sna

Summary

Gene Symbol: sna
Description: snail
Alias: BG:DS01845.1, CG3956, Dmel\CG3956, SNA, SNAIL, Sco, Sna, br28, br29, l(2)35Db, l(2)br28, l(2)br29, l(3)br28, l35Db, snail, CG3956-PA, scutoid, sna-PA
Species: fruit fly
Products:     sna

Top Publications

  1. Alberga A, Boulay J, Kempe E, Dennefeld C, Haenlin M. The snail gene required for mesoderm formation in Drosophila is expressed dynamically in derivatives of all three germ layers. Development. 1991;111:983-92 pubmed
    The zygotic effect gene snail (sna) encodes a zinc-finger protein required for mesoderm formation in Drosophila embryos...
  2. Ratnaparkhi G, Duong H, Courey A. Dorsal interacting protein 3 potentiates activation by Drosophila Rel homology domain proteins. Dev Comp Immunol. 2008;32:1290-300 pubmed publisher
    ..Chromatin immunoprecipitation experiments in S2 cells indicate the presence of Dip3 at the promoters of these genes, and this binding requires the presence of Rel proteins at these promoters. ..
  3. Francois V, Solloway M, O Neill J, Emery J, Bier E. Dorsal-ventral patterning of the Drosophila embryo depends on a putative negative growth factor encoded by the short gastrulation gene. Genes Dev. 1994;8:2602-16 pubmed
    ..These putative soluble Sog peptides may then diffuse into the dorsal region to antagonize the activity of Dpp, leading to the subdivision of the dorsal territory into amnioserosa and dorsal ectoderm. ..
  4. Ashraf S, Ip Y. The Snail protein family regulates neuroblast expression of inscuteable and string, genes involved in asymmetry and cell division in Drosophila. Development. 2001;128:4757-67 pubmed
    ..b>Snail, a zinc-finger transcriptional repressor, is a pan-neural protein, based on its extensive expression in ..
  5. Stathopoulos A, Levine M. Localized repressors delineate the neurogenic ectoderm in the early Drosophila embryo. Dev Biol. 2005;280:482-93 pubmed
    ..Spatially localized repressors such as Snail and Vnd exclude the expression of neurogenic genes in the mesoderm and ventral neuroectoderm, respectively...
  6. Fontenele M, Carneiro K, Agrellos R, Oliveira D, Oliveira Silva A, Vieira V, et al. The Ca2+-dependent protease Calpain A regulates Cactus/I kappaB levels during Drosophila development in response to maternal Dpp signals. Mech Dev. 2009;126:737-51 pubmed publisher
    ..This mechanism may allow coordination of Toll, BMP and Ca(2+) signals, conferring precision to Dorsal-target expression domains. ..
  7. Liberman L, Reeves G, Stathopoulos A. Quantitative imaging of the Dorsal nuclear gradient reveals limitations to threshold-dependent patterning in Drosophila. Proc Natl Acad Sci U S A. 2009;106:22317-22 pubmed publisher
  8. Kosman D, Ip Y, Levine M, Arora K. Establishment of the mesoderm-neuroectoderm boundary in the Drosophila embryo. Science. 1991;254:118-22 pubmed
    ..of gene expression along the dorsal-ventral axis of early embryos and activates the regulatory genes twist and snail, which are responsible for the differentiation of the ventral mesoderm...
  9. Bronner G, Jackle H. Regulation and function of the terminal gap gene huckebein in the Drosophila blastoderm. Int J Dev Biol. 1996;40:157-65 pubmed
    ..Conversely, ectopic expression of hkb inhibits the formation of the major gastrulation fold which gives rise to the mesoderm and prevents normal segmentation in the ectoderm of the trunk region. ..

More Information

Publications74

  1. Biemar F, Nix D, Piel J, Peterson B, Ronshaugen M, Sementchenko V, et al. Comprehensive identification of Drosophila dorsal-ventral patterning genes using a whole-genome tiling array. Proc Natl Acad Sci U S A. 2006;103:12763-8 pubmed
    ..We discuss the potential functions of these recently identified genes and suggest that intronic enhancers are a common feature of the DV gene network. ..
