A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly
Open accessAbstract
Unequivocal identification of the full composition of a gene is made difficult by the cryptic nature of regulatory elements. Regulatory elements are notoriously difficult to locate and may reside at considerable distances from the transcription units on which they operate and, moreover, may be incorporated into the structure of neighbouring genes. The importance of regulatory mutations as the basis of human abnormalities remains obscure. Here, we show that the chromosome 7q36 associated preaxial polydactyly, a frequently observed congenital limb malformation, results from point mutations in a Shh regulatory element. Shh, normally expressed in the ZPA posteriorly in the limb bud, is expressed in an additional ectopic site at the anterior margin in mouse models of PPD. Our investigations into the basis of the ectopic Shh expression identified the enhancer element that drives normal Shh expression in the ZPA. The regulator, designated ZRS, lies within intron 5 of the Lmbr1 gene 1 Mb from the target gene Shh. The ZRS drives the early spatio-temporal expression pattern in the limb of tetrapods. Despite the morphological differences between limbs and fins, an equivalent regulatory element is found in fish. The ZRS contains point mutations that segregate with polydactyly in four unrelated families with PPD and in the Hx mouse mutant. Thus point mutations residing in long-range regulatory elements are capable of causing congenital abnormalities, and possess the capacity to modify gene activity such that a novel gamut of abnormalities is detected.
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.
Integrity signals
Registry
Cites
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.
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?
Non-coding enhancer deletions have been linked to severe human disease phenotypes such as beta thalassaemia and polydactyly.
“It soon became clear that enhancers also played vital roles in humans, with non-coding enhancer deletions starting to be linked to severe disease phenotypes such as beta thalassaemia and polydactyly [25–28].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [27]
The “ZRS and polydactyly” section links mutations in a non-coding regulatory element to preaxial polydactyly. It specifies single-base-pair mutations, not enhancer deletions, and does not address beta thalassaemia. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe Shh ZRS enhancer is located within the intron of the Lmbr1 gene approximately 1 megabase distant from Shh.
“The classic example of this is the Shh ZRS enhancer, which is located within the intron of the Lmbr1 gene approximately 1 megabase distant from Shh [27].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [27]
The “Regulation at a distance” section places the ZRS in intron 5 of Lmbr1 and says it is a considerable distance from Shh. Our copy does not give an approximately 1-megabase physical distance for the ZRS–Shh separation; its reference to about 1 Mb concerns other genes. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn the mouse genome, the Shh gene and its ZRS enhancer are located about 1 Mb apart.
“For example, in the mouse genome, the Shh gene and its ZRS (zone of polarizing activity regulatory sequence) enhancer are located about 1 Mb apart [127].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [127]
The ‘Regulation at a distance’ section places the ZRS in Lmbr1 at a considerable distance from Shh. The ‘ZRS and polydactyly’ section gives an approximate genetic distance of 1.8 cM for Shh and two mouse mutations, but does not give a physical distance of about 1 Mb for Shh and ZRS; its 1 Mb figure refers to Sox9 and MAF. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAt least a few enhancers reside at great distances from their target gene (e.g. ZRS 1 Mb from Shh, MYC enhancer 1.7 Mb downstream), although most are much more proximal.
“At least a few enhancers reside at great distances from their target gene (e.g. the ZRS enhancer located 1 Mb from the Shh gene118, and a MYC enhancer located 1.7 Mb downstream119), although most are much more proximal to their target promoters72.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [118]
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
Thompson, J. (1997) · Nucleic Acids Research · doi:10.1093/nar/25.24.4876 · Cited by 39,119 · see citing works
