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Cited by 94Genomics and Chromatin DynamicsGenetic Associations and EpidemiologyGenomics and Phylogenetic Studies

Analysis of variation at transcription factor binding sites in Drosophila and humans

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Spivakov, Mikhail, Akhtar, Junaid, Kheradpour, Pouya, Beal, Kathryn, Girardot, Charles, Koscielny, Gautier, Herrero, Javier, Kellis, Manolis +2 more·2012·Genome Biology
DOI 10.1186/gb-2012-13-9-r49PMC PMC3491393
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Abstract

Background: Advances in sequencing technology have boosted population genomics and made it possible to map the positions of transcription factor binding sites (TFBSs) with high precision. Here we investigate TFBS variability by combining transcription factor binding maps generated by ENCODE, modENCODE, our previously published data and other sources with genomic variation data for human individuals and Drosophila isogenic lines. Results: We introduce a metric of TFBS variability that takes into account changes in motif match associated with mutation and makes it possible to investigate TFBS functional constraints instance-by-instance as well as in sets that share common biological properties. We also take advantage of the emerging per-individual transcription factor binding data to show evidence that TFBS mutations, particularly at evolutionarily conserved sites, can be efficiently buffered to ensure coherent levels of transcription factor binding. Conclusions: Our analyses provide insights into the relationship between individual and interspecies variation and show evidence for the functional buffering of TFBS mutations in both humans and flies. In a broad perspective, these results demonstrate the potential of combining functional genomics and population genetics approaches for understanding gene regulation.

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  • Natural genetic variation at enhancers is commonly observed in human populations, consistent with the relatively low sequence constraint of these regions.

    “While much of the evidence for enhancer function was obtained through perturbing these regions artificially, natural genetic variation at enhancers is commonly observed in human populations, consistent with the relatively low sequence constraint of these regions [191, 192].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [191]

    The Background says variation at DNA regulatory elements is relatively common, and the Results analyze variation at human transcription-factor binding sites. But the paper does not establish that enhancers generally have low sequence constraint: the Background distinguishes limited base-by-base conservation from lack of functional constraint, and the Conclusions say binding sites are functionally constrained despite tolerating some mutations. Our copy provides no page numbers for these passages. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Much natural variation at enhancers has apparently little phenotypic effect due to redundancy both within enhancers and across them.

    “Much of this variation has apparently little phenotypic effect due to redundancy both within enhancers (such as through multiple homotypic TF binding sites [191, 193]) and across them (such as through multiple enhancers regulating the same gene, as will be discussed below).”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [191]

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Authors
Spivakov, M., Akhtar, J., Kheradpour, P., Beal, K., Girardot, C., Koscielny, G., Herrero, J., Kellis, M., Furlong, E. E., & Birney, E.
Affiliations
  • European Bioinformatics Institute (GB)
  • European Molecular Biology Laboratory (DE)
  • Broad Institute (US)
Corresponding author
  • Spivakov, Mikhail
  • Birney, Ewan
ORCID
Venue
Genome Biology
Publisher
Springer Science and Business Media LLC
Published
2012-09-05
Volume
13
Issue
9
Pages
R49-R49
ISSN
  • 1465-6906 (ISSN-L)
  • 1474-760X
DOI
10.1186/gb-2012-13-9-r49
PMC
PMC3491393
OpenAlex
W2163203447
Cited by
94
References
7
Citations by year
2025: 3 · 2024: 3 · 2023: 1 · 2022: 3 · 2021: 4 · 2020: 5 · 2019: 5 · 2018: 4 · 2017: 3 · 2016: 10 · 2015: 10 · 2014: 23 · 2013: 16 · 2012: 4
FWCI
6.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Genome biology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Deutsche Forschungsgemeinschaft (FU 750)
  • National Human Genome Research Institute (R01HG004037)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
Keywords
transcription factor binding sites, conserved non-coding elements, gene expression regulation, population genomics, human genetic variation, ENCODE, modENCODE
MeSH terms
Analysis of Variance, Animals, Binding Sites, Drosophila, Humans, Models, Genetic, Mutation, Regulatory Sequences, Nucleic Acid, Transcription Factors, Genetic Variation, Genome, Human, Sequence Analysis, DNA, Genome, Insect, Position-Specific Scoring Matrices, Molecular Sequence Annotation, Nucleotide Motifs

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