{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T16:41:41Z","timestamp":1776184901598,"version":"3.50.1"},"reference-count":87,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2016,2,17]],"date-time":"2016-02-17T00:00:00Z","timestamp":1455667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JDB"],"abstract":"<jats:p>HoxA genes encode for important DNA-binding transcription factors that act during limb development, regulating primarily gene expression and, consequently, morphogenesis and skeletal differentiation. Within these genes, HoxA11 and HoxA13 were proposed to have played an essential role in the enigmatic evolutionary transition from fish fins to tetrapod limbs. Indeed, comparative gene expression analyses led to the suggestion that changes in their regulation might have been essential for the diversification of vertebrates\u2019 appendages. In this review, we highlight three potential modifications in the regulation and function of these genes that may have boosted appendage evolution: (1) the expansion of polyalanine repeats in the HoxA11 and HoxA13 proteins; (2) the origin of +a novel long-non-coding RNA with a possible inhibitory function on HoxA11; and (3) the acquisition of cis-regulatory elements modulating 5\u2019 HoxA transcription. We discuss the relevance of these mechanisms for appendage diversification reviewing the current state of the art and performing additional comparative analyses to characterize, in a phylogenetic framework, HoxA11 and HoxA13 expression, alanine composition within the encoded proteins, long-non-coding RNAs and cis-regulatory elements.<\/jats:p>","DOI":"10.3390\/jdb4010010","type":"journal-article","created":{"date-parts":[[2016,2,18]],"date-time":"2016-02-18T22:19:47Z","timestamp":1455833987000},"page":"10","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["HoxA Genes and the Fin-to-Limb Transition in Vertebrates"],"prefix":"10.3390","volume":"4","author":[{"given":"Jo\u00e3o","family":"Leite-Castro","sequence":"first","affiliation":[{"name":"IBMC\u2014Instituto de Biologia Celular e Molecular, Oporto, Portugal"}]},{"given":"Vanessa","family":"Beviano","sequence":"additional","affiliation":[{"name":"IBMC\u2014Instituto de Biologia Celular e Molecular, Oporto, Portugal"},{"name":"I3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3799-1544","authenticated-orcid":false,"given":"Pedro","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"IBMC\u2014Instituto de Biologia Celular e Molecular, Oporto, Portugal"},{"name":"I3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal"},{"name":"ICBAS\u2014Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, University of Oporto, Rua de Jorge Viterbo Ferreira n\u00b0. 228, 4050-313 Oporto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0123-7232","authenticated-orcid":false,"given":"Renata","family":"Freitas","sequence":"additional","affiliation":[{"name":"IBMC\u2014Instituto de Biologia Celular e Molecular, Oporto, Portugal"},{"name":"I3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2016,2,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1038\/nature07891","article-title":"Deep homology and the origins of evolutionary novelty","volume":"457","author":"Shubin","year":"2009","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1046\/j.1525-142X.2002.02026.x","article-title":"Fins to limbs: What the fossils say","volume":"4","author":"Coates","year":"2002","journal-title":"Evol. Dev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/978-1-4615-1847-1_2","article-title":"The evolution of paired fins and the origin of tetrapod limbs\u2014Phylogenetic and transformational approaches","volume":"28","author":"Shubin","year":"1995","journal-title":"Evol. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Janvier, P. (1996). Early Vertebrates, Oxford University Press.","DOI":"10.1093\/oso\/9780198540472.001.0001"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1038\/nature07339","article-title":"The pectoral fin of Panderichthys and the origin of digits","volume":"456","author":"Boisvert","year":"2008","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/347066a0","article-title":"Polydactyly in the earliest known tetrapod limbs","volume":"347","author":"Coates","year":"1990","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Coates, M.I. (1994). The origin of vertebrate limbs. Dev. Suppl., 169\u2013180.","DOI":"10.1242\/dev.1994.Supplement.169"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"13695","DOI":"10.1073\/pnas.94.25.13695","article-title":"Regulation of number and size of digits by posterior Hox genes: A dose-dependent mechanism with potential evolutionary implications","volume":"94","author":"Zakany","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Delgado, I., and Torres, M. (2016). Gradients, waves and timers, an overview of limb patterning