A simple salting out procedure for extracting DNA from human nucleated cells
Miller, S. A., Dykes, D. D., & Polesky, H. F. (1988) · Nucleic Acids Research · doi:10.1093/nar/16.3.1215 · Cited by 20,341 · see citing works
Sonic hedgehog mediates the polarizing activity of the ZPA
Riddle, R. D., Johnson, R. L., Laufer, E., & Tabin, C. J. (1993) · Cell · doi:10.1016/0092-8674(93)90626-2 · Cited by 2,285 · see citing works
Echelard, Y., Epstein, D. J., St-Jacques, B., Shen, L., Mohler, J., McMahon, J. A., & McMahon, A. P. (1993) · Cell · doi:10.1016/0092-8674(93)90627-3 · Cited by 2,154 · see citing works
Krauss, S. J. K., Concordet, J., & Ingham, P. W. (1993) · Cell · doi:10.1016/0092-8674(93)90628-4 · Cited by 1,072 · see citing works
VISTA : visualizing global DNA sequence alignments of arbitrary length
Mayor, C., Brudno, M., Schwartz, J. R., Poliakov, A., Rubin, E. M., Frazer, K. A., Pachter, L. S., & Dubchak, I. L. (2000) · Bioinformatics · doi:10.1093/bioinformatics/16.11.1046 · Cited by 1,017 · see citing works
Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly
Lettice, L. A., Horikoshi, T., Heaney, S. J. H., van Baren, M. J., van der Linde, H. C., Breedveld, G. J., Joosse, M., Akarsu, N. A., Oostra, B. A., Endo, N., et al. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.112212199 · Cited by 458 · see citing works
Self-citationThe regulation of myogenin gene expression during the embryonic development of the mouse.Preprint
Yee, S., & Rigby, P. W. J. (1993) · Genes & Development · doi:10.1101/gad.7.7a.1277 · Cited by 423 · see citing works
Selective agenesis of the dorsal pancreas in mice lacking homeobox gene Hlxb9
Li, H., Arber, S., Jessell, T. M., & Edlund, H. (1999) · Nature Genetics · doi:10.1038/12669 · Cited by 377 · see citing works
Position effect in human genetic disease
Kleinjan, D. A. (1998) · Human Molecular Genetics · doi:10.1093/hmg/7.10.1611 · Cited by 370 · see citing works
A transgenic insertion upstream of Sox9 is associated with dominant XX sex reversal in the mouse
Bishop, C. E., Whitworth, D. J., Qin, Y., Agoulnik, A. I., Agoulnik, I. U., Harrison, W. R., Behringer, R. R., & Overbeek, P. A. (2000) · Nature Genetics · doi:10.1038/82652 · Cited by 356 · see citing works
Mackenzie, M. A. F., Jordan, S. A., Budd, P. S., & Jackson, I. J. (1997) · Developmental Biology · doi:10.1006/dbio.1997.8738 · Cited by 331 · see citing works
Hox gene expression in teleost fins and the origin of vertebrate digits
Sordino, P., van der Hoeven, F., & Duboule, D. (1995) · Nature · doi:10.1038/375678a0 · Cited by 323 · see citing works
Active Conservation of Noncoding Sequences Revealed by Three-Way Species ComparisonsPreprint
Dubchak, I. L., Brudno, M., Loots, G. G., Pachter, L. S., Mayor, C., Rubin, E. M., & Frazer, K. A. (2000) · Genome Research · doi:10.1101/gr.142200 · Cited by 311 · see citing works
A homeobox gene, HLXB9, is the major locus for dominantly inherited sacral agenesis
Ross, A. J., Ruiz‐Pérez, V. L., Wang, Y., Hagan, D.-M., Scherer, S. W., Lynch, S. A., Lindsay, S., Custard, E. J., Belloni, E., Wilson, D. I., et al. (1998) · Nature Genetics · doi:10.1038/3828 · Cited by 288 · see citing works
Jamieson, R. V. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.1.33 · Cited by 269 · see citing works
Polydactyly and ectopic ZPA formation in Alx-4 mutant mice
Qu, S., Niswender, K. D., Ji, Q., van der Meer, R., Keeney, D. S., Magnuson, M. A., & Wisdom, R. (1997) · Development · doi:10.1242/dev.124.20.3999 · Cited by 198 · see citing works
A duplicated zone of polarizing activity in polydactylous mouse mutants.Preprint
Masuya, H., Sagai, T., Wakana, S., Moriwaki, K., & Shiroishi, T. (1995) · Genes & Development · doi:10.1101/gad.9.13.1645 · Cited by 188 · see citing works
Small is beautiful: comparative genomics with the pufferfish (Fugu rubripes)
Elgar, G. S., Sandford, R. N., Aparicio, S. A. J. R., Macrae, A. D., Venkatesh, B., & Brenner, S. (1996) · Trends in Genetics · doi:10.1016/0168-9525(96)10018-4 · Cited by 151 · see citing works
Mutations in mouse Aristaless-like4 cause Strong’s luxoid polydactyly
Qu, S., Tucker, S. C., Ehrlich, J. S., Levorse, J. M., Flaherty, L. A., Wisdom, R., & Vogt, T. (1998) · Development · doi:10.1242/dev.125.14.2711 · Cited by 132 · see citing works
Fin development in a cartilaginous fish and the origin of vertebrate limbs
