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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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References

  1. Zuckerkandl, E. & Pauling, L. in Evolving Genes and Proteins (eds Bryson, V. & Vogel, H.) 97–166 (Academic Press, New York, 1965).

    Google Scholar 

  2. Britten, R. J. & Davidson, E. H. Gene regulation for higher cells: a theory. Science 165, 349–357 (1969).

    CAS  PubMed  Google Scholar 

  3. King, M.-C. & Wilson, A. C. Evolution at two levels in humans and chimpanzees. Science 188, 107–116 (1975).

    CAS  PubMed  Google Scholar 

  4. Carroll, S. B. Evo-devo and an expanding evolutionary synthesis: a genetic theory of morphological evolution. Cell 134, 25–36 (2008).

    CAS  PubMed  Google Scholar 

  5. Stern, D. L. & Orgogozo, V. The loci of evolution: how predictable is genetic evolution? Evolution 62, 2155–2177 (2008).

    PubMed  PubMed Central  Google Scholar 

  6. Ong, C.-T. & Corces, V. G. Enhancer function: new insights into the regulation of tissue-specific gene expression. Nature Rev. Genet. 12, 283–293 (2011).

    CAS  PubMed  Google Scholar 

  7. Levine, M. Transcriptional enhancers in animal development and evolution. Curr. Biol. 20, R754–R763 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Bulger, M. & Groudine, M. Functional and mechanistic diversity of distal transcription enhancers. Cell 144, 327–339 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Brown, R. P. & Feder, M. E. Reverse transcriptional profiling: non-correspondence of transcript level variation and proximal promoter polymorphism. BMC Genomics 6, 110 (2005).

    PubMed  PubMed Central  Google Scholar 

  10. Savinkova, L. K. et al. TATA box polymorphisms in human gene promoters and associated hereditary pathologies. Biochemistry 74, 117–129 (2009).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  12. Hong, J. W., Hendrix, D. A. & Levine, M. S. Shadow enhancers as a source of evolutionary novelty. Science 321, 1314 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Perry, M. W., Boettiger, A. N., Bothma, J. P. & Levine, M. Shadow enhancers foster robustness of Drosophila gastrulation. Current Biol. 20, 1562–1567 (2010).

    CAS  Google Scholar 

  14. Kleinjan, D. A. & van Heyningen, V. Long-range control of gene expression: emerging mechanisms and disruption in disease. Am. J. Hum. Genet. 76, 8–32 (2005).

    CAS  PubMed  Google Scholar 

  15. Hare, E. E., Peterson, B. K., Iyer, V. N., Meier, R. & Eisen, M. B. Sepsid even-skipped enhancers are functionally conserved in Drosophila despite lack of sequence conservation. PLoS Genet. 4, e1000106 (2008).

    PubMed  PubMed Central  Google Scholar 

  16. Cande, J., Goltsev, Y. & Levine, M. S. Conservation of enhancer location in divergent insects. Proc. Natl Acad. Sci. USA 106, 14414–14419, (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Kalay, G. & Wittkopp, P. J. Nomadic enhancers: tissue-specific cis-regulatory elements of yellow have divergent genomic positions among Drosophila species. PLoS Genet. 6, e1001222 (2010).

    PubMed  PubMed Central  Google Scholar 

  18. Cowles, C. R., Hirschhorn, J. N., Altshuler, D. & Lander, E. S. Detection of regulatory variation in mouse genes. Nature Genet. 32, 432–437 (2002).

    CAS  PubMed  Google Scholar 

  19. Wittkopp, P. J., Haerum, B. K. & Clark, A. G. Evolutionary changes in cis and trans gene regulation. Nature 430, 85–88 (2004).

    CAS  PubMed  Google Scholar 

  20. Tirosh, I., Reikhav, S., Levy, A. A. & Barkai, N. A yeast hybrid provides insight into the evolution of gene expression regulation. Science 324, 659–662 (2009).

    CAS  PubMed  Google Scholar 

  21. McManus, C. J. et al. Regulatory divergence in Drosophila revealed by mRNA-seq. Genome Res. 20, 816–825 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. He, X., Ling, X. & Sinha, S. Alignment and prediction of cis-regulatory modules based on a probabilistic model of evolution. PLoS Comput. Biol. 5, e1000299 (2009).

