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Cis-regulatory elements: molecular mechanisms and evolutionary processes underlying divergence

Nature Reviews Genetics volume 13, pages 59–69 (2012)Cite this article

Subjects

Key Points

  • Cis-regulatory elements (CREs) have essential roles in development, and their divergence is a common cause of evolutionary change.

  • Recent technological advances facilitate finding and studying orthologous CREs.

  • Functional divergence of CREs has been shown to result from small numbers of single-nucleotide substitutions, insertions and/or deletions that disrupt transcription factor binding and often interact epistatically.

  • Novel enhancer activities appear frequently to result from the co-option of transcription factor binding sites that are already present in ancestral enhancers.

  • Elucidating the specific genetic changes that are responsible for cis-regulatory divergence has provided insight into the relative contributions of new mutations and standing genetic variation, large and small effect mutations and neutral and non-neutral changes.

  • Studies of cis-regulatory divergence that underlie convergent phenotypes address questions about the repeatability of evolution.

  • Future work should focus on elucidating the relationships among sequence changes in CREs, transcription factor binding, gene expression and organismal phenotypes.

Abstract

Cis-regulatory sequences, such as enhancers and promoters, control development and physiology by regulating gene expression. Mutations that affect the function of these sequences contribute to phenotypic diversity within and between species. With many case studies implicating divergent cis-regulatory activity in phenotypic evolution, researchers have recently begun to elucidate the genetic and molecular mechanisms that are responsible for cis-regulatory divergence. Approaches include detailed functional analysis of individual cis-regulatory elements and comparing mechanisms of gene regulation among species using the latest genomic tools. Despite the limited number of mechanistic studies published to date, this work shows how cis-regulatory activity can diverge and how studies of cis-regulatory divergence can address long-standing questions about the genetic mechanisms of phenotypic evolution.

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Figure 1: Strategies for finding enhancers and divergent sites within them.
Figure 2: Examples of point mutations and deletions causing divergent cis-regulatory activity.
Figure 3: Novel enhancer activities have evolved by co-option of existing enhancers.

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Acknowledgements

This research was supported by National Science Foundation grant MCB-1021398 to P.J.W., who is an Alfred P. Sloan Research Fellow.

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Authors and Affiliations

  1. Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Patricia J. Wittkopp

  2. Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Patricia J. Wittkopp & Gizem Kalay

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Correspondence to Patricia J. Wittkopp.

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Supplementary information S1 (table)

Selected studies identifying the genetic changes responsible for cis-regulatory divergence between species (XLS 46 kb)

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Glossary

Cis-regulatory elements

(CREs). Collections of transcription factor binding sites and other non-coding DNA that are sufficient to activate transcription in a defined spatial and/or temporal expression domain.

Functionally homologous enhancers

Enhancers from different species that drive analogous expression patterns in the same tissue. They may or may not be caused by orthologous DNA sequences.

Divergent sites

Fixed nucleotide differences in orthologous DNA sequences between species.

Pleiotropic

An adjective that is used to describe a mutation or gene that affects multiple (presumably distinct) phenotypes.

Convergent phenotypes

Similar phenotypes that independently evolved in different lineages.

Trans-regulatory factors

Proteins, RNAs or other diffusible molecules that affect gene expression.

Candidate sites

In the context of this article, one or more nucleotide changes that correlate with a change in expression and thus might be causing the change in expression.

Degeneracy

In the context of transcription factor binding sites, this is the ability of a transcription factor to bind to multiple (usually related) DNA sequences.

Outgroup

A related but taxonomically more distant species that can be used to infer the ancestral state of a particular site in DNA.

Trans-regulatory environment

The collection of proteins, RNAs and other trans-acting molecules within a cell.

Host species

In the context of transgenic analysis, the species transformed with foreign DNA.

Position weight matrices

Quantitative representations of DNA-binding specificity for a transcription factor protein.

Selective sweep

The increase in frequency of an allele (and closely linked chromosomal segments) that is caused by selection for the allele.

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Wittkopp, P., Kalay, G. Cis-regulatory elements: molecular mechanisms and evolutionary processes underlying divergence. Nat Rev Genet 13, 59–69 (2012). https://doi.org/10.1038/nrg3095

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