  2. ten Bosch J, Benavides J, Cline T. The TAGteam DNA motif controls the timing of Drosophila pre-blastoderm transcription. Development. 2006;133:1967-77 pubmed publisher
  3. Zinzen R, Papatsenko D. Enhancer responses to similarly distributed antagonistic gradients in development. PLoS Comput Biol. 2007;3:e84 pubmed
  4. Martin A, Gelbart M, Fernandez Gonzalez R, Kaschube M, Wieschaus E. Integration of contractile forces during tissue invagination. J Cell Biol. 2010;188:735-49 pubmed publisher
    ..Thus, pulsed actomyosin contractions require a supracellular, tensile meshwork to transmit cellular forces to the tissue level during morphogenesis. ..
  5. Ratnaparkhi G, Jia S, Courey A. Uncoupling dorsal-mediated activation from dorsal-mediated repression in the Drosophila embryo. Development. 2006;133:4409-14 pubmed
    ..factor Dorsal patterns the dorsoventral axis of the Drosophila embryo by activating genes such as twist and snail and repressing genes such as decapentaplegic and zerknüllt...
  6. Jia S, Flores Saaib R, Courey A. The Dorsal Rel homology domain plays an active role in transcriptional regulation. Mol Cell Biol. 2002;22:5089-99 pubmed
    ..These results provide some of the first evidence that the RHD plays an active role in transcriptional regulation in intact multicellular organisms. ..
  7. Markstein M, Markstein P, Markstein V, Levine M. Genome-wide analysis of clustered Dorsal binding sites identifies putative target genes in the Drosophila embryo. Proc Natl Acad Sci U S A. 2002;99:763-8 pubmed
    ..These results suggest that bioinformatics can be used to identify novel target genes and associated regulatory DNAs in a gene network. ..
  8. Jennings B, Wainwright S, Ish Horowicz D. Differential in vivo requirements for oligomerization during Groucho-mediated repression. EMBO Rep. 2008;9:76-83 pubmed
    ..Our results show that homo-oligomerization of Gro is not obligatory for its action in vivo, and that Gro represses transcription through more than one molecular mechanism. ..
  9. Mathew S, Rembold M, Leptin M. Role for Traf4 in polarizing adherens junctions as a prerequisite for efficient cell shape changes. Mol Cell Biol. 2011;31:4978-93 pubmed publisher
    ..Traf4 acts in a TNF receptor- and Jun N-terminal protein kinase (JNK)-independent manner to fine-tune the assembly of adherens junctions in the invaginating mesodermal cells...
  10. Lu X, Li J, Elemento O, Tavazoie S, Wieschaus E. Coupling of zygotic transcription to mitotic control at the Drosophila mid-blastula transition. Development. 2009;136:2101-10 pubmed publisher
  11. Park K, Hong J. Mesodermal repression of single-minded in Drosophila embryo is mediated by a cluster of Snail-binding sites proximal to the early promoter. BMB Rep. 2012;45:577-82 pubmed
    ..Recent identification of the mesectoderm enhancer (MSE) of sim has led to the hypothesis that two Snail (Sna)-binding sites in the MSE may repress sim expression in the presumptive mesoderm...
  12. Ray R, Arora K, Nusslein Volhard C, Gelbart W. The control of cell fate along the dorsal-ventral axis of the Drosophila embryo. Development. 1991;113:35-54 pubmed
    ..expression patterns of four zygotic patterning genes: decapentaplegic (dpp), zerknüllt (zen), twist (twi), and snail (sna)...
  13. Leptin M. twist and snail as positive and negative regulators during Drosophila mesoderm development. Genes Dev. 1991;5:1568-76 pubmed
    twist and snail are members of the helix-loop-helix and zinc-finger protein families, respectively, and determine the development of the mesoderm in Drosophila...
  14. Mellerick D, Nirenberg M. Dorsal-ventral patterning genes restrict NK-2 homeobox gene expression to the ventral half of the central nervous system of Drosophila embryos. Dev Biol. 1995;171:306-16 pubmed
    ..The NK-2 gene is not expressed in the mesodermal anlage due to repression by snail, in mesectodermal cells due to repression by single-minded, or in the lateral neuroectodermal and/or dorsal ..
  15. Szymanski P, Levine M. Multiple modes of dorsal-bHLH transcriptional synergy in the Drosophila embryo. EMBO J. 1995;14:2229-38 pubmed
    ..We propose that this linkage requirement provides the basis for the evolution of modular promoters composed of discrete, non-overlapping enhancers. ..