Tanaka, M., Münsterberg, A., Anderson, W. G., Prescott, A. R., Hazon, N., & Tickle, C. A. (2002) · Nature · doi:10.1038/416527a · Cited by 127 · see citing works
Masuya, H., Sagai, T., Moriwaki, K., & Shiroishi, T. (1997) · Developmental Biology · doi:10.1006/dbio.1996.8457 · Cited by 112 · see citing works
Sharpe, J., Lettice, L., Hecksher-Sørensen, J., Fox, M., Hill, R., & Krumlauf, R. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80022-0 · Cited by 104 · see citing works
Self-citationThe gene for triphalangeal thumb maps to the subtelomeric region of chromosome 7q
Heutink, P., Zguricas, J., van Oosterhout, L., Breedveld, G. J., Testers, L., Sandkuijl, L. A., Snijders, P. J. L. M., Weissenbach, J., Lindhout, D., Hovius, S. E. R., et al. (1994) · Nature Genetics · doi:10.1038/ng0394-287 · Cited by 101 · see citing works
The tetrapod limb: A hypothesis on its origin
Wagner, G. P., & Chiu, C.-H. (2001) · Journal of Experimental Zoology · doi:10.1002/jez.1100 · Cited by 94 · see citing works
A complex bilateral polysyndactyly disease locus maps to chromosome 7q36
Tsukurov, O. I., Boehmer, A. L. M., Flynn, J. M., Nicolai, J. A., Hamel, B. C. J., Traill, S., Zaleske, D. J., Mankin, H. J., Yeon, H. B., Ho, C., et al. (1994) · Nature Genetics · doi:10.1038/ng0394-282 · Cited by 87 · see citing works
Clark, R. M., Marker, P. C., & Kingsley, D. M. (2000) · Genomics · doi:10.1006/geno.2000.6225 · Cited by 82 · see citing works
Zguricas, J., Heus, H. C., Peralta, E. M., Breedveld, G. J., Kuyt, B., Mumcu, E. F., Bakker, W. F., Akarsu, N. A., Kay, S. P., Hovius, S. E. R., et al. (1999) · Journal of Medical Genetics · doi:10.1136/jmg.36.1.33 · Cited by 72 · see citing works
A Physical and Transcriptional Map of the Preaxial Polydactyly Locus on Chromosome 7q36
Heus, H. C., Hing, A. V., van Baren, M. J., Joosse, M., Breedveld, G. J., Wang, J. C. C., Burgess, A. K., Donnis-Keller, H., Berglund, C., Zguricas, J., et al. (1999) · Genomics · doi:10.1006/geno.1999.5796 · Cited by 68 · see citing works
Knudsen, T. B., & Kochhar, D. M. (1981) · Development · doi:10.1242/dev.65.supplement.289 · Cited by 47 · see citing works
Linkage of preaxial polydactyly type 2 to 7q36
Hing, A. V., Helms, C. A., Slaugh, R., Burgess, A. K., Wang, J. C. C., Herman, T. E., Dowton, S. B., & Donis‐Keller, H. (1995) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320580208 · Cited by 37 · see citing works
Double Labeling for Whole-Mount In Situ Hybridization in Mouse
Hecksher‐Sørensen, J., Hill, R. E., & Lettice, L. A. (1998) · BioTechniques · doi:10.2144/98246bm02 · Cited by 27 · see citing works
Self-citationA Double RING-H2 Domain in RNF32, a Gene Expressed during Sperm Formation
van Baren, M. J., van der Linde, H. C., Breedveld, G. J., Baarends, W. M., Rizzu, P., de Graaff, E., Oostra, B. A., & Heutink, P. (2002) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2002.6612 · Cited by 25 · see citing works
Lettice, L. A., Hecksher‐Sørensen, J., & Hill, R. E. (1999) · Development · doi:10.1242/dev.126.21.4729 · Cited by 20 · see citing works
Self-citation
Flagged first, then by citations
1 of the 35 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- Sanders, J.W. Jr and Gasseling, M.T. (1968) Ectodermal-mesenchymal interactions in the origin of limb symmetry. In Fleischmajar, R. and Billingham, R.F. (eds), Ectodermal-Mesenchymal Interactions. Williams and Wilkins, Baltimore, MD, pp. 78-97.
Cited by
Sorted by citations
GREAT improves functional interpretation of cis-regulatory regions
McLean, C. Y., Bristor, D., Hiller, M., Clarke, S. L., Schaar, B. T., Lowe, C. B., Wenger, A. M., & Bejerano, G. (2010) · Nature Biotechnology · doi:10.1038/nbt.1630 · Cited by 4,502 · see citing works
Three-dimensional Epigenome Statistical Model: Genome-wide Chromatin Looping Prediction
Bkhetan, Z. A., & Plewczyński, D. (2018) · Scientific Reports · doi:10.1038/s41598-018-23276-8 · Cited by 1,667 · see citing works
Transcriptional enhancers: from properties to genome-wide predictions
Shlyueva, D., Stampfel, G., & Stark, A. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3682 · Cited by 1,356 · see citing works
GeneHancer: genome-wide integration of enhancers and target genes in GeneCards
Fishilevich, S., Nudel, R., Rappaport, N., Hadar, R., Plaschkes, I., Stein, T. I., Rosen, N., Kohn, A., Twik, M., Safran, M., et al. (2017) · Database · doi:10.1093/database/bax028 · Cited by 1,219 · see citing works
Hedgehog: functions and mechanisms
