Functional characterization of enhancer evolution in the primate lineage
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Abstract
BACKGROUND: Enhancers play an important role in morphological evolution and speciation by controlling the spatiotemporal expression of genes. Previous efforts to understand the evolution of enhancers in primates have typically studied many enhancers at low resolution, or single enhancers at high resolution. Although comparative genomic studies reveal large-scale turnover of enhancers, a specific understanding of the molecular steps by which mammalian or primate enhancers evolve remains elusive. RESULTS: We identified candidate hominoid-specific liver enhancers from H3K27ac ChIP-seq data. After locating orthologs in 11 primates spanning around 40 million years, we synthesized all orthologs as well as computational reconstructions of 9 ancestral sequences for 348 active tiles of 233 putative enhancers. We concurrently tested all sequences for regulatory activity with STARR-seq in HepG2 cells. We observe groups of enhancer tiles with coherent trajectories, most of which can be potentially explained by a single gain or loss-of-activity event per tile. We quantify the correlation between the number of mutations along a branch and the magnitude of change in functional activity. Finally, we identify 84 mutations that correlate with functional changes; these are enriched for cytosine deamination events within CpGs. CONCLUSIONS: We characterized the evolutionary-functional trajectories of hundreds of liver enhancers throughout the primate phylogeny. We observe subsets of regulatory sequences that appear to have gained or lost activity. We use these data to quantify the relationship between sequence and functional divergence, and to identify CpG deamination as a potentially important force in driving changes in enhancer activity during primate evolution.
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MPRAs have been applied to assess biochemically annotated candidate enhancers, candidate enhancers harbouring variants that potentially mediate eQTLs, and even scans of the entire human genome.
“MPRAs have been applied to assess biochemically annotated candidate enhancers77,176-178, candidate enhancers harbouring variants that potentially mediate eQTLs179-182, and even scans of the entire human genome108,183.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [178]
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Cites
BEDTools: a flexible suite of utilities for comparing genomic features
Quinlan, A. R., & Hall, I. M. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq033 · Cited by 27,437 · see citing works
Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega
Sievers, F., Wilm, A., Dineen, D., Gibson, T., Karplus, K., Li, W.-Z., Lopez, R., McWilliam, H., Remmert, M., Söding, J., et al. (2011) · Molecular Systems Biology · doi:10.1038/msb.2011.75 · Cited by 15,576 · see citing works
The Human Genome Browser at UCSC
Kent, W. J., Sugnet, C. W., Furey, T. S., Roskin, K. M., Pringle, T. H., Zahler, A. M., & Haussler, A. D. (2002) · Genome Research · doi:10.1101/gr.229102 · Cited by 10,400 · see citing works
Aligning sequence reads, clone sequences and assembly con*gs with BWA-MEMPreprint
Li, H. (2014) · arXiv (Cornell University) · doi:10.6084/m9.figshare.963153.v1 · Cited by 5,150 · see citing works
FIMO: scanning for occurrences of a given motif
Grant, C. E., Bailey, T. L., & Noble, W. S. (2011) · Bioinformatics · doi:10.1093/bioinformatics/btr064 · Cited by 4,247 · see citing works
Mapping and analysis of chromatin state dynamics in nine human cell types
Ernst, J., Kheradpour, P., Mikkelsen, T. S., Shoresh, N., Ward, L. D., Epstein, C. B., Zhang, X., Wang, L., Issner, R., Coyne, M., et al. (2011) · Nature · doi:10.1038/nature09906 · Cited by 2,898 · see citing works
Self-citationKing, M.-C., & Wilson, A. C. (1975) · Science · doi:10.1126/science.1090005 · Cited by 2,815 · see citing works
Expression of a β-globin gene is enhanced by remote SV40 DNA sequences
Banerji, J., Rusconi, S., & Schaffner, W. (1981) · Cell · doi:10.1016/0092-8674(81)90413-x · Cited by 1,724 · see citing works
Convergent adaptation of human lactase persistence in Africa and Europe
Tishkoff, S. A., Reed, F. A., Ranciaro, A., Voight, B. F., Babbitt, C. C., Silverman, J. S., Powell, K., Mortensen, H. M., Hirbo, J. B., Osman, M., et al. (2007) · Nature Genetics · doi:10.1038/ng1946 · Cited by 1,615 · see citing works
The evolutionary significance of cis-regulatory mutations
Wray, G. A. (2007) · Nature Reviews Genetics · doi:10.1038/nrg2063 · Cited by 1,521 · see citing works
Cis-regulatory elements: Molecular mechanisms and evolutionary processes underlying divergence
Wittkopp, P. J., & Kalay, G. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3095 · Cited by 1,231 · see citing works
Genome-Wide Quantitative Enhancer Activity Maps Identified by STARR-seq
Arnold, C. D., Gerlach, D., Stelzer, C., Boryń, Ł. M., Rath, M., & Stark, A. (2013) · Science · doi:10.1126/science.1232542 · Cited by 1,125 · see citing works
Genetic signatures of strong recent positive selection at the lactase gene.