    PubMed  PubMed Central  Google Scholar 

  23. Matys, V. et al. Transfac: transcriptional regulation, from patterns to profiles. Nucleic Acids Res. 31, 374–378 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Abdulrehman, D. et al. Yeastract: providing a programmatic access to curated transcriptional regulatory associations in Saccharomyces cerevisiae through a web services interface. Nucleic Acids Res. 39, D136–D140 (2011).

    CAS  PubMed  Google Scholar 

  25. Roy, S. et al. Identification of functional elements and regulatory circuits by Drosophila modENCODE. Science 330, 1787–1797 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Gerstein, M. B. et al. Integrative analysis of the Caenorhabditis elegans genome by the modENCODE project. Science 330, 1775–1787 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Visel, A. et al. ChIP–seq accurately predicts tissue-specific activity of enhancers. Nature 457, 854–858 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Fujita, P. A. et al. The UCSC Genome Browser database: update 2011. Nucleic Acids Res. 39, D876–D882 (2011).

    CAS  PubMed  Google Scholar 

  29. Hudson, M. E. Sequencing breakthroughs for genomic ecology and evolutionary biology. Mol. Ecol. Res. 8, 3–17 (2008).

    CAS  Google Scholar 

  30. Warming, S., Costantino, N., Court, D. L., Jenkins, N. A. & Copeland, N. G. Simple and highly efficient BAC recombineering using GalK selection. Nucleic Acids Res. 33, e36 (2005).

    PubMed  PubMed Central  Google Scholar 

  31. Ghim, C. M., Lee, S. K., Takayama, S. & Mitchell, R. J. The art of reporter proteins in science: past, present and future applications. BMB Reports 43, 451–460 (2010).

    CAS  PubMed  Google Scholar 

  32. Groth, A. C., Fish., M., Nusse, R. & Calos, M. P. Construction of transgenic Drosophila by using the site-specific integrase from phage PhiC31. Genetics 166, 1775–1782 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Holtzman, S. et al. Transgenic tools for members of the genus Drosophila with sequenced genomes. Fly 4, 349–362 (2010).

    CAS  PubMed  Google Scholar 

  34. Gompel, N., Prud'homme, B., Wittkopp, P. J., Kassner, V. A. & Carroll, S. B. Chance caught on the wing: cis-regulatory evolution and the origin of pigment patterns in Drosophila. Nature 433, 481–487 (2005).

    CAS  PubMed  Google Scholar 

  35. Williams, T. M. et al. The regulation and evolution of a genetic switch controlling sexually dimorphic traits in Drosophila. Cell 134, 610–623 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Shirangi, T. R., Dufour, H. D., Williams, T. M. & Carroll, S. B. Rapid evolution of sex pheromone-producing enzyme expression in Drosophila. PLoS Biol. 7, e1000168 (2009). This study shows how deletions in cis -regulatory sequences can lead to the formation of binding sites for transcriptional activators, resulting in divergent expression.

    PubMed  PubMed Central  Google Scholar 

  37. Deplancke, B. et al. A gene-centered C. elegans protein–DNA interaction network. Cell 125, 1193–1205 (2006).

    CAS  PubMed  Google Scholar 

  38. Drewett, V. et al. DNA-bound transcription factor complexes analysed by mass-spectrometry: binding of novel proteins to the human c-fos SRE and related sequences. Nucleic Acids Res. 29, 479–487 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Stormo, G. D. & Zhao, Y. Determining the specificity of protein–DNA interactions. Nature Rev. Genet. 11, 751–760 (2010).

    CAS  PubMed  Google Scholar 

  40. Berger, M. F. et al. Variation in homeodomain DNA binding revealed by high-resolution analysis of sequence preferences. Cell 133, 1266–1276 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Maerkl, S. J. & Quake, S. R. A systems approach to measuring the binding energy landscapes of transcription factors. Science 315, 233–237 (2007).

    CAS  PubMed  Google Scholar 

  42. Frankel, N. et al. Morphological evolution caused by many subtle-effect substitutions in regulatory DNA. Nature 474, 598–603 (2011). This study is one of the most detailed dissections of divergent enhancer activity to date. Divergent sites were tested individually and in combination for their effects on gene expression as well as on the divergent phenotype (loss of trichomes in D. sechellia larvae).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Jeong, S. et al. The evolution of gene regulation underlies a morphological difference between two Drosophila sister species. Cell 132, 783–793 (2008).