Varjosalo, M., & Taipale, J. (2008) · Genes & Development · doi:10.1101/gad.1693608 · Cited by 1,217 · see citing works
In vivo enhancer analysis of human conserved non-coding sequences
Pennacchio, L. A., Ahituv, N., Moses, A. M., Prabhakar, S., Nobrega, M. A., Shoukry, M., Minovitsky, S., Dubchak, I., Holt, A., Lewis, K. D., et al. (2006) · Nature · doi:10.1038/nature05295 · Cited by 1,165 · see citing works
Long-range enhancer–promoter contacts in gene expression control
Schoenfelder, S., & Fraser, P. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0128-0 · Cited by 1,102 · see citing works
Tian, F., Bradbury, P. J., Brown, P. J., Hung, H., Sun, Q., Flint-Garcia, S. A., Rocheford, T., McMullen, M. D., Holland, J. B., & Buckler, E. S. (2011) · Nature Genetics · doi:10.1038/ng.746 · Cited by 1,046 · see citing works
The selection and function of cell type-specific enhancers
Heinz, S., Romanoski, C. E., Benner, C., & Glass, C. K. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3949 · Cited by 1,010 · see citing works
Transcriptional Regulatory Elements in the Human Genome
Maston, G. A., Evans, S. K., & Green, M. R. (2006) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.7.080505.115623 · Cited by 937 · see citing works
Highly Conserved Non-Coding Sequences Are Associated with Vertebrate Development
Woolfe, A., Goodson, M., Goode, D. K., Snell, P., McEwen, G. K., Vavouri, T., Smith, S. F., North, P., Callaway, H., Kelly, K., et al. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0030007 · Cited by 970 · 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
Long-Range Control of Gene Expression: Emerging Mechanisms and Disruption in Disease
Kleinjan, D. A., & van Heyningen, V. (2004) · The American Journal of Human Genetics · doi:10.1086/426833 · Cited by 868 · see citing works
Functional and Mechanistic Diversity of Distal Transcription Enhancers
Bulger, M., & Groudine, M. (2011) · Cell · doi:10.1016/j.cell.2011.01.024 · Cited by 803 · see citing works
MicroRNA expression and function in cancer
Garzon, R., Fabbri, M., Cimmino, A., Calin, G. A., & Croce, C. M. (2006) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2006.10.006 · Cited by 782 · see citing works
Chromosome 21 and Down syndrome: from genomics to pathophysiology
Antonarakis, S. E., Lyle, R., Dermitzakis, E. T., Reymond, A., & Deutsch, S. (2004) · Nature Reviews Genetics · doi:10.1038/nrg1448 · Cited by 703 · see citing works
Determinants of enhancer and promoter activities of regulatory elements
Andersson, R., & Sandelin, A. (2020) · Nature Reviews Genetics · doi:10.1038/s41576-019-0173-8 · Cited by 713 · see citing works
Genomic views of distant-acting enhancers
Visel, A., Rubin, E. M., & Pennacchio, L. A. (2009) · Nature · doi:10.1038/nature08451 · Cited by 610 · see citing works
Smith, J. J., Kuraku, S., Holt, C., Sauka‐Spengler, T., Jiang, N., Campbell, M. S., Yandell, M. D., Manousaki, T., Meyer, A., Bloom, O., et al. (2013) · Nature Genetics · doi:10.1038/ng.2568 · Cited by 618 · see citing works
Enhancers: five essential questions
Pennacchio, L. A., Bickmore, W. A., Dean, A., Nóbrega, M. A., & Bejerano, G. (2013) · Nature Reviews Genetics · doi:10.1038/nrg3458 · Cited by 584 · see citing works
Needles in stacks of needles: finding disease-causal variants in a wealth of genomic data
Cooper, G. M., & Shendure, J. (2011) · Nature Reviews Genetics · doi:10.1038/nrg3046 · Cited by 563 · see citing works
Hu, Z., Zhu, D., Wang, W., Li, W., Jia, W., Zeng, X., Ding, W., Yu, L., Wang, X., Wang, L., et al. (2015) · Nature Genetics · doi:10.1038/ng.3178 · Cited by 568 · see citing works
Ovcharenko, I., Nobrega, M. A., Loots, G. G., & Stubbs, L. (2004) · Nucleic Acids Research · doi:10.1093/nar/gkh355 · Cited by 519 · see citing works
Topology of mammalian developmental enhancers and their regulatory landscapes
de Laat, W., & Duboule, D. (2013) · Nature · doi:10.1038/nature12753 · Cited by 521 · see citing works
Genome-Wide Associations of Gene Expression Variation in Humans
Stranger, B. E., Forrest, M. S., Clark, A. G., Minichiello, M. J., Deutsch, S., Lyle, R., Hunt, S. E., Kahl, B. F., Antonarakis, S. E., Tavaré, S., et al. (2005) · PLoS Genetics · doi:10.1371/journal.pgen.0010078 · Cited by 519 · see citing works
Methods for mapping 3D chromosome architecture
Kempfer, R., & Pombo, A. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0195-2 · Cited by 502 · see citing works
Strategies for mapping and cloning quantitative trait genes in rodents
