species and found that these genes had more interactions in transcription co-expression networks and more annotated protein–protein interactions than did genes with regulatory patterns that were not conserved or tissue specific, a finding that was even more notable when only looking at genes with expression patterns indicative of acting natural selection.

Analysis of DNA methylation, measured by low-coverage whole genome bisulfite sequencing (BS-seq), pinpointed 7,026–41,280 regions that were differentially methylated between tissues (within species) and were conserved across species. To analyse DNA methylation differences that might underlie gene expression differences across species and tissues, the team focused on orthologous genes for which expression and matching promoter DNA methylation data were available across species (7,725 genes in humans and chimpanzees; 4,155 genes for all three species). In brief, differences in promoter DNA methylation accounted for only a modest fraction of expression differences across species and tissues, with the greatest impact seen on genes with conserved tissue-specific expression patterns.

species-specific patterns of tissue-specific gene regulation

This comparative catalogue of gene regulatory phenotypes should be useful to decipher interspecies regulatory differences and how these map to biological and functional phenotypes in primates. In particular, looking at species-specific patterns of tissue-specific gene regulation may help to identify and characterize adaptations specific to humans.