Molecular and evolutionary processes generating variation in gene expression

Abstract

Heritable variation in gene expression is common within and between species. This variation arises from mutations that alter the form or function of molecular gene regulatory networks that are then filtered by natural selection. High-throughput methods for introducing mutations and characterizing their cis- and trans-regulatory effects on gene expression (particularly, transcription) are revealing how different molecular mechanisms generate regulatory variation, and studies comparing these mutational effects with variation seen in the wild are teasing apart the role of neutral and non-neutral evolutionary processes. This integration of molecular and evolutionary biology allows us to understand how the variation in gene expression we see today came to be and to predict how it is most likely to evolve in the future.

Figure 1:. cis- and trans-regulatory contributions to expression differences between and within species.

(a,b) An analysis of allele-specific expression in hybrid yeast (Saccharomyces) species with a range of divergence times (a, branch lengths reflect relative divergence times) showed increasing contributions of cis-regulatory variation to expression differences with increasing divergence time (b, notches in the boxplot indicate 95% CI of the median). (c,d) A highly-powered study of eQTL in Saccharomyces cerevisiae shows how the number of eQTL affecting expression varies among genes (c) and that putatively cis-acting eQTL end to have larger effects than trans-regulatory eQTL (d). Panel (b) reproduced with permission from Coolon et al., and panels (c) and (d) reproduced with permission from Albert et al.

Figure 2.. Sources of cis-regulatory variation in eukaryotes.

Mutations (indicated with lightning bolts) affecting the core promoter (including in motifs such as the TATA box used to assemble the transcription machinery activating RNA polymerase), enhancers (whose functional units are transcription factor binding sites (TFBS)), chromatin accessibility (altered by nucleosome placement and stability) can have cis-regulatory effects on gene expression. Mutations that affect the splicing, stability, and/or translation of mRNA in an allele-specific manner can also be sources of cis-regulatory variation.

Figure 3.. Sources of trans-regulatory variation.

Mutations (indicated by lightning bolts) that can affect expression of a gene via diffusible molecules are trans-acting. These mutations can occur in non-coding or coding sequences of transcription factors, cellular sensors, transporters, and other molecules that influence transcription of many genes via effects on the many interconnected cellular networks.

Figure 4:. Using mutational effects to infer the action of natural selection.

Distinguishing between neutral and adaptive explanations for gene expression variation can be achieved by contrasting the effects of mutations (red, which shows the amount of expression variation expected to result from the accumulation of mutations in the absence of selection) and polymorphisms (blue, which shows expression variation affected by both neutral processes and selection). Dashed lines represent an effect size of zero (that is, no change in expression). If a gene’s expression is evolving neutrally (left panels), the effects of polymorphisms are expected to be consistent with a random sampling of effects from the mutational distribution: there should be no statistically significant difference between the distributions of effects for mutations (red) and polymorphisms (blue). By contrast, if expression of a gene is under stabilizing or directional selection, for example, the distribution of effects for polymorphisms will have lower variance than the distribution of mutational effects. The example shown here (right panels) is consistent with stabilizing selection, which maintains expression at its current level (that is, selection disfavors variants that either decrease or increase expression). Directional selection would also shift the mean effect of polymorphisms to higher or lower expression than the mean effect of mutations.