Jonathan Flint, C., Valdar, W. S. J., Shifman, S., & Mott, R. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1576 · Cited by 497 · see citing works
Enhancer-promoter interactions are encoded by complex genomic signatures on looping chromatin
Whalen, S., Truty, R. M., & Pollard, K. S. (2016) · Nature Genetics · doi:10.1038/ng.3539 · Cited by 456 · see citing works
Vertebrate limb bud development: moving towards integrative analysis of organogenesis
Zeller, R., López-Ríos, J., & Zuniga, A. (2009) · Nature reviews genetics · doi:10.1038/nrg2681 · Cited by 469 · see citing works
The 3D genome in transcriptional regulation and pluripotency
Gorkin, D. U., Leung, D., & Ren, B. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.05.017 · Cited by 391 · see citing works
Deep intronic mutations and human disease
Vaz‐Drago, R., Custódio, N., & Carmo‐Fonseca, M. (2017) · Human Genetics · doi:10.1007/s00439-017-1809-4 · Cited by 448 · see citing works
Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease
Loots, G. G., Kneissel, M., Keller, H., Baptist, M., Chang, J., Collette, N. M., Ovcharenko, D., Plajzer-Frick, I., & Rubin, E. M. (2005) · Genome Research · doi:10.1101/gr.3437105 · Cited by 442 · see citing works
Breaking TADs: How Alterations of Chromatin Domains Result in Disease
Lupiáñez, D. G., Spielmann, M., & Mundlos, S. (2016) · Trends in Genetics · doi:10.1016/j.tig.2016.01.003 · Cited by 439 · see citing works
Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence
Benko, S., Fantes, J. A., Amiel, J., Kleinjan, D., Thomas, S., Ramsay, J. K., Jamshidi, N., Essafi, A., Heaney, S. J. H., Gordon, C. T., et al. (2009) · Nature Genetics · doi:10.1038/ng.329 · Cited by 430 · see citing works
Noncoding Transcription at Enhancers: General Principles and Functional Models
Natoli, G., & Andrau, J. (2012) · Annual Review of Genetics · doi:10.1146/annurev-genet-110711-155459 · Cited by 395 · 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
The role of enhancers in cancer
Sur, I., & Taipale, J. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.62 · Cited by 382 · see citing works
Sagai, T., Hosoya, M., Mizushina, Y., Tamura, M., & Shiroishi, T. (2005) · Development · doi:10.1242/dev.01613 · Cited by 379 · see citing works
A compendium of promoter-centered long-range chromatin interactions in the human genome
Jung, I., Schmitt, A., Diao, Y., Lee, A. J., Liu, T., Yang, D., Tan, C., Eom, J., Chan, M., Chee, S., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0494-8 · Cited by 362 · see citing works
Mechanisms of enhancer action: the known and the unknown
Panigrahi, A., & O’Malley, B. W. (2021) · Genome biology · doi:10.1186/s13059-021-02322-1 · Cited by 351 · see citing works
Progressive Loss of Function in a Limb Enhancer during Snake Evolution
Kvon, E. Z., Kamneva, O. K., Melo, U. S., Barozzi, I., Osterwalder, M., Mannion, B. J., Tissières, V., Pickle, C. S., Plajzer-Frick, I., Lee, E. A., et al. (2016) · Cell · doi:10.1016/j.cell.2016.09.028 · Cited by 339 · see citing works
Regulation of disease-associated gene expression in the 3D genome
Krijger, P. H. L., & de Laat, W. L. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.138 · Cited by 316 · see citing works
Enhancer biology and enhanceropathies
Smith, E. R., & Shilatifard, A. (2014) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2784 · Cited by 310 · see citing works
Remote control of gene transcription
West, A. G., & Fraser, P. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi104 · Cited by 302 · see citing works
De novo mutations in regulatory elements in neurodevelopmental disorders
Short, P. J., McRae, J. F., Gallone, G., Sifrim, A., Won, H., Geschwind, D. H., Wright, C. F., Firth, H. V., FitzPatrick, D. R., Barrett, J. C., et al. (2018) · Nature · doi:10.1038/nature25983 · Cited by 274 · see citing works
Mulan: Multiple-sequence local alignment and visualization for studying function and evolutionPreprint
Ovcharenko, I., Loots, G. G., Giardine, B. M., Hou, M., Ma, J., Hardison, R. C., Stubbs, L. J., & Miller, W. (2004) · Genome Research · doi:10.1101/gr.3007205 · Cited by 275 · see citing works
Galli, A., Robay, D., Osterwalder, M., Bao, X., Bénazet, J.-D., Tariq, M., Paro, R., Mackem, S., & Zeller, R. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1000901 · Cited by 270 · see citing works
