The hypothesis that differences in gene regulation have an important role in speciation and adaptation is more than 40 years old.
RNA sequencing (RNA-seq) allows measurement and comparison of gene expression levels across practically any combination of species at an unprecedented resolution.
Comparative studies of gene expression levels in all species studied to date provide compelling evidence that most gene regulatory patterns evolve under evolutionary constraint.
It is more difficult to infer the action of positive (directional) selection on gene regulation than the action of stabilizing selection, especially in non-model species such as humans and non-human apes, where environmental and genetic effects might be confounded.
Inter-species differences in epigenetic markers can probably explain a substantial fraction of gene expression differences between species.
Because a broad range of experimental manipulations are possible in model organisms, studies that focus on model species can move beyond simple comparisons of gene expression and offer deep insights into the causal relationship between regulatory changes and phenotypic evolution.
Functional studies in model systems can often shed light on the adaptive phenotypes that were affected by regulatory changes between humans and other primates. Some phenotypes, however (for example, the development of language), are inherently difficult to study using model species.
It might be possible to use induced pluripotent stem cells derived differentiated cells from humans and non-human primates to test functionally for the outcomes of inter-species differences in gene regulation.
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.
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We thank M. Nobrega and N. Sakab for helping to generate Fig. 1, M. Ward and D. Odom for generating Fig. 2 on the basis of their comparative data and G. Perry for help with the figures in Boxes 2 and 3. We thank J. Pritchard, Z. Gauhar and the three anonymous reviewers for their comments on the manuscript. This work was supported by US National Science Foundation grant IOS-0843504 and US National Institutes of Health (NIH) grant P50 GM081892 to I.R., and NIH grants GM077959 and GM084996 to Y.G. I.G.R. is a Sir Henry Wellcome Postdoctoral Fellow.
The authors declare no competing financial interests.
- RNA sequencing
(RNA-seq). An experimental protocol that uses next-generation sequencing technologies to sequence the RNA molecules within a biological sample in an effort to determine the primary sequence and relative abundance of each RNA type.
- Expression quantitative trait loci
(eQTLs). Loci at which genetic allelic variation is associated with variation in gene expression levels.
- Stabilizing selection
Natural selection against individuals that deviate from an intermediate optimum; this process tends to stabilize the phenotype. By contrast, directional selection pushes it towards either extreme.
- Ranking-based approach
Genome-wide studies often use model-free ranking to prioritize candidate genes. Ranking is performed on the basis of properties that are expected to be informative with respect to the desired trait (for example, nucleotide diversity across populations when the desired traits is evidence for natural selection).
- Neutral model
A model stating that alleles that reach sufficient frequency within a population to be sampled, or that are fixed between species, are selectively neutral, whereas a subset of alleles are too strongly deleterious either to segregate within a population in appreciable frequencies or to reach fixation.
- Vitamin A toxicity
Having too much vitamin A in the body. This can lead to multiple clinically abnormal conditions including decreased appetite, softening of the skull bone, nausea, vomiting, blurry vision, headaches and hair loss.
- MNase sequencing
Sequencing of chromatin that has been treated with micrococcal nuclease (MNase), which preferentially cuts linker DNA connecting two nucleosomes. MNase sequencing can be used to map nucleosome positions.
A region of DNA that binds to proteins whose function is to promote transcription of genes.
- Positional cloning
A method for identifying the location of a risk variant within a candidate region. Overlapping clones covering the candidate region are typed, and segments that co-segregate perfectly with the disease are identified. These clones are the most likely location of the risk variant.
- Pelvic fin
The fins that are attached to the pelvic girdle on the lower surface of the fish body. They help to control the direction of movement.
When an organism benefits from copying the phenotype of another organism.
- Trans-regulatory elements
Regulatory elements that can affect the transcription rates of both alleles of a gene (examples include transcription factors and small regulatory RNAs). By contrast, cis-regulatory elements have an allele-specific regulatory effect.
- Transposable elements
DNA sequences that can change their position in the genome.
- Induced pluripotent stem cells
(iPSCs). These are derived from somatic cells by 'reprogramming' or de-differentiation triggered by the transfection of pluripotency genes, which alters the somatic cells to a state that is similar to that of embryonic stem cells.
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Romero, I., Ruvinsky, I. & Gilad, Y. Comparative studies of gene expression and the evolution of gene regulation. Nat Rev Genet 13, 505–516 (2012). https://doi.org/10.1038/nrg3229
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