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The evolutionary significance of cis-regulatory mutations

Key Points

  • It is now well established that mutations within cis-regulatory regions are responsible for various significant evolutionary differences in organismal traits.

  • It has been proposed that cis-regulatory mutations make a qualitatively distinct contribution to trait evolution, in part because they might result in more limited pleiotropy and therefore fewer functional trade-offs, and in part because they might commonly be co-dominant and therefore immediately visible to selection.

  • Many species-specific differences in cuticular colouration in fruitflies are the product of mutations in the cis-regulatory regions of yellow (y), ebony (e) and bric a brac 1/2 (bab1/bab2).

  • The loss of pelvic armour in stickleback fish has evolved repeatedly through cis-regulatory mutations in paired-like homeodomain transcription factor 1 (pitx1).

  • Many traits that are unique to humans or that vary among them are also due to mutations within cis-reguatory regions, including functionally significant mutations near Duffy blood group, chemokine receptor (DARC), lactase (LCT) and prodynorphin (PDYN).

  • Taken collectively, the evidence from the best-studied cases supports the idea that cis-regulatory mutations make a qualitatively distinctive contribution to trait evolution.


For decades, evolutionary biologists have argued that changes in cis-regulatory sequences constitute an important part of the genetic basis for adaptation. Although originally based on first principles, this claim is now empirically well supported: numerous studies have identified cis-regulatory mutations with functionally significant consequences for morphology, physiology and behaviour. The focus has now shifted to considering whether cis-regulatory and coding mutations make qualitatively different contributions to phenotypic evolution. Cases in which parallel mutations have produced parallel trait modifications in particular suggest that some phenotypic changes are more likely to result from cis-regulatory mutations than from coding mutations.

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Figure 1: Functional classes of mutations.
Figure 2: Evolution of cuticular pigmentation in Drosophila species.
Figure 3: Evolution of armour reduction in stickleback fish.
Figure 4: Cis-regulatory mutations with phenotypic consequences in humans.


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Thanks to C. Babbitt, D. Garfield, J. Tung, and three anonymous reviewers for helpful comments. G.A.W.'s research is supported by the US National Science Foundation and the Institute for Genome Sciences & Policy at Duke University.

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Cis-regulatory region

A segment of DNA that regulates transcription; such segments typically lie immediately 5′ of the start site of transcription, but are often discontinuous, and individual segments can reside within introns, 5′ and 3′ UTRs, or tens of kilobases on either side of the gene they regulate.


A group of species that share a unique common ancestor.


A mutation that has an additive phenotypic impact, and is therefore apparent in heterozygotes.


The ability of a gene or mutation to alter more than one trait.

Functional trade-off

For many traits, improving one aspect of function might incur a cost in some other aspect of function.


Concealment from predators, usually through shape and colouration of the integument.

Candidate gene

A gene that seems likely, on the basis of its function or a prior association study, to contain a mutation or mutations that underlie a phenotypic trait of interest.


Located far away from the gene of interest; in practical terms, anywhere in the genome except nearby.


The largest bristles on flies; their function is mechanosensory.


The practice of tending domesticated animals for the milk they produce.

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Wray, G. The evolutionary significance of cis-regulatory mutations. Nat Rev Genet 8, 206–216 (2007).

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