Bersaglieri, T., Sabeti, P. C., Patterson, N., VanderPloeg, T., Schaffner, S., Drake, J. A., Rhodes, M., Reich, D., & Hirschhorn, J. (2004) · American Journal of Human Genetics · doi:10.1086/421051 · Cited by 1,098 · see citing works
Chan, Y. F., Marks, M. E., Jones, F. C., Villarreal, G., Shapiro, M. D., Brady, S. D., Southwick, A. M., Absher, D. M., Grimwood, J., Schmutz, J., et al. (2010) · Science · doi:10.1126/science.1182213 · Cited by 1,020 · see citing works
Ever-Changing Landscapes: Transcriptional Enhancers in Development and Evolution
Long, H. K., Prescott, S. L., & Wysocka, J. (2016) · Cell · doi:10.1016/j.cell.2016.09.018 · Cited by 945 · see citing works
Enhancer Evolution across 20 Mammalian Species
Villar, D., Berthelot, C., Aldridge, S., Rayner, T. F., Lukk, M., Pignatelli, M., Park, T. J., Deaville, R., Erichsen, J. T., Jasinska, A. J., et al. (2015) · Cell · doi:10.1016/j.cell.2015.01.006 · Cited by 825 · see citing works
Repetitive and Non-Repetitive DNA Sequences and a Speculation on the Origins of Evolutionary Novelty
Britten, R. J., & Davidson, E. H. (1971) · The Quarterly Review of Biology · doi:10.1086/406830 · Cited by 789 · see citing works
Transposable elements have rewired the core regulatory network of human embryonic stem cells
Kunarso, G., Chia, N., Jeyakani, J., Hwang, C., Lu, X., Chan, Y.-S., Ng, H., & Bourque, G. (2010) · Nature Genetics · doi:10.1038/ng.600 · Cited by 777 · see citing works
Moreau, P., Hen, R., Wasylyk, B., Everett, R., Gaub, M. P., & Chambon, P. (1981) · Nucleic Acids Research · doi:10.1093/nar/9.22.6047 · Cited by 761 · see citing works
Melnikov, A., Murugan, A., Zhang, X., Tesileanu, T., Wang, L., Rogov, P., Feizi, S., Gnirke, A., Callan, C. G., Kinney, J. B., et al. (2012) · Nature Biotechnology · doi:10.1038/nbt.2137 · Cited by 711 · see citing works
Chance caught on the wing: cis-regulatory evolution and the origin of pigment patterns in Drosophila
Gompel, N., Prud'homme, B., Wittkopp, P. J., Kassner, V. A., & Carroll, S. B. (2005) · Nature · doi:10.1038/nature03235 · Cited by 646 · see citing works
Massively parallel functional dissection of mammalian enhancers in vivo
Patwardhan, R. P., Hiatt, J. B., Witten, D. M., Kim, M. J., Smith, R. P., May, D., Lee, C., Andrie, J. M., Lee, S.-I., Cooper, G. M., et al. (2012) · Nature Biotechnology · doi:10.1038/nbt.2136 · Cited by 536 · see citing works
Self-citationComparative Epigenomic Analysis of Murine and Human Adipogenesis
Mikkelsen, T. S., Zhao, X. D., Zhang, X., Wang, L., Gimble, J. M., Lander, E. S., & Rosen, E. D. (2010) · Cell · doi:10.1016/j.cell.2010.09.006 · Cited by 519 · see citing works
Phenotypic robustness conferred by apparently redundant transcriptional enhancers
Frankel, N., Davis, G. K., Vargas, D., Wang, S., Payre, F., & Stern, D. L. (2010) · Nature · doi:10.1038/nature09158 · Cited by 510 · see citing works
Gene Co-Option in Physiological and Morphological Evolution
True, J., & Carroll, S. B. (2002) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.18.020402.140619 · Cited by 502 · see citing works
Enhanced Regulatory Sequence Prediction Using Gapped k-mer Features
Ghandi, M., Lee, D., Mohammad-Noori, M., & Beer, M. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003711 · Cited by 484 · see citing works
