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Cited by 66Developmental Biology and Gene RegulationGenomics and Chromatin DynamicsBat Biology and Ecology Studies

Bat accelerated regions identify a bat forelimb specific enhancer in the HoxD locus

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Booker, Betty M., Friedrich, Tara, Mason, Mandy K., VanderMeer, Julia E., Zhao, Jingjing, Eckalbar, Walter L., Logan, Malcolm, Illing, Nicola +2 more·2016·PLOS Genetics
DOI 10.1371/journal.pgen.1005738PMC PMC4809552

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Abstract

Abstract The molecular events leading to the development of the bat wing remain largely unknown, and are thought to be caused, in part, by changes in gene expression during limb development. These expression changes could be instigated by variations in gene regulatory enhancers. Here, we used a comparative genomics approach to identify regions that evolved rapidly in the bat ancestor but are highly conserved in other vertebrates. We discovered 166 bat accelerated regions (BARs) that overlap H3K27ac and p300 ChIP-seq peaks in developing mouse limbs. Using a mouse enhancer assay, we show that five Myotis lucifugus BARs drive gene expression in the developing mouse limb, with the majority showing differential enhancer activity compared to the mouse orthologous BAR sequences. These include BAR116, which is located telomeric to the HoxD cluster and had robust forelimb expression for the M. lucifugus sequence and no activity for the mouse sequence at embryonic day 12.5. Developing limb expression analysis of Hoxd10 - Hoxd13 in Miniopterus natalensis bats showed a high-forelimb weak-hindlimb expression for Hoxd10 - Hoxd11 , similar to the expression trend observed for M. lucifugus BAR116 in mice, suggesting that it could be involved in the regulation of the bat HoxD complex. Combined, our results highlight novel regulatory regions that could be instrumental for the morphological differences leading to the development of the bat wing. Author Summary The limb is a classic example of vertebrate homology and is represented by a large range of morphological structures such as fins, legs and wings. The evolution of these structures could be driven by alterations in gene regulatory elements that have critical roles during development. To identify elements that may contribute to bat wing development, we characterized sequences that are conserved between vertebrates, but changed significantly in the bat lineage. We then overlapped these sequences with predicted developing limb enhancers as determined by ChIP-seq, finding 166 bat accelerated sequences (BARs). Five BARs that were tested for enhancer activity in mice all drove expression in the limb. Testing the mouse orthologous sequence showed that three had differences in their limb enhancer activity as compared to the bat sequence. Of these, BAR116 was of particular interest as it is located near the HoxD locus, an essential gene complex required for proper spatiotemporal patterning of the developing limb. The bat BAR116 sequence drove robust forelimb expression but the mouse BAR116 sequence did not show enhancer activity. These experiments correspond to analyses of HoxD gene expressions in developing bat limbs, which had strong forelimb versus weak hindlimb expression for Hoxd10 - 11 . Combined, our studies highlight specific genomic regions that could be important in shaping the morphological differences that led to the development of the bat wing.

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  • Changes in conservation of conserved noncoding or nonexonic elements in a subset of lineages are often associated with altered regulatory activity and ultimately phenotypic divergence.

    “Changes in conservation of elements, such as conserved noncoding or nonexonic elements, in a subset of lineages are often associated with altered regulatory activity and ultimately phenotypic divergence”

    From Bayesian Detection of Convergent Rate Changes of Conserved Noncoding Elements on Phylogenetic Trees (2019) · cites this paper as Booker et al. 2016

    The Introduction (page unavailable) reports differential enhancer activity in some accelerated noncoding regions, and the Discussion (page unavailable) reports differential activity for bat BAR116. But the paper says these regulatory changes could possibly contribute to species-specific phenotypes; it does not establish the claimed progression to phenotypic divergence as a general outcome. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Booker et al. discovered 166 bat-accelerated regions overlapping with enhancers in developing mouse limbs, including one that likely regulated expression of the HoxD cluster important for forelimb development.

    “Booker et al. (2016) discovered 166 bat-accelerated regions overlapping with enhancers in developing mouse limbs, including one that likely regulated expression of the HoxD cluster important for forelimb development.”

    From Bayesian Detection of Convergent Rate Changes of Conserved Noncoding Elements on Phylogenetic Trees (2019) · cites this paper as Booker et al. (2016)

    The Abstract reports 166 bat-accelerated regions overlapping H3K27ac and p300 peaks in developing mouse limbs, but does not establish that all 166 overlap confirmed enhancers. It also reports that BAR116 has forelimb enhancer activity and could be involved in regulating the bat HoxD complex; “likely regulated” is stronger than that conclusion. The indexed passages provide section labels but no page numbers. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Existing relaxed clock methods are not easily scalable to genome-wide data such as is typically encountered when testing for rate changes in conserved elements across a clade for which whole-genomes have been sequenced.

    “Moreover, although highly accurate and useful for validating various clock models, these methods are not easily scalable to genome-wide data such as is typically encountered when testing for rate changes in conserved elements across a clade for which whole-genomes have been sequenced”

    From Bayesian Detection of Convergent Rate Changes of Conserved Noncoding Elements on Phylogenetic Trees (2019) · cites this paper as Booker et al. 2016

    The Computational analyses section describes testing conserved elements for accelerated evolution with PhyloP using genome-wide alignments. It does not assess relaxed-clock methods or say whether they scale to genome-wide data; searches for relaxed-clock scalability and clock-model limitations found no such passage in our copy. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

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Authors
Booker, B. M., Friedrich, T., Mason, M. K., VanderMeer, J. E., Zhao, J., Eckalbar, W. L., Logan, M., Illing, N., Pollard, K. S., & Ahituv, N.
Affiliations
  • University of California, San Francisco (US)
  • Gladstone Institutes (US)
  • University of Cape Town (ZA)
  • East China University of Science and Technology (CN)
  • King's College London (GB)
Corresponding author
  • Pollard, Katherine S.
  • Ahituv, Nadav
ORCID
Venue
PLOS Genetics
Publisher
Public Library of Science (PLoS)
Published
2016-03-28
Volume
12
Issue
3
Pages
e1005738
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1005738
PMC
PMC4809552
OpenAlex
W2305784951
Cited by
66
References
5
Citations by year
2026: 7 · 2025: 5 · 2024: 8 · 2023: 4 · 2022: 4 · 2021: 6 · 2020: 6 · 2019: 10 · 2018: 7 · 2017: 7 · 2016: 2
FWCI
3.70
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Research Portal (King's College London) (submittedVersion, cc-by)
  • Open University of Cape Town (University of Cape Town) (submittedVersion, cc-by)
Funders
  • National Science Foundation
  • Texas Tech University
  • Gladstone Institutes
  • National Research Foundation
  • University of Cape Town
  • National Institutes of Health (1s10od021596-01)
  • Medical Research Council (MC_PC_13052)
  • National Cancer Institute (R01CA197139)
  • National Institute of General Medical Sciences (T32GM008284, T32GM067547)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK090382)
  • National Institute of Neurological Disorders and Stroke (R01NS079231)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD059862)
Topics
  • 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 Chromatin Dynamics
  • Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Bat Biology and Ecology Studies
Keywords
HoxD cluster, limb development, Myotis lucifugus, Miniopterus natalensis, H3K27ac, P300, comparative genomics
MeSH terms
Animals, Chiroptera, Embryo, Mammalian, Forelimb, Transcription Factors, Vertebrates, Wings, Animal, Sequence Alignment, Sequence Analysis, Homeodomain Proteins, Gene Expression Regulation, Developmental, Genomics, Organogenesis, Mice

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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