Highly Conserved Non-Coding Sequences Are Associated with Vertebrate Development
Open accessAbstract
In addition to protein coding sequence, the human genome contains a significant amount of regulatory DNA, the identification of which is proving somewhat recalcitrant to both in silico and functional methods. An approach that has been used with some success is comparative sequence analysis, whereby equivalent genomic regions from different organisms are compared in order to identify both similarities and differences. In general, similarities in sequence between highly divergent organisms imply functional constraint. We have used a whole-genome comparison between humans and the pufferfish, Fugu rubripes, to identify nearly 1,400 highly conserved non-coding sequences. Given the evolutionary divergence between these species, it is likely that these sequences are found in, and furthermore are essential to, all vertebrates. Most, and possibly all, of these sequences are located in and around genes that act as developmental regulators. Some of these sequences are over 90% identical across more than 500 bases, being more highly conserved than coding sequence between these two species. Despite this, we cannot find any similar sequences in invertebrate genomes. In order to begin to functionally test this set of sequences, we have used a rapid in vivo assay system using zebrafish embryos that allows tissue-specific enhancer activity to be identified. Functional data is presented for highly conserved non-coding sequences associated with four unrelated developmental regulators (SOX21, PAX6, HLXB9, and SHH), in order to demonstrate the suitability of this screen to a wide range of genes and expression patterns. Of 25 sequence elements tested around these four genes, 23 show significant enhancer activity in one or more tissues. We have identified a set of non-coding sequences that are highly conserved throughout vertebrates. They are found in clusters across the human genome, principally around genes that are implicated in the regulation of development, including many transcription factors. These highly conserved non-coding sequences are likely to form part of the genomic circuitry that uniquely defines vertebrate development.
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Regions of the genome outside protein-coding genes exhibit considerable levels of conservation across evolutionary time.
“One of the major revelations of comparative genomics has been the discovery of regions of the genome falling well outside protein-coding genes that nonetheless exhibit considerable levels of conservation across evolutionary time”
From Bayesian Detection of Convergent Rate Changes of Conserved Noncoding Elements on Phylogenetic Trees (2019) · cites this paper as Woolfe et al. 2005
Similar expression patterns were observed in transgenic zebrafish bearing constructs for the orthologous human and pufferfish CNRs.
“Similar expression patterns were observed in transgenic zebra fi sh bearing constructs for the orthologous human and puffer fi sh CNRs (25, 26).”
From Transphyletic conservation of developmental regulatory state in animal evolution (2011) · cites this paper as [25]
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- Authors
- Woolfe, A., Goodson, M., Goode, D. K., Snell, P., McEwen, G. K., Vavouri, T., Smith, S. F., North, P., Callaway, H., Kelly, K., Walter, K., Abnizova, I., Gilks, W., Edwards, Y. J. K., Cooke, J. E., & Elgar, G.
- Affiliations
- Medical Research Council (GB)
- MRC Biostatistics Unit (GB)
- Corresponding author
- Elgar, Greg
- ORCID
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2004-11-11
- Volume
- 3
- Issue
- 1
- Pages
- e7
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC526512
- OpenAlex
- W2116251070
- Cited by
- 970
- References
- 79
- Citations by year
- 2026: 17 · 2025: 15 · 2024: 22 · 2023: 16 · 2022: 16 · 2021: 21 · 2020: 30 · 2019: 36 · 2018: 32 · 2017: 24 · 2016: 35 · 2015: 38 · 2014: 46 · 2013: 46 · 2012: 59
- FWCI
- 24.50
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- regulatory DNA, vertebrate development, Fugu rubripes, human genome, sequence comparison, zebrafish embryos, developmental regulators, Sox21, Pax6, HLXB9, Sonic hedgehog, transcription factors
- MeSH terms
- PAX6 Transcription Factor, Animals, Enhancer Elements, Genetic, Eye Proteins, Multigene Family, High Mobility Group Proteins, Humans, Molecular Sequence Data, Neoplasm Proteins, Regulatory Sequences, Nucleic Acid, Repressor Proteins, Species Specificity, Transcription Factors, Trans-Activators, Genome, Human, Genome, Conserved Sequence, Sequence Analysis, DNA, Homeodomain Proteins, Gene Expression Regulation, Developmental, Takifugu, Databases, Genetic, Green Fluorescent Proteins, Paired Box Transcription Factors, Hedgehog Proteins, SOXB2 Transcription Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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