Tewhey, R., Kotliar, D., Park, D. S., Liu, B., Winnicki, S., Reilly, S. K., Andersen, K. G., Mikkelsen, T. S., Lander, E. S., Schaffner, S. F., et al. (2016) · Cell · doi:10.1016/j.cell.2016.04.027 · Cited by 480 · see citing works
Transcriptional Enhancers in Animal Development and Evolution
Levine, M. (2010) · Current Biology · doi:10.1016/j.cub.2010.06.070 · Cited by 449 · see citing works
A method to predict the impact of regulatory variants from DNA sequence
Lee, D., Gorkin, D. U., Baker, M., Strober, B. J., Asoni, A. L., McCallion, A. S., & Beer, M. (2015) · Nature Genetics · doi:10.1038/ng.3331 · Cited by 417 · see citing works
High-resolution analysis of DNA regulatory elements by synthetic saturation mutagenesis
Patwardhan, R. P., Lee, C., Litvin, O., Young, D. L., Pe'er, D., & Shendure, J. (2009) · Nature Biotechnology · doi:10.1038/nbt.1589 · Cited by 377 · see citing works
Self-citationNitta, K. R., Jolma, A., Yin, Y., Morgunova, E. Y., Kivioja, T., Akhtar, J., Hens, K., Toivonen, J., Deplancke, B., Furlong, E. E. M., et al. (2015) · eLife · doi:10.7554/elife.04837 · Cited by 358 · see citing works
Inoue, F., Kircher, M., Martin, B., Cooper, G. M., Witten, D. M., McManus, M. T., Ahituv, N., & Shendure, J. (2017) · Genome Research · doi:10.1101/gr.212092.116 · Cited by 331 · see citing works
Self-citationSystematic Functional Dissection of Common Genetic Variation Affecting Red Blood Cell Traits
Ulirsch, J. C., Nandakumar, S. K., Wang, L., Giani, F. C., Zhang, X., Rogov, P., Melnikov, A., McDonel, P., Do, R., Mikkelsen, T. S., et al. (2016) · Cell · doi:10.1016/j.cell.2016.04.048 · Cited by 328 · see citing works
FastML: a web server for probabilistic reconstruction of ancestral sequences
Ashkenazy, H., Penn, O., Doron‐Faigenboim, A., Cohen, O., Cannarozzi, G. M., Zomer, O., & Pupko, T. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks498 · Cited by 327 · see citing works
Wittkopp, P. J., True, J., & Carroll, S. B. (2002) · Development · doi:10.1242/dev.129.8.1849 · Cited by 325 · see citing works
Suboptimization of developmental enhancers
Farley, E. K., Olson, K. M., Zhang, W., Brandt, A. J., Rokhsar, D. S., & Levine, M. S. (2015) · Science · doi:10.1126/science.aac6948 · Cited by 319 · see citing works
Kheradpour, P., Ernst, J., Melnikov, A., Rogov, P., Wang, L., Zhang, X., Alston, J., Mikkelsen, T. S., & Kellis, M. (2013) · Genome Research · doi:10.1101/gr.144899.112 · Cited by 315 · see citing works
Transposable elements are the primary source of novelty in primate gene regulationPreprint
Trizzino, M., Park, Y., Beltrame, M. H., Aracena, K. A., Mika, K. M., Çalışkan, M., Perry, G. H., Lynch, V. J., & Brown, C. D. (2017) · Genome Research · doi:10.1101/gr.218149.116 · Cited by 273 · see citing works
Smith, R. P., Taher, L., Patwardhan, R. P., Kim, M. J., Inoue, F., Shendure, J., Ovcharenko, I., & Ahituv, N. (2013) · Nature Genetics · doi:10.1038/ng.2713 · Cited by 239 · see citing works
Self-citationHOCOMOCO: a comprehensive collection of human transcription factor binding sites models
Kulakovskiy, I. V., Medvedeva, Y. A., Schaefer, U., Kasianov, A. S., Vorontsov, I. E., Bajić, V. B., & Makeev, V. J. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks1089 · Cited by 230 · see citing works
High-throughput functional testing of ENCODE segmentation predictions