models. Semin. Cell Dev. Biol.","DOI":"10.1016\/j.semcdb.2015.12.016"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/nrg2681","article-title":"Vertebrate limb bud development: Moving towards integrative analysis of organogenesis","volume":"10","author":"Zeller","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1038\/nature06876","article-title":"Genetic evidence that FGFs have an instructive role in limb proximal-distal patterning","volume":"453","author":"Mariani","year":"2008","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1126\/science.1199499","article-title":"Initiation of proximal-distal patterning in the vertebrate limb by signals and growth","volume":"332","author":"Cooper","year":"2011","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/S0925-4773(98)00176-2","article-title":"The development of the paired fins in the zebrafish (Danio rerio)","volume":"79","author":"Grandel","year":"1998","journal-title":"Mech. Dev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"15940","DOI":"10.1073\/pnas.1521818112","article-title":"Molecular mechanisms underlying the exceptional adaptations of batoid fins","volume":"112","author":"Nakamura","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2916","DOI":"10.1242\/dev.075572","article-title":"Mechanism of pectoral fin outgrowth in zebrafish development","volume":"139","author":"Yano","year":"2012","journal-title":"Development"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.ydbio.2009.11.026","article-title":"Analysis of hoxa11 and hoxa13 expression during patternless limb regeneration in Xenopus","volume":"338","author":"Ohgo","year":"2010","journal-title":"Dev. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.ydbio.2008.06.032","article-title":"Tri-phasic expression of posterior Hox genes during development of pectoral fins in zebrafish: Implications for the evolution of vertebrate paired appendages","volume":"322","author":"Ahn","year":"2008","journal-title":"Dev. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1126\/science.1226804","article-title":"Hox genes regulate digit patterning by controlling the wavelength of a turing-type mechanism","volume":"338","author":"Sheth","year":"2012","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1038\/nature05247","article-title":"Regulatory constraints in the evolution of the tetrapod limb anterior-posterior polarity","volume":"443","author":"Tarchini","year":"2006","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/0092-8674(93)90378-4","article-title":"Disruption of the Hoxd-13 gene induces localized heterochrony leading to mice with neotenic limbs","volume":"75","author":"Dolle","year":"1993","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/375678a0","article-title":"Hox gene expression in teleost fins and the origin of vertebrate digits","volume":"375","author":"Sordino","year":"1995","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1016\/j.devcel.2012.10.015","article-title":"Hoxd13 contribution to the evolution of vertebrate appendages","volume":"23","author":"Freitas","year":"2012","journal-title":"Dev. Cell."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1242\/dev.122.5.1449","article-title":"Analysis of Hox gene expression in the chick limb bud","volume":"122","author":"Nelson","year":"1996","journal-title":"Development"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1002\/dvdy.22183","article-title":"Survival of Hoxa13 homozygous mutants reveals a novel role in digit patterning and appendicular skeletal development","volume":"239","author":"Perez","year":"2010","journal-title":"Dev. Dyn."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4581","DOI":"10.1242\/dev.01327","article-title":"HOXA13 regulates the expression of bone morphogenetic proteins 2 and 7 to control distal limb morphogenesis","volume":"131","author":"Knosp","year":"2004","journal-title":"Development"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1111\/j.1525-142X.2005.05021.x","article-title":"Expression of Hoxa-11 and Hoxa-13 in the pectoral fin of a basal ray-finned fish, Polyodon spathula: Implications for the origin of tetrapod limbs","volume":"7","author":"Metscher","year":"2005","journal-title":"Evol. Dev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1101\/gad.9.20.2509","article-title":"Misexpression of Hoxa-13 induces cartilage homeotic transformation and changes cell adhesiveness in chick limb buds","volume":"9","author":"Yokouchi","year":"1995","journal-title":"Genes Dev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1242\/dev.113.2.431","article-title":"Chicken Homeobox gene Msx-1\u2014Structure, expression in limb buds and effect of retinoic acid","volume":"113","author":"Yokouchi","year":"1991","journal-title":"Development"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/353443a0","article-title":"Homeobox gene-expression correlated with the bifurcation process of limb cartilage development","volume":"353","author":"Yokouchi","year":"1991","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/46580","article-title":"Conserved regulation of proximodistal limb axis development by Meis1\/Hth","volume":"402","author":"Mercader","year":"1999","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1387\/ijdb.072430nm","article-title":"Ectopic Meis1 expression in the mouse limb bud alters P-D patterning in a Pbx1-independent manner","volume":"53","author":"Mercader","year":"2009","journal-title":"Int. J. Dev. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1242\/dev.02822","article-title":"Specification of cell fate along the proximal-distal axis in the developing chick limb bud","volume":"134","author":"Sato","year":"2007","journal-title":"Development"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1101\/gad.1547407","article-title":"Rethinking the proximodistal axis of the vertebrate limb in the molecular era","volume":"21","author":"Tabin","year":"2007","journal-title":"Genes Dev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4817","DOI":"10.1242\/dev.126.21.4817","article-title":"Transient establishment of anteroposterior polarity in the zebrafish pectoral fin bud in the absence of sonic hedgehog activity","volume":"126","author":"Neumann","year":"1999","journal-title":"Development"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Sakamoto, K., Onimaru, K., Munakata, K., Suda, N., Tamura, M., Ochi, H., and Tanaka, M. (2009). Heterochronic shift in Hox-mediated activation of sonic hedgehog leads to morphological changes during fin development. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005121"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/nature05838","article-title":"An autopodial-like pattern of Hox expression in the fins of a basal actinopterygian fish","volume":"447","author":"Davis","year":"2007","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1111\/j.1469-7580.2012.01491.x","article-title":"The making of differences between fins and limbs","volume":"222","author":"Yano","year":"2013","journal-title":"J. Anat."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1002\/jez.b.22563","article-title":"New frontiers in the evolution of fin development","volume":"322","author":"Freitas","year":"2014","journal-title":"J. Exp. Zool. B Mol. Dev. Evol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1126\/science.1241796","article-title":"Progressive specification rather than intercalation of segments during limb regeneration","volume":"342","author":"Roensch","year":"2013","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s003350010029","article-title":"Evolution of N-terminal sequences of the vertebrate HOXA13 protein","volume":"11","author":"Mortlock","year":"2000","journal-title":"Mamm. Genome"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1006\/mpev.2000.0837","article-title":"Evolution of Hoxa-11 in lineages phylogenetically positioned along the fin-limb transition","volume":"17","author":"Chiu","year":"2000","journal-title":"Mol. Phylogenet. Evol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1007\/s003359900870","article-title":"Evolutionary conservation and tissue-specific processing of Hoxa 11 antisense transcripts","volume":"9","author":"Potter","year":"1998","journal-title":"Mamm. Genome"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1073\/pnas.1420208112","article-title":"Deep conservation of wrist and digit enhancers in fish","volume":"112","author":"Gehrke","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s00239-009-9305-7","article-title":"The origin of conserved protein domains and amino acid repeats via adaptive competition for control over amino acid residues","volume":"70","author":"Rorick","year":"2010","journal-title":"J. Mol. Evol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1101\/gr.101261.109","article-title":"Natural selection drives the accumulation of amino acid tandem repeats in human proteins","volume":"20","author":"Mularoni","year":"2010","journal-title":"Genome Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"18058","DOI":"10.1073\/pnas.0408118101","article-title":"Molecular origins of rapid and continuous morphological evolution","volume":"101","author":"Fondon","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1111\/j.1525-142X.2008.00254.x","article-title":"Expanded HOXA13 polyalanine tracts in a monotreme","volume":"10","author":"Lehoczky","year":"2008","journal-title":"Evol. Dev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/0168-9525(96)10022-6","article-title":"Active repression mechanisms of eukaryotic transcription repressors","volume":"12","author":"HannaRose","year":"1996","journal-title":"Trends Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2967","DOI":"10.1093\/hmg\/ddg329","article-title":"Polymorphism, shared functions and convergent evolution of genes with sequences coding for polyalanine domains","volume":"12","author":"Lavoie","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e49","DOI":"10.1136\/jmg.40.4.e49","article-title":"A novel duplication in the HOXA13 gene in a family with atypical hand-foot-genital syndrome","volume":"40","author":"Frisen","year":"2003","journal-title":"J. Med. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1093\/molbev\/msl161","article-title":"Morphological change caused by loss of the taxon-specific polyalanine tract in Hoxd-13","volume":"24","author":"Anan","year":"2007","journal-title":"Mol. Biol. Evol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1093\/hmg\/7.6.1033","article-title":"A new spontaneous mouse mutation of Hoxd13 with a polyalanine expansion and phenotype similar to human synpolydactyly","volume":"7","author":"Johnson","year":"1998","journal-title":"Hum. Mol. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1006\/dbio.2001.0382","article-title":"The mouse Hoxd13(spdh) mutation, a polyalanine expansion similar to human type II synpolydactyly (SPD), disrupts the function but not the expression of other Hoxd genes","volume":"237","author":"Bruneau","year":"2001","journal-title":"Dev. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1002\/ajmg.10776","article-title":"Limb malformations and the human HOX genes","volume":"112","author":"Goodman","year":"2002","journal-title":"Am. J. Med. Genet."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/ng0297-179","article-title":"Mutation of HOXA13 in hand-foot-genital syndrome","volume":"15","author":"Mortlock","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2841","DOI":"10.1093\/hmg\/ddh306","article-title":"Polyalanine expansion in HOXA13: Three new affected families and the molecular consequences in a mouse model","volume":"13","author":"Innis","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1242\/dev.121.5.1373","article-title":"Hoxa 11 structure, extensive antisense transcription, and function in male and female fertility","volume":"121","author":"Witte","year":"1995","journal-title":"Development"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2947","DOI":"10.1093\/bioinformatics\/btm404","article-title":"Clustal W and Clustal X version 2.0","volume":"23","author":"Larkin","year":"2007","journal-title":"Bioinformatics"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1006\/dbio.1998.8956","article-title":"Expression of HoxD genes in developing and regenerating axolotl limbs","volume":"200","author":"Torok","year":"1998","journal-title":"Dev. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1002\/dvdy.24351","article-title":"Xenopus limb bud morphogenesis","volume":"245","author":"Keenan","year":"2016","journal-title":"Dev. Dyn."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1469-185X.2006.00001.x","article-title":"The anuran Bauplan: A review of the adaptive, developmental, and genetic underpinnings of frog and tadpole morphology","volume":"82","author":"Handrigan","year":"2007","journal-title":"Biol. Rev. Camb. Philos. Soc."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1126\/science.2667136","article-title":"Transcriptional regulation in mammalian-cells by sequence-specific dna-binding proteins","volume":"245","author":"Mitchell","year":"1989","journal-title":"Science"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1002\/jez.b.21061","article-title":"Repressor domain and nuclear localization signal of the murine Hoxa-11 protein are located in the homeodomain, no evidence for role of poly alanine stretches in transcriptional repression","volume":"304","author":"Roth","year":"2005","journal-title":"J. Exp. Zool. B Mol. Dev. Evol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1093\/genetics\/116.4.607","article-title":"A mouse homeo box gene, Hox-1.5, and the morphological locus, Hd, map to within 1 cM on chromosome 6","volume":"116","author":"Mock","year":"1987","journal-title":"Genetics"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2678","DOI":"10.1128\/MCB.16.6.2678","article-title":"Repression by HoxA7 is mediated by the homeodomain and the modulatory action of its N-terminal-arm residues","volume":"16","author":"Schnabel","year":"1996","journal-title":"Mol. Cell. Biol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Berlivet, S., Paquette, D., Dumouchel, A., Langlais, D., Dostie, J., and Kmita, M. (2013). Clustering of tissue-specific sub-TADs accompanies the regulation of HoxA genes in developing limbs. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1004018"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.tig.2013.01.012","article-title":"The origin of the tetrapod limb: From expeditions to enhancers","volume":"29","author":"Schneider","year":"2013","journal-title":"Trends Genet."