  16. Gray S, Szymanski P, Levine M. Short-range repression permits multiple enhancers to function autonomously within a complex promoter. Genes Dev. 1994;8:1829-38 pubmed
    ..This study centers on a zinc finger repressor, snail (sna), which represses the expression of neuroectodermal regulatory genes in the presumptive mesoderm...
  17. MacArthur S, Li X, Li J, Brown J, Chu H, Zeng L, et al. Developmental roles of 21 Drosophila transcription factors are determined by quantitative differences in binding to an overlapping set of thousands of genomic regions. Genome Biol. 2009;10:R80 pubmed publisher
  18. Dubnicoff T, Valentine S, Chen G, Shi T, Lengyel J, Paroush Z, et al. Conversion of dorsal from an activator to a repressor by the global corepressor Groucho. Genes Dev. 1997;11:2952-7 pubmed
    ..Groucho is therefore a critical component of the dorsal/ventral patterning system. ..
  19. Nibu Y, Zhang H, Bajor E, Barolo S, Small S, Levine M. dCtBP mediates transcriptional repression by Knirps, Krüppel and Snail in the Drosophila embryo. EMBO J. 1998;17:7009-20 pubmed
    ..Here we present evidence that three different repressors, Knirps, Krüppel and Snail, recruit a different co-repressor, dCtBP...
  20. Jiang J, Levine M. Binding affinities and cooperative interactions with bHLH activators delimit threshold responses to the dorsal gradient morphogen. Cell. 1993;72:741-52 pubmed
    ..The snail repressor blocks this interaction and restricts expression to the neuroectoderm...
  21. Fakhouri W, Ay A, Sayal R, Dresch J, Dayringer E, Arnosti D. Deciphering a transcriptional regulatory code: modeling short-range repression in the Drosophila embryo. Mol Syst Biol. 2010;6:341 pubmed publisher
    ..of these proteins' activity that allow accurate predictions of regulation by the Giant, Knirps, Krüppel, and Snail repressors, including modeling of an endogenous enhancer...
  22. Costa M, Wilson E, Wieschaus E. A putative cell signal encoded by the folded gastrulation gene coordinates cell shape changes during Drosophila gastrulation. Cell. 1994;76:1075-89 pubmed
    ..Our analyses indicate that cell-cell communication ensures the rapid, orderly progression of constriction initiations from the middle of invagination primordia out toward the margins. ..
  23. Nguyen H, Bodmer R, Abmayr S, McDermott J, Spoerel N. D-mef2: a Drosophila mesoderm-specific MADS box-containing gene with a biphasic expression profile during embryogenesis. Proc Natl Acad Sci U S A. 1994;91:7520-4 pubmed
    ..twi activity is required for D-mef2 expression, while sna function may be needed for the maintenance of D-mef2 expression but not its initiation...
  24. Fernandez Gonzalez R, Simões S, Röper J, Eaton S, Zallen J. Myosin II dynamics are regulated by tension in intercalating cells. Dev Cell. 2009;17:736-43 pubmed publisher
    ..These results demonstrate that myosin II dynamics are regulated by tension in a positive feedback loop that leads to multicellular actomyosin cable formation and efficient tissue elongation. ..
  25. Cowden J, Levine M. Ventral dominance governs sequential patterns of gene expression across the dorsal-ventral axis of the neuroectoderm in the Drosophila embryo. Dev Biol. 2003;262:335-49 pubmed
  26. Shishido E, Higashijima S, Emori Y, Saigo K. Two FGF-receptor homologues of Drosophila: one is expressed in mesodermal primordium in early embryos. Development. 1993;117:751-61 pubmed
    ..In early embryos, DFR1 RNA expression, requiring both twist and snail proteins, is specific to mesodermal primordium and invaginated mesodermal cells...
  27. Copley R, Totrov M, Linnell J, Field S, Ragoussis J, Udalova I. Functional conservation of Rel binding sites in drosophilid genomes. Genome Res. 2007;17:1327-35 pubmed
    ..We discuss how two types of conservation may contribute to the stabilization and optimization of a functional gene regulatory code in evolution. ..
