When we say that a trait is deeply canalized we mean that

1. Waddington CH. The canalisation of development and the inheritance of acquired characters. Nature. 1942;150:563. [Google Scholar]

2. Waddington CH. Selection of the genetic basis for an acquired character. Nature. 1952;169(4302):625–6. [PubMed] [Google Scholar]

3. Waddington CH. The genetic assimilation of an acquired character. Evolution. 1953;7:118–126. [Google Scholar]

4. Waddington CH. On a case of quantitative inheritence on either side of the wild-type. Z in Abstammungs u Vererb Lehre. 1955;87:208–28. [PubMed] [Google Scholar]

5. Waddington CH. Genetic assimilation of the bithorax phenotype. Evolution. 1956;10:1–13. [Google Scholar]

6. Waddington CH. The genetic basis of the ‘assimilated bithorax’ stock. J Genet. 1956;55:241–245. [PubMed] [Google Scholar]

7. Waddington CH. The Strategy of the Genes. MacMillan Company; New York: 1957. [Google Scholar]

8. Wagner GP, Booth G, Bagheri-Chaichian H. A population genetic theory of canalization. Evolution. 1997;51(2):329–347. [PubMed] [Google Scholar]

9. Scharloo W. Canalization - Genetic and Developmental Aspects. Annual Review of Ecology and Systematics. 1991;22:65–93. [Google Scholar]

10. de Visser JA, Hermisson J, Wagner GP, Ancel Meyers L, Bagheri-Chaichian H, Blanchard JL, Chao L, Cheverud JM, Elena SF, Fontana W, Gibson G, Hansen TF, Krakauer D, Lewontin RC, Ofria C, Rice SH, von Dassow G, Wagner A, Whitlock MC. Perspective: Evolution and detection of genetic robustness. Evolution. 2003;57(9):1959–72. [PubMed] [Google Scholar]

11. Henn BM, Botigue LR, Bustamante CD, Clark AG, Gravel S. Estimating the mutation load in human genomes. Nat Rev Genet. 2015;16(6):333–43. [PMC free article] [PubMed] [Google Scholar]

12. Méndez A, Mendoza L. A Network Model to Describe the Terminal Differentiation of B Cells. PLOS Computational Biology. 2016;12(1):e1004696. [PMC free article] [PubMed] [Google Scholar]

13. Moris N, Pina C, Arias AM. Transition states and cell fate decisions in epigenetic landscapes. Nat Rev Genet. 2016;17(11):693–703. [PubMed] [Google Scholar]

14. Wang J, Zhang K, Xu L, Wang E. Quantifying the Waddington landscape and biological paths for development and differentiation. Proc Natl Acad Sci U S A. 2011;108(20):8257–62. [PMC free article] [PubMed] [Google Scholar]

15. Guo J, Lin F, Zhang X, Tanavde V, Zheng J. NetLand: quantitative modeling and visualization of Waddington’s epigenetic landscape using probabilistic potential. Bioinformatics. 2017;33(10):1583–1585. [PMC free article] [PubMed] [Google Scholar]

16. Gilbert SF. Epigenetic landscaping: Waddington’s use of cell fate bifurcation diagrams. Biology and Philosophy. 1991;6(2):135–154. [Google Scholar]

17. Waddington CH. Towards a theoretical biology. Nature. 1968;218(5141):525–7. [PubMed] [Google Scholar]

18. Davidson EH, Levine MS. Properties of developmental gene regulatory networks. Proceedings of the National Academy of Sciences. 2008;105(51):20063–20066. [PMC free article] [PubMed] [Google Scholar]

19. Rutherford SL. From genotype to phenotype: buffering mechanisms and the storage of genetic information. Bioessays. 2000;22(12):1095–105. [PubMed] [Google Scholar]

20. Rutherford SL, Lindquist S. Hsp90 as a capacitor for morphological evolution. Nature. 1998;396(6709):336–42. [PubMed] [Google Scholar]

21. Wagner A. Robustness and evolvability in living systems. Princeton university press; 2013. [Google Scholar]

22. Hallgrimsson B, Willmore K, Hall B. Canalization, developmental stability, and morphological integration in primate limbs. Yearbook of Physical Anthropology. 2002;45:131–158. [PMC free article] [PubMed] [Google Scholar]