    CAS  PubMed  Google Scholar 

  44. Prabhakar, S. et al. Human-specific gain of function in a developmental enhancer. Science 321, 1346–1350, (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Rebeiz, M., Jikomes, N., Kassner, V. A. & Carroll, S. B. Evolutionary origin of a novel gene expression pattern through co-option of the latent activities of existing regulatory sequences. Proc. Natl Acad. Sci.USA 108, 10036–10043 (2011). This study screened tissue-specific gene expression across multiple developmental stages among closely related species of Drosophila to identify novel expression patterns. Genetic changes responsible for these putatively novel enhancer activities were then identified.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Chan, Y. F. et al. Adaptive evolution of pelvic reduction in sticklebacks by recurrent deletion of a Pitx1 enhancer. Science 327, 302–305 (2010). This study implicates recurrent deletions of fragile cis -regulatory DNA in the repeated loss of pelvic structures in freshwater threespine stickleback.

    CAS  PubMed  Google Scholar 

  47. McLean, C. Y. et al. Human-specific loss of regulatory DNA and the evolution of human-specific traits. Nature 471, 216–219 (2011). This study identifies over 500 sequences that are highly conserved among chimpanzees and other mammals but that are deleted in humans. In two cases, the deletions are confirmed to remove cis -regulatory sequences and to cause changes in expression that correlate with human-specific traits.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Kidwell, M. G. & Lisch, D. Transposable elements as sources of variation in animals and plants. Proc. Natl Acad. Sci. USA 94, 7704–7711 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Daborn, P. J. et al. A single p450 allele associated with insecticide resistance in Drosophila. Science 297, 2253–2256 (2002).

    CAS  PubMed  Google Scholar 

  50. Chung, H. et al. Cis-regulatory elements in the accord retrotransposon result in tissue-specific expression of the Drosophila melanogaster insecticide resistance gene Cyp6g1. Genetics 175, 1071–1077 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Schlenke, T. A. & Begun, D. J. Strong selective sweep associated with a transposon insertion in Drosophila simulans. Proc. Natl Acad. USA 101, 1626–1631 (2004).

    CAS  Google Scholar 

  52. Bejerano, G. et al. A distal enhancer and an ultraconserved exon are derived from a novel retroposon. Nature 441, 87–90 (2006).

    CAS  PubMed  Google Scholar 

  53. Wang, T. et al. Species-specific endogenous retroviruses shape the transcriptional network of the human tumour suppressor protein p53. Proc. Natl Acad. Sci. USA 104, 18613–18618 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Jeong, S., Rokas, A. & Carroll, S. B. Regulation of body pigmentation by the abdominal-b hox protein and its gain and loss in Drosophila evolution. Cell 125, 1387–1399 (2006).

    CAS  PubMed  Google Scholar 

  55. He, B. Z., Holloway, A. K., Maerkl, S. J. & Kreitman, M. Does positive selection drive transcription factor binding site turnover? A test with Drosophila cis-regulatory modules. PLoS Genet. 7, e1002053 (2011). This study identifies derived changes in either Drosophila melanogaster or D. simulans in 645 experimentally identified binding sites for 30 different TFs across 118 CREs and infers the effect of the derived change on TF binding affinity.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Dowell, R. D. Transcription factor binding variation in the evolution of gene regulation. Trends Genet. 26, 468–475 (2010).

    CAS  PubMed  Google Scholar 

  57. Odom, D. T. et al. Tissue-specific transcriptional regulation has diverged significantly between human and mouse. Nature Genet. 39, 730–732 (2007).

    CAS  PubMed  Google Scholar 

  58. Borneman, A. R. et al. Divergence of transcription factor binding sites across related yeast species. Science 317, 815–819 (2007).

    CAS  PubMed  Google Scholar 

  59. Tuch, B. B., Galgoczy, D. J., Hernday, A. D., Li, H. & Johnson, A. D. The evolution of combinatorial gene regulation in fungi. PLoS Biol. 6, e38 (2008).

    PubMed  PubMed Central  Google Scholar 

  60. Schmidt, D. et al. Five-vertebrate ChIP–seq reveals the evolutionary dynamics of transcription factor binding. Science 328, 1036–1040 (2010). This study uses ChIP coupled with next-generation sequencing to quantify the binding of two TFs in liver cells from five vertebrate species.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Kasowski, M. et al. Variation in transcription factor binding among humans. Science 328, 232–235 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Wilson, M. D. et al. Species-specific transcription in mice carrying human chromosome 21. Science 322, 434–438 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Zheng, W., Zhao, H., Mancera, E., Steinmetz, L. M. & Snyder, M. Genetic analysis of variation in transcription factor binding in yeast. Nature 464, 1187–1191 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Bradley, R. K. et al. Binding site turnover produces pervasive quantitative changes in transcription factor binding between closely related Drosophila species. PLoS Biol. 8, e1000343 (2010).