  28. Ip Y, Park R, Kosman D, Yazdanbakhsh K, Levine M. dorsal-twist interactions establish snail expression in the presumptive mesoderm of the Drosophila embryo. Genes Dev. 1992;6:1518-30 pubmed
    ..step in the differentiation of the Drosophila mesoderm is the activation of two regulatory genes, twist (twi) and snail (sna), in ventral regions of early embryos...
  29. de Renzis S, Yu J, Zinzen R, Wieschaus E. Dorsal-ventral pattern of Delta trafficking is established by a Snail-Tom-Neuralized pathway. Dev Cell. 2006;10:257-64 pubmed
    ..We have addressed the snail-dependent regulation of Delta trafficking during the plasma membrane growth of the mesoderm in the Drosophila ..
  30. Crocker J, Tamori Y, Erives A. Evolution acts on enhancer organization to fine-tune gradient threshold readouts. PLoS Biol. 2008;6:e263 pubmed publisher
    ..Our study demonstrates that equivalence classes of CRMs are powerful tools for detecting lineage-specific adaptations by gene regulatory sequences. ..
  31. Van Doren M, Williamson A, Lehmann R. Regulation of zygotic gene expression in Drosophila primordial germ cells. Curr Biol. 1998;8:243-6 pubmed
    ..This expression does not require proper patterning of the soma, indicating that it is likely to be controlled by the germ plasm. ..
  32. Seher T, Narasimha M, Vogelsang E, Leptin M. Analysis and reconstitution of the genetic cascade controlling early mesoderm morphogenesis in the Drosophila embryo. Mech Dev. 2007;124:167-79 pubmed
    ..activator Twist, which acts at the top of the mesodermal developmental cascade in Drosophila, two targets, Snail and Fog, are known to be necessary for the first morphogenetic event, the orderly invagination of the mesoderm...
  33. Biemar F, Zinzen R, Ronshaugen M, Sementchenko V, Manak J, Levine M. Spatial regulation of microRNA gene expression in the Drosophila embryo. Proc Natl Acad Sci U S A. 2005;102:15907-11 pubmed
    ..These results provide evidence that restricted activities of the 8-miR and miR-1 miRNAs are mediated by classical tissue-specific enhancers. ..
  34. Leptin M, Grunewald B. Cell shape changes during gastrulation in Drosophila. Development. 1990;110:73-84 pubmed
    ..Two known zygotic genes that are required for the formation of the mesoderm, twist and snail, are expressed in ventral furrow cells, and the correct execution of cell shape changes in the mesoderm depends on ..
  35. Papatsenko D, Kislyuk A, Levine M, Dubchak I. Conservation patterns in different functional sequence categories of divergent Drosophila species. Genomics. 2006;88:431-42 pubmed publisher
    ..We discuss how restraining conservation patterns may help in mapping functional sequence categories and improve genome annotation...
  36. García M, Nahmad M, Reeves G, Stathopoulos A. Size-dependent regulation of dorsal-ventral patterning in the early Drosophila embryo. Dev Biol. 2013;381:286-99 pubmed publisher
    ..In particular, the patterns of snail (sna) and ventral nervous system defective (vnd) correlate with nuclear Dorsal levels and exhibit scaling to DV ..
  37. Lilly B, Galewsky S, Firulli A, Schulz R, Olson E. D-MEF2: a MADS box transcription factor expressed in differentiating mesoderm and muscle cell lineages during Drosophila embryogenesis. Proc Natl Acad Sci U S A. 1994;91:5662-6 pubmed
    ..Expression of D-mef2 is dependent on the mesodermal determinants twist and snail but independent of the homeobox-containing gene tinman, which is required for visceral muscle and heart ..
  38. Leptin M. Gastrulation in Drosophila: the logic and the cellular mechanisms. EMBO J. 1999;18:3187-92 pubmed
  39. Farge E. Mechanical induction of Twist in the Drosophila foregut/stomodeal primordium. Curr Biol. 2003;13:1365-77 pubmed
    ..I propose that anterior-gut formation is mechanically induced by the movement of germ-band extension through the induction of Twist expression in stomodeal cells. ..
