Comparative studies of gene expression and the evolution of gene regulation

Abstract

The hypothesis that differences in gene regulation have an important role in speciation and adaptation is more than 40 years old. With the advent of new sequencing technologies, we are able to characterize and study gene expression levels and associated regulatory mechanisms in a large number of individuals and species at an unprecedented resolution and scale. We have thus gained new insights into the evolutionary pressures that shape gene expression levels and have developed an appreciation for the relative importance of evolutionary changes in different regulatory genetic and epigenetic mechanisms. The current challenge is to link gene regulatory changes to adaptive evolution of complex phenotypes. Here we mainly focus on comparative studies in primates and how they are complemented by studies in model organisms.

Figure 1. Regulatory mechanisms that can be investigated using comparative genomic approaches

Changes in a large number of genetic and epigenetic regulatory mechanisms can underlie inter-species differences in gene expression levels. Second-generation sequencing technologies allow us to obtain genome-wide profiles of transcription factor binding and epigenetic markers and thus identify correlations between variation in gene expression and variation in regulatory mechanisms. Using this paradigm, current studies are actively estimating the relative contribution of changes in different mechanisms to regulatory evolution, including chromatin accessibility (using DNaseI sequencing), Nucleosome positions (using MNase sequencing), transcription factor binding (using Chip-seq), promoter methylation profiling (using microarrays or bisulfite sequencing), and a number of histone modification profiles (using ChIP-seq). Figure is modified, with permission, from reference [Copy-ed: permission received.]

Figure 2. Inter-species differences in transcription factor binding

Ward, Odom, and colleagues have performed and analyzed comparative ChIP-seq experiments for the transcriptional regulator CTCF in human and gorilla cell 122 After ChIP-seq reads are mapped to the respective genomes, the resulting peaks (read counts are plotted on the y-axis) indicate the locations of chromatin enrichment and hence of CTCF binding. Examples are shown of a site bound in humans but not in gorilla within 2 kb of the GPR88 gene (G-protein coupled receptor expressed in striatum) (this gene is not shown on the figure), a shared site at FHIT (triphosphate hydrolase possible tumour suppressor) and a site bound in gorillas but not in humans at GRIK1 (glutamate receptor subunit involved in neurotransmission). The data for this figure are from reference .