Kwasnieski, J. C., Fiore, C., Chaudhari, H. G., & Cohen, B. A. (2014) · Genome Research · doi:10.1101/gr.173518.114 · Cited by 224 · see citing works
The Evolution of Lineage-Specific Regulatory Activities in the Human Embryonic Limb
Cotney, J. L., Leng, J., Yin, J., Reilly, S. K., DeMare, L. E., Emera, D., Ayoub, A. E., RAKIC, P. T., & Noonan, J. P. (2013) · Cell · doi:10.1016/j.cell.2013.05.056 · Cited by 208 · see citing works
uShuffle: A useful tool for shuffling biological sequences while preserving the k-let counts
Jiang, M., Anderson, J., Gillespie, J. R., & Mayne, M. (2008) · BMC Bioinformatics · doi:10.1186/1471-2105-9-192 · Cited by 176 · see citing works
Arnold, C. D., Gerlach, D., Spies, D., Matts, J. A., Sytnikova, Y. A., Pagani, M., Lau, N. C., & Stark, A. (2014) · Nature Genetics · doi:10.1038/ng.3009 · Cited by 175 · see citing works
DNA Methylation of Transcriptional Enhancers and Cancer Predisposition
Aran, D., & Hellman, A. (2013) · Cell · doi:10.1016/j.cell.2013.06.018 · Cited by 161 · see citing works
Cooper, D. N., Mort, M. E., Stenson, P. D., Ball, E. V., & Chuzhanova, N. A. (2010) · Human Genomics · doi:10.1186/1479-7364-4-6-406 · Cited by 150 · see citing works
A Direct In Vivo RNAi Screen Identifies MKK4 as a Key Regulator of Liver Regeneration
Wuestefeld, T., Pesic, M., Rudalska, R., Dauch, D., Longerich, T., Kang, T.-W., Yevsa, T., Heinzmann, F., Hoenicke, L., Hohmeyer, A., et al. (2013) · Cell · doi:10.1016/j.cell.2013.03.026 · Cited by 149 · see citing works
E2F1 mediates sustained lipogenesis and contributes to hepatic steatosis
Denechaud, P., López‐Mejía, I. C., Giralt, A., Lai, Q., Blanchet, É., Delacuisine, B., Nicolay, B., Dyson, N. J., Bonner, C., Pattou, F. N., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci81542 · Cited by 142 · see citing works
The Genomic Impact of DNA CpG Methylation on Gene Expression; Relationships in Prostate Cancer
Long, M. D., Smiraglia, D. J., & Campbell, M. J. (2017) · Biomolecules · doi:10.3390/biom7010015 · Cited by 108 · see citing works
Vockley, C. M., Guo, C., Majoros, W. H., Nodzenski, M., Scholtens, D. M., Hayes, M. G., Lowe, W. L., & Reddy, T. E. (2015) · Genome Research · doi:10.1101/gr.190090.115 · Cited by 99 · see citing works
Regulatory Variation Within and Between Species
Zheng, W., Gianoulis, T. A., Karczewski, K. J., Zhao, H., & Snyder, M. P. (2011) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-082908-150139 · Cited by 67 · see citing works
CpG Deamination Creates Transcription Factor–Binding Sites with High Efficiency
Żemojtel, T., Kiełbasa, S. M., Arndt, P. F., Behrens, S., Bourque, G., & Vingron, M. (2011) · Genome Biology and Evolution · doi:10.1093/gbe/evr107 · Cited by 61 · see citing works
Transcription factor binding variation in the evolution of gene regulation
Dowell, R. D. (2010) · Trends in Genetics · doi:10.1016/j.tig.2010.08.005 · Cited by 61 · see citing works
Tewhey, R., Kotliar, D., Park, D. S., Liu, B., Winnicki, S., Reilly, S. K., Andersen, K. G., Mikkelsen, T. S., Lander, E. S., Schaffner, S. F., et al. (2018) · Cell · doi:10.1016/j.cell.2018.02.021 · Cited by 51 · cited 1× · see citing works
“First, while most non-coding mutations are not expression-modulating [23, 24], we cannot rule out within-species sequence variation between the tissues tested and reference genomes contributing to functional differences.”