    PubMed  PubMed Central  Google Scholar 

  65. Conte, C., Dastugue, B. & Vaury, C. Coupling of enhancer and insulator properties identified in two retrotransposons modulates their mutagenic impact on nearby genes. Mol. Cell. Biol. 22, 1767–1777 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Lerman, D. N., Michalak, P., Helin, A. B., Bettencourt, B. R. & Feder, M. E. Modification of heat-shock gene expression in Drosophila melanogaster populations via transposable elements. Mol. Biol. Evol. 20, 135–144 (2003).

    CAS  PubMed  Google Scholar 

  67. Eichenlaub, M. P. & Ettwiller, L. De novo genesis of enhancers in vertebrates. PLoS Biol. 9, e1001188 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Prud'homme, B. et al. Repeated morphological evolution through cis-regulatory changes in a pleiotropic gene. Nature 440, 1050–1053 (2006). This study identifies the enhancers as well as localizes the specific mutations within those enhancers responsible for the independent gain of wing-specific pigmentation spots in two Drosophila species.

    CAS  PubMed  Google Scholar 

  69. Sumiyama, K. & Saitou, N. Loss-of-function mutation in a repressor module of human-specifically activated enhancer HACNS1. Mol. Biol. Evol. 28, 3005–3007 (2011). This study shows that expression appearing to result from the evolution of a novel CRE in humans was more likely caused by human-specific mutations disrupting ancestral repressive sequences masking latent cis -regulatory activities.

    CAS  PubMed  Google Scholar 

  70. Rebeiz, M., Pool, J. E., Kassner, V. A., Aquadro, C. F. & Carroll, S. B. Stepwise modification of a modular enhancer underlies adaptation in a Drosophila population. Science 326, 1663–1667 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Babbitt, C. C. et al. Multiple functional variants in cis modulate PDYN expression. Mol Biol. Evol. 27, 465–479 (2010).

    CAS  PubMed  Google Scholar 

  72. Przeworski, M. The signature of positive selection at randomly chosen loci. Genetics 160, 1179–1189 (2002).

    PubMed  PubMed Central  Google Scholar 

  73. Pool, J. E. & Aquadro, C. F. The genetic basis of adaptive pigmentation variation in Drosophila melanogaster. Mol. Ecol. 16, 2844–2851 (2007).

    PubMed  PubMed Central  Google Scholar 

  74. Wittkopp, P. J. et al. Intraspecific polymorphism to interspecific divergence: genetics of pigmentation in Drosophila. Science 326, 540–544 (2009).

    CAS  PubMed  Google Scholar 

  75. Colosimo, P. F. et al. Widespread parallel evolution in sticklebacks by repeated fixation of ectodysplasin alleles. Science 307, 1928–1933 (2005).

    CAS  PubMed  Google Scholar 

  76. Orr, H. A. The genetic theory of adaptation: a brief history. Nature Rev. Genet. 6, 119–127 (2005).

    CAS  PubMed  Google Scholar 

  77. Mackay, T. F. Mutations and quantitative genetic variation: lessons from Drosophila. Phil. Trans. R. Soc. B 365, 1229–1239 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Charlesworth, B. Fundamental concepts in genetics: effective population size and patterns of molecular evolution and variation. Nature Rev. Genet. 10, 195–205 (2009).

    CAS  PubMed  Google Scholar 

  79. Arendt, J. & Reznick, D. Convergence and parallelism reconsidered: what have we learned about the genetics of adaptation? Trends Ecol. Evol. 23, 26–32 (2008).

    PubMed  Google Scholar 

  80. Sucena, E., Delon, I., Jones, I., Payre, F. & Stern, D. L. Regulatory evolution of shavenbaby/ovo underlies multiple cases of morphological parallelism. Nature 424, 935–938 (2003).

    CAS  PubMed  Google Scholar 

  81. Duret, L. & Galtier, N. Comment on “human-specific gain of function in a developmental enhancer”. Science 323, 714; author reply 714 (2009).