Amano, T., Sagai, T., Tanabe, H., Mizushina, Y., Nakazawa, H., & Shiroishi, T. (2009) · Developmental Cell · doi:10.1016/j.devcel.2008.11.011 · Cited by 268 · see citing works
Turner, T. N., Hormozdiari, F., Duyzend, M., McClymont, S. A., Hook, P. W., Iossifov, I. H., Raja, A. N., Baker, C. A., Hoekzema, K., Stessman, H. A. F., et al. (2015) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2015.11.023 · Cited by 263 · see citing works
Conserved non-genic sequences — an unexpected feature of mammalian genomes
Dermitzakis, E. T., Reymond, A., & Antonarakis, S. E. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1527 · Cited by 261 · see citing works
Comparative genomics at the vertebrate extremes
Boffelli, D., Nóbrega, M. A., & Rubin, E. M. (2004) · Nature Reviews Genetics · doi:10.1038/nrg1350 · Cited by 256 · see citing works
Kayser, M., Liu, F., Janssens, A. C. J. W., Rivadeneira, F., Lao, O., van Duijn, K., Vermeulen, M., Arp, P., Jhamai, M. M., van IJcken, W. F. J., et al. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2007.10.003 · Cited by 260 · see citing works
Mouse regulatory DNA landscapes reveal global principles of cis-regulatory evolution
Vierstra, J. D., Rynes, E., Sandstrom, R. S., Zhang, M., Canfield, T. K., Hansen, R. S., Stehling-Sun, S., Sabo, P. J., Byron, R., Humbert, R., et al. (2014) · Science · doi:10.1126/science.1246426 · Cited by 253 · see citing works
A High-Resolution Enhancer Atlas of the Developing Telencephalon
Visel, A., Taher, L., Girgis, H., May, D., Golonzhka, O., Hoch, R. V., McKinsey, G. L., Pattabiraman, K., Silberberg, S. N., Blow, M. J., et al. (2013) · Cell · doi:10.1016/j.cell.2012.12.041 · Cited by 257 · see citing works
Kern, C., Wang, Y., Xu, X., Pan, Z., Halstead, M. M., Chanthavixay, G., Saelao, P., Waters, S., Xiang, R., Chamberlain, A. J., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22100-8 · Cited by 249 · see citing works
Yip, K. Y.-L., Cheng, C., Bhardwaj, N., Brown, J., Leng, J., Kundaje, A. B., Rozowsky, J. S., Birney, E., Bickel, P. J., Snyder, M. P., et al. (2012) · Genome biology · doi:10.1186/gb-2012-13-9-r48 · Cited by 244 · see citing works
Genomic approaches towards finding cis-regulatory modules in animals
Hardison, R. C., & Taylor, J. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3242 · Cited by 234 · see citing works
Enhancer variants: evaluating functions in common disease
Corradin, O., & Scacheri, P. C. (2014) · Genome Medicine · doi:10.1186/s13073-014-0085-3 · Cited by 241 · see citing works
Cheng, Y., Wu, W., Ashok Kumar, S., Yu, D., Deng, W., Tripic, T., King, D. C., Chen, K.-B., Zhang, Y., Drautz, D., et al. (2009) · Genome Research · doi:10.1101/gr.098921.109 · Cited by 223 · see citing works
Jeong, Y., El-Jaick, K. B., Roessler, E., Muenke, M., & Epstein, D. J. (2006) · Development · doi:10.1242/dev.02239 · Cited by 227 · see citing works
An Overview of Genome Organization and How We Got There: from FISH to Hi-C
Fraser, J., Williamson, I., Bickmore, W. A., & Dostie, J. (2015) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00006-15 · Cited by 218 · see citing works
Evaluating Enhancer Function and Transcription
Field, A. R., & Adelman, K. (2020) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-011420-095916 · Cited by 218 · see citing works
Transcription in Living Cells: Molecular Mechanisms of Bursting
Rodriguez, J., & Larson, D. R. (2020) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-011520-105250 · Cited by 224 · see citing works
Replication and transcription: Shaping the landscape of the genome
Chakalova, L., Debrand, E., Mitchell, J. A., Osborne, C. S., & Fraser, P. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1673 · Cited by 218 · see citing works
Symmons, O., Pan, L., Remeseiro, S., Aktas, T., Klein, F., Huber, W., & Spitz, F. (2016) · Developmental Cell · doi:10.1016/j.devcel.2016.10.015 · Cited by 222 · 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
Fabp7 Maps to a Quantitative Trait Locus for a Schizophrenia Endophenotype
Watanabe, A., Toyota, T., Owada, Y., Hayashi, T., Iwayama, Y., Matsumata, M., Ishitsuka, Y., Nakaya, A., Maekawa, M., Ohnishi, T., et al. (2007) · PLoS Biology · doi:10.1371/journal.pbio.0050297 · Cited by 218 · see citing works
Megabase deletions of gene deserts result in viable mice
Nóbrega, M. A., Zhu, Y., Plajzer-Frick, I., Afzal, V., & Rubin, E. M. (2004) · Nature · doi:10.1038/nature03022 · Cited by 214 · see citing works
