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.
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The author thanks members of the Wittkopp laboratory for helpful discussions during drafting of the manuscript. Support for this work was provided by the John Simon Guggenheim Memorial Foundation, Alexander von Humboldt Foundation, National Science Foundation (DEB-1911322) and National Institutes of Health (NIH) (R35GM118073) to P.J.W. and the NIH Training Grant T32GM007544 to P.V.Z.
The authors declare no competing interests.
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- Genetic drift
Variation in allele frequencies caused by random sampling of individuals.
The phenomenon whereby a single genetic variant affects multiple independent traits.
- Bulk segregant analysis
A technique used to associate genetic markers with trait variation by contrasting allele frequencies between two groups of individuals defined by differences in trait values.
- TATA box
An element of some promoter sequences that serves as a binding site for certain general transcription factors and is rich in T/A nucleotides.
- Core promoter element
Functional sequences proximal to the transcription start site that are sufficient to initiate transcription.
- CpG islands
Regions of the genome containing a large number of CpG dinucleotide repeats, found in the promoters of many mammalian genes.
- Initiator region
An element of the core promoter sequence located downstream of the TATA box that overlaps with the transcription start site.
A measure of the asymmetry of a distribution about its mean.
A measure of how much weight is concentrated in the tails of a distribution, relative to its centre.
The extent to which a set of values is clustered or dispersed, often measured by the variance or standard deviation of a distribution.
- Gene expression noise
The variability of expression level among genetically identical cells in the same environment.
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Hill, M.S., Vande Zande, P. & Wittkopp, P.J. Molecular and evolutionary processes generating variation in gene expression. Nat Rev Genet 22, 203–215 (2021). https://doi.org/10.1038/s41576-020-00304-w