Predicting enhancer activity and variant impact using gkm‐SVM
Beer, M. (2017) · Human Mutation · doi:10.1002/humu.23185 · Cited by 46 · see citing works
Trizzino, M., Park, Y., Beltrame, M. H., Aracena, K. A., Mika, K. M., Çalışkan, M., Perry, G. H., Lynch, V. J., & Brown, C. D. (2016) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/083980 · Cited by 7 · see citing works
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Research works printed but not linked: 2
- [28]Villar D, Berthelot C, Aldridge S, Rayner TF, Lukk M, Pignatelli M, Park TJ, Deaville R, Erichsen JT, Jasinska AJ, Turner JMA, Bertelsen MF, Murchison EP, Flicek P, Odom DT. Enhancer evolution across 20 mammalian species. ArrayExpress. 2015; https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-2633/. PMC4313353 25635462
- [53]Klein JC, Keith A, Agarwal V, Durham TJ, Shendure J. Functional characterization of enhancer evolution in the primate lineage. GEO. 2018; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE113978. PMC6060477 30045748
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Wessels, H.-H., Méndez-Mancilla, A., Guo, X., Legut, M., Daniloski, Z., & Sanjana, N. E. (2020) · Nature Biotechnology · doi:10.1038/s41587-020-0456-9 · Cited by 418 · see citing works
Towards a comprehensive catalogue of validated and target-linked human enhancers
Gasperini, M., Tome, J. M., & Shendure, J. (2020) · Nature Reviews Genetics · doi:10.1038/s41576-019-0209-0 · Cited by 396 · see citing works
Self-citationTørresen, O. K., Star, B., Mier, P., Andrade-Navarro, M. A., Bateman, A., Jarnot, P., Gruca, A., Grynberg, M., Kajava, A. V., Promponas, V. J., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz841 · Cited by 347 · see citing works
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Hill, M. S., Zande, P. V., & Wittkopp, P. J. (2020) · Nature Reviews Genetics · doi:10.1038/s41576-020-00304-w · Cited by 262 · see citing works
A systematic evaluation of the design and context dependencies of massively parallel reporter assays
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Self-citationHuman-specific genetics: new tools to explore the molecular and cellular basis of human evolution
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Adaptive sequence divergence forged new neurodevelopmental enhancers in humans
Mangan, R. J., Alsina, F. C., Mosti, F., Sotelo-Fonseca, J. E., Snellings, D. A., Au, E. H., Carvalho, J., Sathyan, L., Johnson, G. D., Reddy, T. E., et al. (2022) · Cell · doi:10.1016/j.cell.2022.10.016 · Cited by 111 · see citing works
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Klein, J. C., Agarwal, V., Inoue, F., Keith, A., Martin, B., Kircher, M., Ahituv, N., & Shendure, J. (2020) · doi:10.21203/rs.3.pex-1065/v1 · Cited by 11 · see citing works
Self-citationAccurate allocation of multimapped reads enables regulatory element analysis at repeatsPreprint
Morrissey, A., Shi, J., James, D. Q., & Mahony, S. (2024) · Genome Research · doi:10.1101/gr.278638.123 · Cited by 11 · see citing works
Pietro, L. D., Barba, M., Palacios, D., Tiberio, F., Prampolini, C., Baranzini, M., Parolini, O., Arcovito, A., & Lattanzi, W. (2021) · Scientific Reports · doi:10.1038/s41598-021-00511-3 · Cited by 10 · see citing works
Edsall, L., Berrío, A., Majoros, W. H., Swain-Lenz, D., Morrow, S., Shibata, Y., Safi, A., Wray, G. A., Crawford, G. E., & Allen, A. S. (2019) · Genome Biology and Evolution · doi:10.1093/gbe/evz218 · Cited by 10 · see citing works