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1007\/s00239-008-9156-7","article-title":"A molecular footprint of limb loss: Sequence variation of the autopodial identity gene Hoxa-13","volume":"67","author":"Kohlsdorf","year":"2008","journal-title":"J. Mol. Evol."},{"key":"ref_69","first-page":"123","article-title":"Why does a trait evolve multiple times within a clade? Repeated evolution of snakelike body form in squamate reptiles","volume":"60","author":"Wiens","year":"2006","journal-title":"Evolution"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"13904","DOI":"10.1073\/pnas.1308335110","article-title":"Efficient multiplex biallelic zebrafish genome editing using a CRISPR nuclease system","volume":"110","author":"Jao","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.cell.2009.02.006","article-title":"Evolution and functions of long noncoding RNAs","volume":"136","author":"Ponting","year":"2009","journal-title":"Cell"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1093\/cvr\/cvr097","article-title":"Non-coding RNAs as regulators of gene expression and epigenetics","volume":"90","author":"Kaikkonen","year":"2011","journal-title":"Cardiovasc. Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1093\/embo-reports\/kve230","article-title":"Non-coding RNAs: The architects of eukaryotic complexity","volume":"2","author":"Mattick","year":"2001","journal-title":"EMBO Rep."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Yu, H.S., Lindsay, J., Feng, Z.P., Frankenberg, S., Hu, Y., Carone, D., Shaw, G., Pask, A.J., O\u2019Neill, R., and Papenfuss, A.T. (2012). Evolution of coding and non-coding genes in HOX clusters of a marsupial. BMC Genomics, 13.","DOI":"10.1186\/1471-2164-13-251"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1016\/j.celrep.2015.04.023","article-title":"Principles of long noncoding RNA evolution derived from direct comparison of transcriptomes in 17 species","volume":"11","author":"Hezroni","year":"2015","journal-title":"Cell Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"18610","DOI":"10.1073\/pnas.0910374106","article-title":"In ovo application of antagomiRs indicates a role for miR-196 in patterning the chick axial skeleton through Hox gene regulation","volume":"106","author":"McGlinn","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_77","first-page":"77","article-title":"Hox gene regulation in vertebrates","volume":"8","author":"Rodrigues","year":"2014","journal-title":"Trends Dev. Biol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1002\/jcp.21993","article-title":"Genomic organization of microRNAs","volume":"222","author":"Olena","year":"2010","journal-title":"J. Cell. Physiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1016\/j.cell.2007.05.022","article-title":"Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs","volume":"129","author":"Rinn","year":"2007","journal-title":"Cell"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1146\/annurev-biochem-051410-092902","article-title":"Genome regulation by long noncoding RNAs","volume":"81","author":"Rinn","year":"2012","journal-title":"Annu. Rev. Biochem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1080\/10425170290029981","article-title":"Phylogenetic analysis of Hoxa 11 sequences reveals absence of transposable elements, conservation of transcription factor binding sites, and suggests antisense coding function","volume":"13","author":"Bodenmiller","year":"2002","journal-title":"DNA Sequence"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"D749","DOI":"10.1093\/nar\/gkt1196","article-title":"Ensembl 2014","volume":"42","author":"Flicek","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1016\/j.cell.2011.11.055","article-title":"Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution","volume":"147","author":"Ulitsky","year":"2011","journal-title":"Cell"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.ympev.2003.08.009","article-title":"Surveying phylogenetic footprints in large gene clusters: Applications to Hox cluster duplications","volume":"31","author":"Prohaska","year":"2004","journal-title":"Mol. Phylogenet. Evol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1101\/gad.1631708","article-title":"Modeling Hox gene regulation in digits: Reverse collinearity and the molecular origin of thumbness","volume":"22","author":"Montavon","year":"2008","journal-title":"Genes Dev."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Woltering, J.M., Noordermeer, D., Leleu, M., and Duboule, D. (2014). Conservation and divergence of regulatory strategies at Hox Loci and the origin of tetrapod digits. PLoS Biol., 12.","DOI":"10.1371\/journal.pbio.1001773"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Andrey, G., and Duboule, D. (2014). SnapShot: Hox gene regulation. 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