Cited by 184Genomics and Chromatin DynamicsChromosomal and Genetic VariationsDevelopmental Biology and Gene Regulation

Quantitative genome-wide enhancer activity maps for five Drosophila species show functional enhancer conservation and turnover during cis-regulatory evolution

Open access
Arnold, Cosmas D, Gerlach, Daniel, Spies, Daniel, Matts, Jessica A, Sytnikova, Yuliya A, Pagani, Michaela, Lau, Nelson C, Stark, Alexander·2014·Nature Genetics

Abstract

Phenotypic differences between closely related species are thought to arise primarily from changes in gene expression due to mutations in cis-regulatory sequences (enhancers). However, it has remained unclear how frequently mutations alter enhancer activity or create functional enhancers de novo. Here we use STARR-seq, a recently developed quantitative enhancer assay, to determine genome-wide enhancer activity profiles for five Drosophila species in the constant trans-regulatory environment of Drosophila melanogaster S2 cells. We find that the functions of a large fraction of D. melanogaster enhancers are conserved for their orthologous sequences owing to selection and stabilizing turnover of transcription factor motifs. Moreover, hundreds of enhancers have been gained since the D. melanogaster-Drosophila yakuba split about 11 million years ago without apparent adaptive selection and can contribute to changes in gene expression in vivo. Our finding that enhancer activity is often deeply conserved and frequently gained provides functional insights into regulatory evolution.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/ng.3009

Cites

46 of 46 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Enhancer conservation is typically modular, commonly preserving the sets of binding sites for the required transcription factors, but often not their exact sequence and orientation.

    “Instead, enhancer conservation is typically “modular”, commonly preserving the sets of binding sites for the required TFs, but often not their exact sequence and orientation [101–109].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [106]

    The Results sections “Specific selection of transcription factor sequence motifs” and “Compensatory changes stabilize regulatory output” link conserved enhancer activity to transcription-factor motifs rather than overall sequence identity, and show that lost motifs can be replaced at different positions. The paper does not establish that binding-site orientation is often unconserved, and its findings concern the assayed Drosophila enhancers rather than enhancers generally. Page numbers are unavailable in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. [2]King MC Wilson AC Evolution at two levels in humans and chimpanzees Science 188 107 116 1975 1090005

Cited by

Sorted by citations

Authors
Arnold, C. D., Gerlach, D., Spies, D., Matts, J. A., Sytnikova, Y. A., Pagani, M., Lau, N. C., & Stark, A.
Affiliations
  • Research Institute of Molecular Pathology (AT)
  • Brandeis University (US)
Corresponding author
Stark, Alexander
Venue
Nature Genetics
Published
2014-06-08
Volume
46
Issue
7
Pages
685-692
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
OpenAlex
W2170739826
Cited by
175
References
46
Citations by year
2026: 6 · 2025: 9 · 2024: 11 · 2023: 15 · 2022: 17 · 2021: 13 · 2020: 18 · 2019: 14 · 2018: 14 · 2017: 11 · 2016: 19 · 2015: 23 · 2014: 5
FWCI
7.93
Type
journal article
Language
en
Open access
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD057298, R00HD057298, K99HD057298)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
enhancer activity, cis-regulatory evolution, enhancer conservation, STARR-seq, Drosophila species, Drosophila melanogaster, Drosophila yakuba, transcription factor binding motifs, gene expression evolution
MeSH terms
Animals, Cells, Cultured, Drosophila, Enhancer Elements, Genetic, Luciferases, Transcription Factors, Genome, Evolution, Molecular, Gene Expression Profiling, Drosophila Proteins, High-Throughput Nucleotide Sequencing

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 ›

Are you an author, or do you see a problem with this page? Request a review