23. Van Valen L. A Study of Fluctuating Asymmetry. Evolution. 1962;16:125–142. [Google Scholar]

24. Hallgrimsson B, Donnabhain BO, Blom DE, Lozada MC, Willmore KT. Why are rare traits unilaterally expressed?: trait frequency and unilateral expression for cranial nonmetric traits in humans. American Journal of Physical Anthropology. 2005;128(1):14–25. [PubMed] [Google Scholar]

25. Palmer AR. Asymmetry Breaking and the Evolution of Development. Science. 2004;306(828):833. [PubMed] [Google Scholar]

26. Debat V, Alibert P, David P, Paradis E, Auffray JC. Independence between developmental stability and canalisation in the skull of the house mouse. Proc Roy Soc Lond B. 2000;267:423–430. [PMC free article] [PubMed] [Google Scholar]

27. Takahashi KH, Rako L, Takano-Shimizu T, Hoffmann AA, Lee SF. Effects of small Hsp genes on developmental stability and microenvironmental canalization. BMC Evol Biol. 2010;10:284. [PMC free article] [PubMed] [Google Scholar]

28. Breno M, Leirs H, Van Dongen S. No relationship between canalization and developmental stability of the skull in a natural population of Mastomys natalensis (Rodentia: Muridae) Biological Journal of the Linnean Society. 2011;104(1):207–216. [Google Scholar]

29. Willmore K, Klingenberg C, Hallgrimsson H. Congruence between canalization and developmental stability in Macaca mulatta crania. American Journal of Physical Anthropology. 2005:224. [Google Scholar]

30. Santos M, Iriarte PF, Cespedes W. Genetics and geometry of canalization and developmental stability in Drosophila subobscura. BMC Evol Biol. 2005;5:7. [PMC free article] [PubMed] [Google Scholar]

31. Breuker CJ, Patterson JS, Klingenberg CP. A single basis for developmental buffering of Drosophila wing shape. PLoS ONE. 2006;1:e7. [PMC free article] [PubMed] [Google Scholar]

32. Padro J, Carreira V, Corio C, Hasson E, Soto IM. Host alkaloids differentially affect developmental stability and wing vein canalization in cactophilic Drosophila buzzatii. J Evol Biol. 2014;27(12):2781–97. [PubMed] [Google Scholar]

33. Gonzalez PN, Lotto FP, Hallgrimsson B. Canalization and developmental instability of the fetal skull in a mouse model of maternal nutritional stress. Am J Phys Anthropol. 2014;154(4):544–53. [PMC free article] [PubMed] [Google Scholar]

34. Roff DA. Evolutionary Quantitative Genetics. Chapman & Hall; New York: 1997. [Google Scholar]

35. Flatt T. The evolutionary genetics of canalization. Quarterly Review of Biology. 2005;80(3):287–316. [PubMed] [Google Scholar]

36. Stearns SC, Kawecki TJ. Fitness sensitivity and the canalization of life-history traits. Evolution. 1994;48:1438–1450. [PubMed] [Google Scholar]

37. Woltereck R. Weitere experimenelle Untersuchungen uber Artveranderung, speziell uber des Wesen quantitativer Artunterschiede bei Daphniden. Ver Deutsche Zool Gesell. 1909;19:110–172. [Google Scholar]

38. Schmalhausen II. Factors of Evolution. University of Chicago Press; Chicago: 1949. [Google Scholar]

39. Scheiner SM, Holt RD. The genetics of phenotypic plasticity. X. Variation versus uncertainty. Ecology and Evolution. 2012;2(4):751–767. [PMC free article] [PubMed] [Google Scholar]

40. Stearns SC. The evolutionary significance of phenotypic plasticity. BioScience. 1989;39(7):436–445. [Google Scholar]

41. Pigliucci M, Murren CJ, Schlichting CD. Phenotypic plasticity and evolution by genetic assimilation. Journal of Experimental Biology. 2006;209(12):2362–2367. [PubMed] [Google Scholar]

42. Forsman A. Rethinking phenotypic plasticity and its consequences for individuals, populations and species. Heredity. 2014;115:276. [PMC free article] [PubMed] [Google Scholar]

43. Liefting M, Hoffmann AA, Ellers J. PLASTICITY VERSUS ENVIRONMENTAL CANALIZATION: POPULATION DIFFERENCES IN THERMAL RESPONSES ALONG A LATITUDINAL GRADIENT IN DROSOPHILA SERRATA. Evolution. 2009;63(8):1954–1963. [PubMed] [Google Scholar]