Beyond the zebrafish: diverse fish species for modeling human disease
Schartl, M. (2013) · Disease Models & Mechanisms · doi:10.1242/dmm.012245 · Cited by 214 · see citing works
Long non‐coding RNA modifies chromatin
Saxena, A., & Carninci, P. (2011) · BioEssays · doi:10.1002/bies.201100084 · Cited by 211 · see citing works
Developmental Biology and Classification of Congenital Anomalies of the Hand and Upper Extremity
Oberg, K. C., Feenstra, J. M., Manske, P. R., & Tonkin, M. A. (2010) · The Journal Of Hand Surgery · doi:10.1016/j.jhsa.2010.09.031 · Cited by 210 · see citing works
Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease
Smemo, S., Campos, L. C. G., Moskowitz, I. P. G., Krieger, J. E., Pereira, A. C., & Nóbrega, M. A. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds165 · Cited by 204 · see citing works
Sequence determinants of human gene regulatory elements
Sahu, B., Hartonen, T., Pihlajamaa, P., Wei, B., Dave, K., Zhu, F., Kaasinen, E., Lidschreiber, K., Lidschreiber, M., Daub, C. O., et al. (2022) · Nature Genetics · doi:10.1038/s41588-021-01009-4 · Cited by 198 · see citing works
Cellular and molecular mechanisms of Hedgehog signalling
Zhang, Y., & Beachy, P. A. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-023-00591-1 · Cited by 203 · see citing works
Ebbert, M., Jensen, T. D., Jansen‐West, K. R., Sens, J. P., Reddy, J. S., Ridge, P. G., Kauwe, J. S. K., Belzil, V., Pregent, L., Carrasquillo, M. M., et al. (2019) · Genome biology · doi:10.1186/s13059-019-1707-2 · Cited by 192 · see citing works
Moorthy, S. D., Davidson, S., Shchuka, V. M., Singh, G., Malek-Gilani, N., Langroudi, L., Martchenko, A., So, V., Macpherson, N. N., & Mitchell, J. A. (2016) · Genome Research · doi:10.1101/gr.210930.116 · Cited by 190 · see citing works
A <i>Sox2</i> distal enhancer cluster regulates embryonic stem cell differentiation potential
Zhou, H. Y., Katsman, Y., Dhaliwal, N. K., Davidson, S., Macpherson, N. N., Sakthidevi, M., Collura, F., & Mitchell, J. A. (2014) · Genes & Development · doi:10.1101/gad.248526.114 · Cited by 192 · see citing works
Ron, G., Globerson, Y., Moran, D., & Kaplan, T. (2017) · Nature Communications · doi:10.1038/s41467-017-02386-3 · Cited by 182 · see citing works
Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics
Cooper, D. N., Chen, J., Ball, E. V., Howells, K., Mort, M. E., Phillips, A. D., Chuzhanova, N. A., Krawczak, M., Kehrer‐Sawatzki, H., & Stenson, P. D. (2010) · Human Mutation · doi:10.1002/humu.21260 · Cited by 181 · see citing works
Velagaleti, G. V. N., Bien-Willner, G. A., Northup, J. K., Lockhart, L. H., Hawkins, J. C., Jalal, S. M., Withers, M. A., Lupski, J. R., & Stankiewicz, P. (2005) · The American Journal of Human Genetics · doi:10.1086/429252 · Cited by 183 · see citing works
Paliou, C., Guckelberger, P., Schöpflin, R., Heinrich, V., Esposito, A., Chiariello, A. M., Bianco, S., Annunziatella, C., Helmuth, J., Haas, S., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1900672116 · Cited by 163 · see citing works
Subfunctionalization of Duplicated Zebrafish pax6 Genes by cis-Regulatory Divergence
Kleinjan, D. A., Bancewicz, R. M., Gautier, P. E., Dahm, R., Schönthaler, H. B., Damante, G., Seawright, A., Hever, A. M., Yeyati, P. L., van Heyningen, V., et al. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.0040029 · Cited by 179 · see citing works
Kouwenhoven, E. N., van Heeringen, S. J., Tena, J. J., Oti, M., Dutilh, B. E., Alonso, M. E., de la Calle‐Mustienes, E., Smeenk, L., Rinne, T., Parsaulian, L., et al. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001065 · Cited by 179 · see citing works
A Muscle-Specific Enhancer RNA Mediates Cohesin Recruitment and Regulates Transcription In trans
Tsai, P.-F., Dell’Orso, S., Rodriguez, J., Vivanco, K. O., Ko, K.-D., Jiang, K., Juan, A. H., Sarshad, A. A., Vian, L., Tran, M. D., et al. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.06.008 · Cited by 178 · see citing works
Merla, G., Howald, C., Hor, C. N., Lyle, R., Wyss, C., Zabot, M. T., Antonarakis, S. E., & Reymond, A. (2006) · The American Journal of Human Genetics · doi:10.1086/506371 · Cited by 178 · see citing works
Capellini, T. D., Giacomo, G. D., Salsi, V., Brendolan, A., Ferretti, E., Srivastava, D., Zappavigna, V., & Selleri, L. (2006) · Development · doi:10.1242/dev.02395 · Cited by 178 · see citing works
Close sequence comparisons are sufficient to identify human cis -regulatory elementsPreprint