Pizzollo, J., Zintel, T. M., & Babbitt, C. C. (2022) · Genome Biology and Evolution · doi:10.1093/gbe/evac108 · Cited by 7 · see citing works
Evolutionary genomics: the fruits of genomic approaches applied to evolutionary biology
Sands, T. R. (2019) · Genome biology · doi:10.1186/s13059-018-1615-x · Cited by 7 · see citing works
Novelty versus innovation of gene regulatory elements in human evolution and disease
Katikaneni, A., & Lowe, C. B. (2024) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2024.102279 · Cited by 6 · see citing works
Emergence of enhancers at late DNA replicating regions
Cornejo‐Páramo, P., Petrova, V., Zhang, X., Young, R. S., & Wong, E. S. W. (2024) · Nature Communications · doi:10.1038/s41467-024-47391-5 · Cited by 5 · see citing works
Applications of high-throughput reporter assays to gene regulation studies
D’Elia, B., & Bass, J. I. F. (2025) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2025.103105 · Cited by 4 · see citing works
HDI-STARR-seq: Condition-specific enhancer discovery in mouse liver in vivo
Chang, T.-Y., & Waxman, D. J. (2024) · BMC Genomics · doi:10.1186/s12864-024-11162-9 · Cited by 4 · see citing works
Investigating enhancer evolution with massively parallel reporter assays
Kwon, S. B., & Ernst, J. (2018) · Genome biology · doi:10.1186/s13059-018-1502-5 · Cited by 4 · see citing works
Multi-dimensional annotation of porcine variants using genomic and epigenomic features in pigs
Yin, H. H., Yang, L., Zhao, Q., Yao, W., Teng, J., Gao, Y., Xu, Z., Lin, Q., Diao, S., Liu, X., et al. (2025) · BMC Biology · doi:10.1186/s12915-025-02279-8 · Cited by 3 · see citing works
You, J. S., Pierce, S., Liang, G., & Jones, P. A. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2502963122 · Cited by 3 · see citing works
Barr, K., Rhodes, K., & Gilad, Y. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.07.20.500831 · Cited by 3 · see citing works
Okamoto, A. S., Coveney, C. R., Ganapathee, D. S., & Capellini, T. D. (2026) · Genome Biology and Evolution · doi:10.1093/gbe/evag121 · Cited by 3 · see citing works
W2V-repeated index: Prediction of enhancers and their strength based on repeated fragments
Xie, W., Yao, Z., Yuan, Y., Too, J., Li, F., Wang, H., Zhan, Y., Wu, X., Wang, Z., & Zhang, G. (2024) · Genomics · doi:10.1016/j.ygeno.2024.110906 · Cited by 2 · see citing works
Allo: Accurate allocation of multi-mapped reads enables regulatory element analysis at repeatsPreprint
Morrissey, A., Shi, J., James, D. Q., & Mahony, S. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.09.12.556916 · Cited by 2 · see citing works
Becker, R., Choudhury, P., Oti, M., Fouani, Y., Strobel, B., Ketterer, S., Rumpel, S., Park, J., Kreuz, S., Maier, U., et al. (2026) · iScience · doi:10.1016/j.isci.2026.115469 · Cited by 1 · see citing works
Using Synthetic DNA Libraries to Investigate Chromatin and Gene Regulation
Kleinschmidt, H., Xu, C., & Bai, L. (2023) · Chromosoma · doi:10.1007/s00412-023-00796-5 · Cited by 1 · see citing works
Evolution of transposable element-derived enhancer activityPreprint
Du, A. Y., Zhuo, X., Sundaram, V., Jensen, N. O., Chaudhari, H. G., Saccone, N. L., Cohen, B. A., & Wang, T. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.03.16.483999 · Cited by 1 · see citing works
Okamoto, A. S., Coveney, C. R., Ganapathee, D. S., & Capellini, T. D. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.21.683789 · Cited by 1 · see citing works
Retracing and rewriting the evolutionary trajectories of mammalian developmental enhancersPreprint