    PubMed  Google Scholar 

  82. Houle, D., Govindaraju, D. R. & Omholt, S. Phenomics: the next challenge. Nature Rev. Genet. 11, 855–866 (2010).

    CAS  PubMed  Google Scholar 

  83. Hoekstra, H. E. & Coyne, J. A. The locus of evolution: evo devo and the genetics of adaptation. Evolution 61, 995–1016 (2007).

    PubMed  Google Scholar 

  84. Lynch, V. J. & Wagner, G. P. Resurrecting the role of transcription factor change in developmental evolution. Evolution 62, 2131–2154 (2008).

    CAS  PubMed  Google Scholar 

  85. Wittkopp, P. J., Haerum, B. K. & Clark, A. G. Regulatory changes underlying expression differences within and between Drosophila species. Nature Genet. 40, 346–350 (2008).

    CAS  PubMed  Google Scholar 

  86. Emerson, J. J. et al. Natural selection on cis and trans regulation in yeasts. Genome Res. 20, 826–836 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Cretekos, C. J. et al. Regulatory divergence modifies limb length between mammals. Genes Dev. 22, 141–151 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Reed, R. D. et al. Optix drives the repeated convergent evolution of butterfly wing pattern mimicry. Science 333, 1137–1141 (2011).

    CAS  PubMed  Google Scholar 

  89. Gomez-Skarmeta, J. L., Lenhard, B. & Becker, T. S. New technologies, new findings, and new concepts in the study of vertebrate cis-regulatory sequences. Dev. Dyn. 235, 870–885 (2006).

    CAS  PubMed  Google Scholar 

  90. Richards, S. et al. Comparative genome sequencing of Drosophila pseudoobscura: chromosomal, gene, and cis-element evolution. Genome Res. 15, 1–18 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Peterson, B. K. et al. Big genomes facilitate the comparative identification of regulatory elements. PLoS ONE 4, e4688 (2009).

    PubMed  PubMed Central  Google Scholar 

  92. Wittkopp, P. J. Evolution of cis-regulatory sequence and function in Diptera. Heredity 97, 139–147 (2006).

    CAS  PubMed  Google Scholar 

  93. Weirauch, M. T. & Hughes, T. R. Conserved expression without conserved regulatory sequence: the more things change, the more they stay the same. Trends Genet. 26, 66–74 (2010).

    CAS  PubMed  Google Scholar 

  94. Meireles-Filho, A. C. & Stark, A. Comparative genomics of gene regulation-conservation and divergence of cis-regulatory information. Curr. Opin. Genet. Dev. 19, 565–570 (2009).

    CAS  PubMed  Google Scholar 

  95. Ludwig, M. Z., Bergman, C., Patel, N. H. & Kreitman, M. Evidence for stabilizing selection in a eukaryotic enhancer element. Nature 403, 564–567 (2000).

    CAS  PubMed  Google Scholar 

  96. Ludwig, M. Z. et al. Functional evolution of a cis-regulatory module. PLoS Biol. 3, e93 (2005).

    PubMed  PubMed Central  Google Scholar 

  97. Piano, F., Parisi, M. J., Karess, R. & Kambysellis, M. P. Evidence for redundancy but not trans factor—cis element co-evolution in the regulation of Drosophila Yp genes. Genetics 152, 605–616, (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Wittkopp, P. J., Vaccaro, K. & Carroll, S. B. Evolution of yellow gene regulation and pigmentation in Drosophila. Curr. Biol. 12, 1547–1556 (2002).

    CAS  PubMed  Google Scholar 

  99. Swanson, C. I., Schwimmer, D. B. & Barolo, S. Rapid evolutionary rewiring of a structurally constrained eye enhancer. Curr. Biol. 21, 1186–1196 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Arnone, M. I., Dmochowski, I. J. & Gache, C. Using reporter genes to study cis-regulatory elements. Methods Cell Biol. 74, 621–652 (2004).

    CAS  PubMed  Google Scholar 

  101. O'Doherty, A. et al. An aneuploid mouse strain carrying human chromosome 21 with down syndrome phenotypes. Science 309, 2033–2037 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Berman, B. P. et al. Computational identification of developmental enhancers: conservation and function of transcription factor binding-site clusters in Drosophila melanogaster and Drosophila pseudoobscura. Genome Biol. 5, R61 (2004).

    PubMed  PubMed Central  Google Scholar 

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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

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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