Prabhakar, S., Poulin, F., Shoukry, M. I., Afzal, V., Rubin, E. M., Couronne, O., & Pennacchio, L. A. (2006) · Genome Research · doi:10.1101/gr.4717506 · Cited by 177 · see citing works
Lettice, L. A., Hill, A. E., Devenney, P. S., & Hill, R. E. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm370 · Cited by 172 · see citing works
Self-citationComprehensive In Vivo Interrogation Reveals Phenotypic Impact of Human Enhancer Variants
Kvon, E. Z., Zhu, Y., Kelman, G., Novak, C. S., Plajzer-Frick, I., Kato, M., Garvin, T. H., Pham, Q. T., Harrington, A. N., Hunter, R. D., et al. (2020) · Cell · doi:10.1016/j.cell.2020.02.031 · Cited by 161 · see citing works
Identification of a chronic obstructive pulmonary disease genetic determinant that regulates HHIP
Zhou, X., Baron, R. M., Hardin, M. E., Cho, M. H., Zielinski, J., Hawryłkiewicz, I., Śliwiński, P., Hersh, C. P., Mancini, J. D., Lu, K., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr569 · Cited by 173 · see citing works
Gli Proteins: Regulation in Development and Cancer
Niewiadomski, P., Niedziółka, S. M., Markiewicz, Ł., Uśpieński, T., Baran, B., & Chojnowska, K. (2019) · Cells · doi:10.3390/cells8020147 · Cited by 175 · see citing works
Loss of Extreme Long-Range Enhancers in Human Neural Crest Drives a Craniofacial Disorder
Long, H. K., Osterwalder, M., Welsh, I. C., Hansen, K. L., Davies, J. O. J., Liu, Y. E., Koska, M., Adams, A. T., Aho, R., Arora, N., et al. (2020) · Cell stem cell · doi:10.1016/j.stem.2020.09.001 · Cited by 160 · see citing works
Peterson, K. A., Nishi, Y., Ma, W., Vedenko, A., Shokri, L., Zhang, X., McFarlane, M., Baizabal, J., Junker, J. P., van Oudenaarden, A., et al. (2012) · Genes & Development · doi:10.1101/gad.207142.112 · Cited by 169 · see citing works
Long-range regulation at the SOX9 locus in development and disease: Figure 1
Gordon, C. T., Tan, T. Y., Benko, S., FitzPatrick, D. R., Lyonnet, S., & Farlie, P. G. (2009) · Journal of Medical Genetics · doi:10.1136/jmg.2009.068361 · Cited by 163 · see citing works
Genomics of Long-Range Regulatory Elements
Noonan, J. P., & McCallion, A. S. (2010) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-082509-141651 · Cited by 159 · see citing works
How subtle changes in 3D structure can create large changes in transcription
Xiao, J. Y., Hafner, A., & Boettiger, A. N. (2021) · eLife · doi:10.7554/elife.64320 · Cited by 162 · see citing works
Evolutionary mutant models for human disease
Albertson, R. C., Cresko, W. A., Detrich, H. W., & Postlethwait, J. H. (2008) · Trends in Genetics · doi:10.1016/j.tig.2008.11.006 · Cited by 158 · see citing works
Genomic Perspectives of Transcriptional Regulation in Forebrain Development
Nord, A. S., Pattabiraman, K., Visel, A., & Rubenstein, J. L. R. (2015) · Neuron · doi:10.1016/j.neuron.2014.11.011 · Cited by 152 · see citing works
Ruf, S., Symmons, O., Uslu, V. V., Dolle, D. D., Hot, C., Ettwiller, L. M., & Spitz, F. (2011) · Nature Genetics · doi:10.1038/ng.790 · Cited by 157 · see citing works
Enhancer grammar in development, evolution, and disease: dependencies and interplay
Jindal, G. A., & Farley, E. K. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.02.016 · Cited by 147 · see citing works
- Authors
- Lettice, L. A.
- Affiliations
- Western General Hospital (GB)
- Corresponding author
- Lettice, L. A.
- ORCID
- Lettice, L. A.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2003-07-15
- Volume
- 12
- Issue
- 14
- Pages
- 1725-1735
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2145144631
- Cited by
- 1,164
- References
- 35
- Citations by year
- 2026: 26 · 2025: 40 · 2024: 50 · 2023: 58 · 2022: 66 · 2021: 78 · 2020: 52 · 2019: 49 · 2018: 50 · 2017: 50 · 2016: 64 · 2015: 56 · 2014: 78 · 2013: 64 · 2012: 60
- FWCI
- 26.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Lirias (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Keywords
- Sonic hedgehog, preaxial polydactyly, limb bud, fin development, zirconium, LMBR1, point mutations, congenital limb anomalies, chromosome 7q36
- MeSH terms
- Zona Pellucida Glycoproteins, Animals, Base Sequence, Chromosomes, Human, Pair 7, Egg Proteins, Enhancer Elements, Genetic, Extremities, Female, Humans, Male, Membrane Glycoproteins, Membrane Proteins, Molecular Sequence Data, Pedigree, Receptors, Cell Surface, Trans-Activators, Polydactyly, Takifugu, Mice, Hedgehog Proteins
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
