Evolutionary significance of gene expression divergence

Abstract

Recent large-scale studies of evolutionary changes in gene expression among mammalian species have led to the proposal that gene expression divergence may be neutral with respect to organismic fitness. Here, we employ a comparative analysis of mammalian gene sequence divergence and gene expression divergence to test the hypothesis that the evolution of gene expression is predominantly neutral. Two models of neutral gene expression evolution are considered: 1-purely neutral evolution (i.e., no selective constraint) of gene expression levels and patterns and 2-neutral evolution accompanied by selective constraint. With respect to purely neutral evolution, levels of change in gene expression between human-mouse orthologs are correlated with levels of gene sequence divergence that are determined largely by purifying selection. In contrast, evolutionary changes of tissue-specific gene expression profiles do not show such a correlation with sequence divergence. However, divergence of both gene expression levels and profiles are significantly lower for orthologous human-mouse gene pairs than for pairs of randomly chosen human and mouse genes. These data clearly point to the action of selective constraint on gene expression divergence and are inconsistent with the purely neutral model; however, there is likely to be a neutral component in evolution of gene expression, particularly, in tissues where the expression of a given gene is low and functionally irrelevant. The model of neutral evolution with selective constraint predicts a regular, clock-like accumulation of gene expression divergence. However, relative rate tests of the divergence among human-mouse-rat orthologous gene sets reveal clock-like evolution for gene sequence divergence, and to a lesser extent for gene expression level divergence, but not for the divergence of tissue-specific gene expression profiles. Taken together, these results indicate that gene expression divergence is subject to the effects of purifying selective constraint and suggest that it might also be substantially influenced by positive Darwinian selection.

Fig. 1

Comparison between human and mouse orthologous protein sequence divergence and gene expression levels. 9059 pairs of human–mouse orthologs were compared. (a) Human–mouse ortholog pair expression levels plotted against human–mouse ortholog protein distances. (b) Relative differences between human–mouse expression levels plotted against human–mouse ortholog protein distances. For (a) and (b), average expression values are shown for eight bins of ascending protein distances. Spearman rank correlations (R) and P-values for the correlations are shown. (c) Cumulative frequency distributions of the relative expression level differences for human–mouse orthologs (black line) and for 10,000 randomly chosen human–mouse gene pairs.

Fig. 2

Comparison between human and mouse orthologous gene expression profile divergence and gene sequence divergence. (a) Euclidean distances between human–mouse orthologous tissue-specific gene expression profiles plotted against human–mouse ortholog protein distances. Average expression values are shown for eight bins of ascending protein distances. The Spearman rank correlation (R) and P-value for the correlation are shown. (b) Cumulative frequency distributions are shown for the gene expression profile Euclidean distances between human–mouse orthologs (black line) and between 10,000 randomly chosen human–mouse gene pairs (gray line).

Fig. 3

Schematic of the relative rates test for gene sequence and gene expression divergence. The neutral model predicts a constant ratio of divergence within (W) and between (B) the two phylogenetic partitions. Expressed in terms of phylogenetic branch lengths, the null hypothesis of the test is constant (bM+bR)/bH.

Fig. 4

Results of the relative rates test for gene sequence and gene expression divergence. 1427 sets of human–mouse–rat orthologs were compared. (a) Within (bM+bR) against between (bH) partition nucleotide divergence. Nucleotide divergence is measured as the Jukes–Cantor distance (Jukes and Cantor, 1969). (b) Within (bM+bR) against between (bH) partition expression level divergence. Expression level divergence is measured as the absolute difference between the species-specific relative gene expression levels. (c) Within (bM+bR) against between (bH) partition gene expression profile divergence. Tissue-specific gene expression profile divergence is measured as the Euclidean distance between orthologous vectors of tissue-specific expression values. For all plots, Pearson correlation coefficients (r) and P-values for the correlations are shown.