Key Points
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Transcription factors orchestrate tissue-specific gene expression and thus tissue identity. Metazoan gene regulation is highly complex, and comparative analyses of transcription factor binding across species have revealed mechanisms underlying both genome evolution and gene regulation.
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Early studies focused on individual loci and showed both conservation and divergence of putative transcription factor binding sites across metazoan species.
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Direct global mapping of transcription factor binding locations in multiple mammalian and fruitfly species revealed that tissue-specific transcription factor binding evolves rapidly in mammals, whereas developmental transcription factor binding in fruitflies seems to be under substantially greater constraint.
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Comparative studies in mammals and fruitflies have also highlighted common properties of metazoan transcription factor binding evolution, such as dependence on genetic sequence changes, combinatorial co-evolution of binding and partially compensatory turnover.
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Observed differences in transcription factor binding evolution and densities of conserved non-coding elements among different metazoan families might be the result of different pressures from extreme differences in effective population sizes.
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In mammals, cross-species chromatin immunoprecipitation followed by sequencing studies have further revealed how transposable element-derived sequences help to generate novel lineage-specific transcription factor binding.
Abstract
Differences in transcription factor binding can contribute to organismal evolution by altering downstream gene expression programmes. Genome-wide studies in Drosophila melanogaster and mammals have revealed common quantitative and combinatorial properties of in vivo DNA binding, as well as marked differences in the rate and mechanisms of evolution of transcription factor binding in metazoans. Here, we review the recently discovered rapid 're-wiring' of in vivo transcription factor binding between related metazoan species and summarize general principles underlying the observed patterns of evolution. We then consider what might explain the differences in genome evolution between metazoan phyla and outline the conceptual and technological challenges facing this research field.
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Acknowledgements
The authors thank J. C. Marioni (European Bioinformatics Institute, Cambridge, UK), Anders Eriksson (Evolutionary Ecology Group, Department of Zoology, University of Cambridge, UK), members of D.T.O and P.F.'s laboratories, particularly C. Kutter, K. Stefflova and E. Wong, and three anonymous reviewers for their comments on the manuscript. D.V. thanks Cancer Research UK for funding. This work has been funded by the European Research Council, EMBO Young Investigators Programme and Cancer Research UK (to D.T.O.), and by the European Molecular Biology Laboratory, Wellcome Trust and the European Union (to P.F.). The authors apologize to colleagues whose work could not be covered owing to space limitations.
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Glossary
- Chromatin immunoprecipitation followed by sequencing
-
(ChIP–seq). A technique that identifies potential regulatory sequences which are bound by a protein of interest and that is based on the immunoprecipitation of covalently crosslinked chromatin complexes using antibodies against a specific DNA-binding protein.
- Cis-regulatory modules
-
(CRMs). Discrete arrangements of transcription factor binding sites in the DNA sequence that often contain motifs for several transcription factors. These can be defined using computational predictions and investigated through experimental approaches such as chromatin immunoprecipitation followed by sequencing. The definition of CRMs is useful for pinpointing functional regulatory elements.
- Neutral evolution
-
A pattern of evolutionary change that is consistent with random drift of mutant alleles that are neutral or nearly neutral. The neutral theory of evolution states that the dynamics of the majority of changes observed at the molecular level are governed by non-adaptive evolutionary forces rather than by Darwinian (that is, positive) natural selection.
- Positive selection
-
(Also known as directional selection). A mode of natural selection that pushes the phenotype towards an extreme, which causes the allelic frequency to shift over time towards that phenotype. Comparative genomic approaches can often infer positive selection by detecting directional patterns of nucleotide substitutions across species.
- Purifying selection
-
(Also known as negative selection). Natural selection against individuals that deviate from an intermediate optimum; this process tends to stabilize the phenotype. Genomic segments that have been subject to purifying selection can be inferred from nucleotide substitution patterns in aligned genomes of multiple species.
- Accessible genome
-
Segments of DNA sequence that lie in an open chromatin environment, based on the biophysics of protein–DNA interactions that can occur in these regions. Open or accessible chromatin can be readily bound by transcription factors and other effectors of the transcriptional machinery. Accessible regions are both ubiquitous and tissue specific, and can be inferred from experimental approaches such as DNase I hypersensitivity or chromatin immunoprecipitation followed by sequencing.
- Non-synonymous to synonymous polymorphisms ratios
-
Ratios of non-synonymous substitutions (those that alter the amino acid sequence) and synonymous substitutions (that is, silent mutations) in a collection of protein-coding DNA sequences. This measure can be used to infer the evolutionary distance between species and to measure adaptive evolution. These ratios are lower in larger populations, which reflects an increased efficiency of selection versus drift.
- Transposable elements
-
DNA sequences of exogenous origin that can insert themselves into the genome and change their position, thereby altering genome structure and, ultimately, genome size. A large proportion of mammalian genomes is thought to be derived from transposable elements.
- Genetic drift
-
Evolutionary change that involves random sampling of genetic variants in a finite population, which causes the composition of the offspring and parental generations to differ. This process constitutes a ubiquitous source of evolutionary stochasticity.
- Fossilized repeats
-
Ancient repeat events that are, at least partially, visible on the basis of their consensus sequence. Exapted repeat instances (for example, regulatory elements) that are derived from transposable elements often become fossilized and have been identified among evolutionarily conserved sequences.
- Exaptation
-
Evolutionary co-option of a functionally unrelated DNA sequence for a novel function. This process has been specifically studied for transposable elements which, in spite of their exogenous origin, are often functionally adopted by the host genome, for example, as regulatory sequences.
- Non-adaptive forces of evolution
-
Features of the population genetic environment that operate in a stochastic manner. These include random genetic drift, recombination and mutation, and the relative power of these forces conditions the types of evolutionary changes that are possible in various contexts.
- Average genomic diversity
-
Average synonymous nucleotide heterozygosity, which is a measure of the number of heterozygotes in a population and hence genomic diversity. It is predicted to decrease in populations with smaller effective population sizes (for example, it is higher in Drosophila spp. than in mammals).
- Effective population sizes
-
Effective number of gametes sampled per generation. They determine the rates of change in the composition of populations that is caused by genetic drift.
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Villar, D., Flicek, P. & Odom, D. Evolution of transcription factor binding in metazoans — mechanisms and functional implications. Nat Rev Genet 15, 221–233 (2014). https://doi.org/10.1038/nrg3481
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DOI: https://doi.org/10.1038/nrg3481
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