  40. Isshiki T, Takeichi M, Nose A. The role of the msh homeobox gene during Drosophila neurogenesis: implication for the dorsoventral specification of the neuroectoderm. Development. 1997;124:3099-109 pubmed
  41. Stathopoulos A, Levine M. Linear signaling in the Toll-Dorsal pathway of Drosophila: activated Pelle kinase specifies all threshold outputs of gene expression while the bHLH protein Twist specifies a subset. Development. 2002;129:3411-9 pubmed
    ..We discuss how the Dorsal gradient system can be modified during metazoan evolution and conclude that Dorsal-Twist interactions are distinct from the interplay between Bicoid and Hunchback, which pattern the anteroposterior axis. ..
  42. Chahda J, Sousa Neves R, Mizutani C. Variation in the dorsal gradient distribution is a source for modified scaling of germ layers in Drosophila. Curr Biol. 2013;23:710-6 pubmed publisher
    ..We propose that variation in mesodermal size occurs at a fast evolutionary rate and is an important mechanism to define the ventral boundary of the neuroectoderm...
  43. Hasson P, Muller B, Basler K, Paroush Z. Brinker requires two corepressors for maximal and versatile repression in Dpp signalling. EMBO J. 2001;20:5725-36 pubmed
    ..Our results show that Brk utilizes multiple means to repress its endogenous target genes, allowing repression of a multitude of complex Dpp target promoters. ..
  44. Fernandez Gonzalez R, Zallen J. Oscillatory behaviors and hierarchical assembly of contractile structures in intercalating cells. Phys Biol. 2011;8:045005 pubmed publisher
    ..We discuss models to explain how the architecture of cytoskeletal networks regulates their contractile behavior and the mechanisms that give rise to oscillatory cell behaviors in intercalating cells...
  45. Ip Y, Park R, Kosman D, Bier E, Levine M. The dorsal gradient morphogen regulates stripes of rhomboid expression in the presumptive neuroectoderm of the Drosophila embryo. Genes Dev. 1992;6:1728-39 pubmed
    ..Expression is blocked in ventral regions (the presumptive mesoderm) by snail (sna), which is also a direct target of the dl morphogen...
  46. Gao Q, Wang Y, Finkelstein R. Orthodenticle regulation during embryonic head development in Drosophila. Mech Dev. 1996;56:3-15 pubmed
    ..Finally, we identify a novel pathway mediated by the gap gene huckebein through which three maternal systems cooperate to repress otd expression at the anterior terminus of the embryo. ..
  47. Arnosti D, Gray S, Barolo S, Zhou J, Levine M. The gap protein knirps mediates both quenching and direct repression in the Drosophila embryo. EMBO J. 1996;15:3659-66 pubmed
    ..Our studies suggest that short-range repression represents a flexible form of gene regulation, exhibiting enhancer- or promoter-specific effects depending on the location of repressor binding sites. ..
  48. Martin A, Kaschube M, Wieschaus E. Pulsed contractions of an actin-myosin network drive apical constriction. Nature. 2009;457:495-9 pubmed publisher
    ..The transcription factors Twist and Snail differentially regulate pulsed constriction...
  49. Zeitlinger J, Stark A, Kellis M, Hong J, Nechaev S, Adelman K, et al. RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo. Nat Genet. 2007;39:1512-6 pubmed
    ..We propose that Pol II stalling facilitates rapid temporal and spatial changes in gene activity during development. ..
  50. Kölsch V, Seher T, Fernandez Ballester G, Serrano L, Leptin M. Control of Drosophila gastrulation by apical localization of adherens junctions and RhoGEF2. Science. 2007;315:384-6 pubmed
    ..Together with G protein signaling, T48 recruits adherens junctions and the cytoskeletal regulator RhoGEF2 to the sites of apical constriction, ensuring rapid and intense changes in cell shape. ..
  51. Papatsenko D, Levine M. Quantitative analysis of binding motifs mediating diverse spatial readouts of the Dorsal gradient in the Drosophila embryo. Proc Natl Acad Sci U S A. 2005;102:4966-71 pubmed
    ..Similar motif arrangements were identified in orthologous loci in the distant mosquito genome, Anopheles gambiae. We discuss how Dorsal and Twist work either additively or synergistically to activate different target enhancers. ..
  52. Reuter R, Leptin M. Interacting functions of snail, twist and huckebein during the early development of germ layers in Drosophila. Development. 1994;120:1137-50 pubmed
    Two zygotic genes, snail (sna) and twist (twi), are required for mesoderm development, which begins with the formation of the ventral furrow...