Li, T., Lalanne, J., Kajiwara, E. A. N., Jain, S., Li, X., Do, T. V., Martin, B. K., Regalado, S. G., Daza, R. M., & Shendure, J. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.04.20.719714 · Cited by 1 · see citing works
Self-citationEmergence of new enhancers at late DNA replicating regionsPreprint
Cornejo‐Páramo, P., Petrova, V., Zhang, X., Young, R. S., & Wong, E. S. W. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.12.22.521323
Barr, K., Rhodes, K., & Gilad, Y. (2023) · Figshare · doi:10.6084/m9.figshare.24124019
Barr, K., Rhodes, K., & Gilad, Y. (2023) · Figshare · doi:10.6084/m9.figshare.24124016
Barr, K., Rhodes, K., & Gilad, Y. (2023) · Figshare · doi:10.6084/m9.figshare.24124013
Adaptation to Freshwater in Allis Shad Involved a Combination of Genomic and Epigenomic Changes
Pereira, P., Afonso, S., Múrias, A., Carneiro, M., & Sabatino, S. J. (2025) · Journal of Molecular Evolution · doi:10.1007/s00239-025-10253-9
Becker, R., Choudhury, P., Oti, M., Fouani, Y., Strobel, B., Ketterer, S., Rumpel, S., Park, J., Kreuz, S., Maier, U., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.04.657008
Challenges in predicting chromatin accessibility differences between species
Stephen, A. Z. M., Raje, A., Sestili, H. H., Wirthlin, M. E., Lawler, A. J., Brown, A. R., Ma, J., Stauffer, W. R., Pfenning, A. R., & Kaplow, I. M. (2026) · NAR Genomics and Bioinformatics · doi:10.1093/nargab/lqag059
Barr, K., Rhodes, K., & Gilad, Y. (2023) · Figshare · doi:10.6084/m9.figshare.24124022
Barr, K., Rhodes, K., & Gilad, Y. (2023) · Figshare · doi:10.6084/m9.figshare.24124010
Additional file 1 of Evolution of mouse circadian enhancers from transposable elements
Judd, J., Sanderson, H., & Feschotte, C. (2021) · Figshare · doi:10.6084/m9.figshare.14881014
Kaplow, I. M., Schäffer, D. E., Wirthlin, M. E., Lawler, A. J., Brown, A. R., Kleyman, M., & Pfenning, A. R. (2022) · Figshare · doi:10.6084/m9.figshare.19582522
Additional file 2 of Evolution of mouse circadian enhancers from transposable elements
Judd, J., Sanderson, H., & Feschotte, C. (2021) · Figshare · doi:10.6084/m9.figshare.14881017
Bellesis, A., Li, X., Moore-Frederick, D., Xu, D., Delbridge, K., Ma, J., Vaccaro, G., Edward, B. A. A., Kellogg, M., Creeger, Y., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.05.730479
- Authors
- Klein, J. C., Keith, A., Agarwal, V., Durham, T., & Shendure, J.
- Affiliations
- University of Washington (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Klein, Jason C.
- Shendure, Jay
- Venue
- Genome Biology
- Published
- 2018-07-25
- Volume
- 19
- Issue
- 1
- Pages
- 99-99
- ISSN
- 1465-6906 (ISSN-L)
- 1474-760X
- PMC
- PMC6060477
- OpenAlex
- W2950235380
- Cited by
- 63
- References
- 56
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 8 · 2023: 11 · 2022: 8 · 2021: 7 · 2020: 8 · 2019: 7 · 2018: 2
- FWCI
- 2.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Genome biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (UM1HG009408, R01CA197139, R01HG006768, 5T32HL007093-43, U24HG009446)
- National Human Genome Research Institute (1F30HG009479)
- Howard Hughes Medical Institute
- 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 › Genomics and Phylogenetic Studies
- Keywords
- enhancer evolution, primate evolution, H3K27ac, ancestral sequence reconstruction, STARR-seq, regulatory evolution, orthologs
- MeSH terms
- Animals, Callitrichinae, Cebidae, Cercopithecidae, Enhancer Elements, Genetic, Biological Evolution, Histones, Humans, Liver, Mutation, Phylogeny, Hominidae, Hylobatidae, CpG Islands, Atelidae, Hep G2 Cells
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