Accelerated evolution of enhancer hotspots in the mammal ancestor
Open accessAbstract
Mammals have evolved remarkably different sensory, reproductive, metabolic, and skeletal systems. To explore the genetic basis for these differences, we developed a comparative genomics approach to scan whole-genome multiple sequence alignments to identify regions that evolved rapidly in an ancestral lineage but are conserved within extant species. This pattern suggests that ancestral changes in function were maintained in descendants. After applying this test to therian mammals, we identified 4,797 accelerated regions, many of which are noncoding and located near developmental transcription factors. We then used mouse transgenic reporter assays to test if noncoding accelerated regions are enhancers and to determine how therian-specific substitutions affect their activity in vivo. We discovered enhancers with expression specific to the therian version in brain regions involved in the hormonal control of milk ejection, uterine contractions, blood pressure, temperature, and visual processing. This work underscores the idea that changes in developmental gene expression are important for mammalian evolution, and it pinpoints candidate genes for unique aspects of mammalian biology.
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Numerous studies have used changes in sequence conservation of conserved elements to identify regulatory regions that may be important for lineage-specific phenotypes.
“Numerous studies have used changes in sequence conservation of conserved elements as means to identify regulatory regions which may be of particular importance for lineage-specific phenotypes.”
From Bayesian Detection of Convergent Rate Changes of Conserved Noncoding Elements on Phylogenetic Trees (2019) · cites this paper as Holloway et al. (2016)
Holloway et al. identified 4,797 regions accelerated at the base of therian mammals, many of which are noncoding and located close to developmental transcription factors.
“Holloway et al. (2016) identified 4,797 regions accelerated at the base of therian mammals, many of which are noncoding and located close to developmental transcription factors.”
From Bayesian Detection of Convergent Rate Changes of Conserved Noncoding Elements on Phylogenetic Trees (2019) · cites this paper as Holloway et al. (2016)
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 Holloway et al. 2016
The Introduction describes genome-wide testing for evolutionary rate changes, and Comparative Genomics Methods describes the paper’s internal-branch test (page numbers unavailable). Neither passage assesses whether existing relaxed-clock methods scale to genome-wide data. Searches for relaxed-clock scalability and computational cost found no passage addressing that point. (LLM, conf=0.72)
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A map of the cis-regulatory sequences in the mouse genome
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Bayesian Detection of Convergent Rate Changes of Conserved Noncoding Elements on Phylogenetic Trees
Hu, Z., Sackton, T. B., Edwards, S. V., & Liu, J. S. (2019) · Molecular Biology and Evolution · doi:10.1093/molbev/msz049 · Cited by 69 · see citing works
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- Authors
- Holloway, A. K., Bruneau, B. G., Sukonnik, T., Rubenstein, J. L., & Pollard, K. S.
- Affiliations
- Gladstone Institutes (US)
- University of California, San Francisco (US)
- Corresponding author
- Pollard, Katherine S.
- Venue
- Molecular Biology and Evolution
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-12-29
- Volume
- 33
- Issue
- 4
- Pages
- 1008-1018
- ISSN
- 0737-4038 (ISSN-L)
- 1537-1719
- PMC
- PMC4776709
- OpenAlex
- W2217279525
- Cited by
- 27
- References
- 4
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 2 · 2016: 2
- FWCI
- 0.79
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Molecular Biology and Evolution (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- American Heart Association
- Gladstone Institutes
- Lawrence J. and Florence A. DeGeorge Charitable Trust
- National Institutes of Health (1c06rr018928-01)
- National Institute of Mental Health (MH049428, R37MH049428)
- National Institute of General Medical Sciences (R01GM082901)
- National Center for Research Resources (C06-RR-018928, RR018928)
- 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
- mammalian evolution, therian mammals, accelerated evolution, non-coding DNA, transcription factor binding sites, developmental gene expression, milk ejection, uterine contraction, brain gene expression, comparative genomics
- MeSH terms
- Animals, Brain, Enhancer Elements, Genetic, Mammals, Conserved Sequence, Homeodomain Proteins, Gene Expression Regulation, Developmental, Evolution, Molecular, Genomics, Mice
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