  53. Zinzen R, Senger K, Levine M, Papatsenko D. Computational models for neurogenic gene expression in the Drosophila embryo. Curr Biol. 2006;16:1358-65 pubmed publisher
    ..Quantitative models based on the fractional occupancy of Dorsal, Twist, and Snail binding sites raise the possibility that cooperative interactions among these regulatory proteins mediate subtle ..
  54. Boulay J, Dennefeld C, Alberga A. The Drosophila developmental gene snail encodes a protein with nucleic acid binding fingers. Nature. 1987;330:395-8 pubmed
    ..We have cloned snail (sna), a zygotic gene, whose expression is essential for the correct specification of dorsal-ventral pattern...
  55. Mauhin V, Lutz Y, Dennefeld C, Alberga A. Definition of the DNA-binding site repertoire for the Drosophila transcription factor SNAIL. Nucleic Acids Res. 1993;21:3951-7 pubmed
    The Drosophila gene snail (sna) which encodes a zinc finger protein is essential for dorsal-ventral pattern formation in the developing embryo...
  56. Pouille P, Ahmadi P, Brunet A, Farge E. Mechanical signals trigger Myosin II redistribution and mesoderm invagination in Drosophila embryos. Sci Signal. 2009;2:ra16 pubmed publisher
    ..by the constriction of 40% of randomly positioned mesodermal cells and is controlled by the transcription factor Snail. The second constriction wave immediately follows and involves the other 60% of the mesodermal cells...
  57. Jimenez G, Paroush Z, Ish Horowicz D. Groucho acts as a corepressor for a subset of negative regulators, including Hairy and Engrailed. Genes Dev. 1997;11:3072-82 pubmed
    ..In contrast, repressor regions from the Even-skipped, Snail, Krüppel, and Knirps transcription factors are effective in the absence of Gro...
  58. Courey A, Jia S. Transcriptional repression: the long and the short of it. Genes Dev. 2001;15:2786-96 pubmed
  59. Jennings B, Pickles L, Wainwright S, Roe S, Pearl L, Ish Horowicz D. Molecular recognition of transcriptional repressor motifs by the WD domain of the Groucho/TLE corepressor. Mol Cell. 2006;22:645-55 pubmed
    ..Our structural and functional analysis explains the rigid conservation of the WRPW motif, the sequence flexibility of eh1 motifs, and other aspects of repressor recognition by Gro in vivo. ..
  60. Grosshans J, Wieschaus E. A genetic link between morphogenesis and cell division during formation of the ventral furrow in Drosophila. Cell. 2000;101:523-31 pubmed
    ..Effective inhibition of mitosis in the cells of the ventral furrow depends on the transcription factor Snail that triggers the ventral cell shape changes...
  61. Yagi Y, Hayashi S. Role of the Drosophila EGF receptor in determination of the dorsoventral domains of escargot expression during primary neurogenesis. Genes Cells. 1997;2:41-53 pubmed
    ..The effect of dorsoventral patterning genes on esg expression was studied. decapentaplegic, snail and twist were found to repress esg expression outside the neuroectoderm...
  62. Castanon I, Baylies M. A Twist in fate: evolutionary comparison of Twist structure and function. Gene. 2002;287:11-22 pubmed
    ..Conserved principles and the molecular mechanisms underlying them are discussed. ..
  63. Papatsenko D, Goltsev Y, Levine M. Organization of developmental enhancers in the Drosophila embryo. Nucleic Acids Res. 2009;37:5665-77 pubmed publisher
    ..We conclude that grammar of gene control regions is pervasively used in the patterning of the Drosophila embryo. ..
  64. Li X, MacArthur S, Bourgon R, Nix D, Pollard D, Iyer V, et al. Transcription factors bind thousands of active and inactive regions in the Drosophila blastoderm. PLoS Biol. 2008;6:e27 pubmed publisher
  65. Reeves G, Trisnadi N, Truong T, Nahmad M, Katz S, Stathopoulos A. Dorsal-ventral gene expression in the Drosophila embryo reflects the dynamics and precision of the dorsal nuclear gradient. Dev Cell. 2012;22:544-57 pubmed publisher
    ..We propose that mRNA levels remain plastic during transient signaling events, allowing tissues to refine patterns in the face of genetic or environmental variation. ..