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Molecular and evolutionary processes generating variation in gene expression


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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Fig. 1: cis- and trans-regulatory contributions to expression differences between and within species.
Fig. 2: Sources of cis-regulatory variation in eukaryotes.
Fig. 3: Sources of trans-regulatory variation.
Fig. 4: The action of natural selection can be inferred from mutational effects.


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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.

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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).

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