Evo-Devo and an Expanding Evolutionary Synthesis: A Genetic Theory of Morphological Evolution
Open accessAbstract
Biologists have long sought to understand which genes and what kinds of changes in their sequences are responsible for the evolution of morphological diversity. Here, I outline eight principles derived from molecular and evolutionary developmental biology and review recent studies of species divergence that have led to a genetic theory of morphological evolution, which states that (1) form evolves largely by altering the expression of functionally conserved proteins, and (2) such changes largely occur through mutations in the cis-regulatory sequences of pleiotropic developmental regulatory loci and of the target genes within the vast networks they control.
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Changes in transcription regulatory networks during evolution contribute substantially to phenotypic diversity.
“Interestingly, the evolution of transcription regulatory networks is a rich source of phenotypic diversity (Carroll, 2008).”
From The Aging Epigenome (2016) · cites this paper as Carroll, 2008
Cites
Evolutionary divergence and convergence in proteins.
ZUCKERKANDL, E., & PAULING, L. (1965) · Evolving Genes and Proteins · doi:10.1016/b978-1-4832-2734-4.50017-6 · Cited by 3,020 · see citing works
The evolutionary significance of cis-regulatory mutations
Wray, G. A. (2007) · Nature Reviews Genetics · doi:10.1038/nrg2063 · Cited by 1,521 · see citing works
SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans
Lamason, R. L., Mohideen, M.-A. P. K., Mest, J. R., Wong, A. C., Norton, H. L., Aros, M. C., Jurynec, M. J., Mao, X., Humphreville, V. R., Humbert, J. E., et al. (2005) · Science · doi:10.1126/science.1116238 · Cited by 1,043 · see citing works
Evolution at Two Levels: On Genes and Form
Carroll, S. B. (2005) · PLoS Biology · doi:10.1371/journal.pbio.0030245 · Cited by 882 · see citing works
Self-citationUnexpected complexity of the Wnt gene family in a sea anemone
Kusserow, A., Pang, K., Sturm, C., Hrouda, M., Lentfer, J., Schmidt, H. A., Technau, U., von Haeseler, A., Hobmayer, B., Martindale, M. Q., et al. (2005) · Nature · doi:10.1038/nature03158 · Cited by 599 · see citing works
Genetic analysis of cavefish reveals molecular convergence in the evolution of albinism
Protas, M. E., Hersey, C., Kochanek, D., Zhou, Y., Wilkens, H., Jeffery, W. R., Zon, L. I., Borowsky, R., & Tabin, C. J. (2006) · Nature Genetics · doi:10.1038/ng1700 · Cited by 543 · see citing works
Repeated morphological evolution through cis-regulatory changes in a pleiotropic gene
Prud'homme, B., Gompel, N., Rokas, A., Kassner, V. A., Williams, T. M., Yeh, S.-D., True, J. R., & Carroll, S. B. (2006) · Nature · doi:10.1038/nature04597 · Cited by 507 · see citing works
Self-citationMiller, C. T., Beleza, S., Pollen, A. A., Schluter, D., Kittles, R. A., Shriver, M. D., & Kingsley, D. M. (2007) · Cell · doi:10.1016/j.cell.2007.10.055 · Cited by 388 · see citing works
A core transcriptional network for early mesoderm development in <i>Drosophila melanogaster</i>
Sandmann, T., Girardot, C., Brehme, M., Tongprasit, W., Stolc, V., & Furlong, E. E. M. (2007) · Genes & Development · doi:10.1101/gad.1509007 · Cited by 286 · see citing works
Regulatory divergence modifies limb length between mammals
Cretekos, C. J., Wang, Y., Green, E. D., Program, N. C. S., Martin, J. F., Rasweiler, J. J., & Behringer, R. R. (2008) · Genes & Development · doi:10.1101/gad.1620408 · Cited by 232 · see citing works
The evolution of combinatorial gene regulation in fungi
Tuch, B. B., Galgoczy, D. J., Hernday, A. D., Li, H., & Johnson, A. D. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060038 · Cited by 228 · see citing works
Parallel genetic origins of pelvic reduction in vertebrates
Shapiro, M. D., Bell, M. A., & Kingsley, D. M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604706103 · Cited by 216 · see citing works
Evolutionary plasticity of developmental gene regulatory network architecture
Hinman, V. F., & Davidson, E. H. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709994104 · Cited by 154 · see citing works
Identification of novel direct Stat3 target genes for control of growth and differentiation
Snyder, M., Huang, X.-Y., & Zhang, J. J. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m706976200 · Cited by 108 · cited 2× · see citing works
“, 2007) and the number of signal-regulated STAT3 targets in another cell type (~300; Snyder et al., 2008).”
BackgroundHinman, V. F., Nguyen, A., & Davidson, E. H. (2007) · Developmental Biology · doi:10.1016/j.ydbio.2007.09.006 · Cited by 67 · see citing works
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Lambert, S. A., Jolma, A., Campitelli, L. F., Das, P. K., Yin, Y., Albu, M., Chen, X., Taipale, J., Hughes, T. R., & Weirauch, M. T. (2018) · Cell · doi:10.1016/j.cell.2018.01.029 · Cited by 3,399 · see citing works
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Chan, Y. F., Marks, M. E., Jones, F. C., Villarreal, G., Shapiro, M. D., Brady, S. D., Southwick, A. M., Absher, D. M., Grimwood, J., Schmutz, J., et al. (2010) · Science · doi:10.1126/science.1182213 · Cited by 1,020 · see citing works
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- Authors
- Carroll, S. B.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Carroll, Sean B.
- ORCID
- Carroll, Sean B.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 134
- Issue
- 1
- Pages
- 25-36
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2171193618
- Cited by
- 2,067
- References
- 15
- Citations by year
- 2026: 82 · 2025: 91 · 2024: 114 · 2023: 113 · 2022: 100 · 2021: 156 · 2020: 100 · 2019: 123 · 2018: 126 · 2017: 115 · 2016: 129 · 2015: 139 · 2014: 137 · 2013: 126 · 2012: 106
- FWCI
- 42.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Physical Sciences › Mathematics › Geometry and Topology › Morphological variations and asymmetry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- morphological evolution, evolutionary developmental biology, cis-regulatory mutations, gene expression changes, species divergence, cis-regulatory sequences, target genes, gene regulatory networks
- MeSH terms
- Animals, Biological Evolution, Humans, Proteins, Developmental Biology, Evolution, Molecular, Gene Regulatory Networks
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