44. Takahashi KH, Daborn PJ, Hoffmann AA, Takano-Shimizu T. Environmental Stress-Dependent Effects of Deletions Encompassing Hsp70Ba on Canalization and Quantitative Trait Asymmetry in Drosophila melanogaster. PLOS ONE. 2011;6(4):e17295. [PMC free article] [PubMed] [Google Scholar]

45. Scharloo W. The influence of selection and temperature on a mutant character (ciD) in Drosophila melanogaster. Arch Neerl Zool. 1962;14:431–512. [Google Scholar]

46. Scharloo W. Mutant expression and canalization. Nature. 1964;203:1095–1096. [PubMed] [Google Scholar]

47. Debat V, Debelle A, Dworkin I. Plasticity, canalization, and developmental stability of the Drosophila wing: joint effects of mutations and developmental temperature. Evolution. 2009;63(11):2864–76. [PubMed] [Google Scholar]

48. Rendel JM. CANALIZATION OF THE SCUTE PHENOTYPE OF DROSOPHILA. Evolution. 1959;13(4):425–439. [Google Scholar]

49. Rendel JM. Canalization and gene control. Logos Press; London: 1967. [Google Scholar]

50. Dun RB, Fraser AS. Selection for an Invariant Character - Vibrissa Number - in the House Mouse. Nature. 1958;181(4614):1018–1019. [PubMed] [Google Scholar]

51. Mather K. Genetical control of stability in development. Heredity. 1953;7:297–336. [Google Scholar]

52. Hall MC, Dworkin I, Ungerer MC, Purugganan M. Genetics of microenvironmental canalization in Arabidopsis thaliana Proceedings of the National Academy of Sciences. 2007;104(34):13717–13722. [PMC free article] [PubMed] [Google Scholar]

53. Gonzalez PN, Pavlicev M, Mitteroecker P, Pardo-Manuel de Villena F, Spritz RA, Marcucio RS, Hallgrimsson B. Genetic structure of phenotypic robustness in the collaborative cross mouse diallel panel. J Evol Biol. 2016;29(9):1737–51. [PMC free article] [PubMed] [Google Scholar]

54. Hallgrimsson B, Jamniczky H, Young NM, Rolian C, Parsons TE, Boughner JC, Marcucio RS. Deciphering the Palimpsest: Studying the Relationship Between Morphological Integration and Phenotypic Covariation. Evol Biol. 2009;36(4):355–376. [PMC free article] [PubMed] [Google Scholar]

55. Baer CF. Quantifying the decanalizing effects of spontaneous mutations in rhabditid nematodes. Am Nat. 2008;172(2):272–81. [PMC free article] [PubMed] [Google Scholar]

56. DeLaurier A, Huycke TR, Nichols JT, Swartz ME, Larsen A, Walker C, Dowd J, Pan L, Moens CB, Kimmel CB. Role of mef2ca in developmental buffering of the zebrafish larval hyoid dermal skeleton. Developmental Biology. 2014;385(2):189–199. [PMC free article] [PubMed] [Google Scholar]

57. Chen R, Shi L, Hakenberg J, Naughton B, Sklar P, Zhang J, Zhou H, Tian L, Prakash O, Lemire M, Sleiman P, Cheng WY, Chen W, Shah H, Shen Y, Fromer M, Omberg L, Deardorff MA, Zackai E, Bobe JR, Levin E, Hudson TJ, Groop L, Wang J, Hakonarson H, Wojcicki A, Diaz GA, Edelmann L, Schadt EE, Friend SH. Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases. Nat Biotechnol. 2016;34(5):531–8. [PubMed] [Google Scholar]

58. Tarailo-Graovac M, Zhu JYA, Matthews A, van Karnebeek CDM, Wasserman WW. Assessment of the ExAC data set for the presence of individuals with pathogenic genotypes implicated in severe Mendelian pediatric disorders. Genet Med. 2017;19(12):1300–1308. [PMC free article] [PubMed] [Google Scholar]

59. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O’Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper DN, Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki MI, Moonshine AL, Natarajan P, Orozco L, Peloso GM, Poplin R, Rivas MA, Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K, Stenson PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna MT, Weisburd B, Won HH, Yu D, Altshuler DM, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez JC, Gabriel SB, Getz G, Glatt SJ, Hultman CM, Kathiresan S, Laakso M, McCarroll S, McCarthy MI, McGovern D, McPherson R, Neale BM, Palotie A, Purcell SM, Saleheen D, Scharf JM, Sklar P, Sullivan PF, Tuomilehto J, Tsuang MT, Watkins HC, Wilson JG, Daly MJ, MacArthur DG, Exome C. Aggregation, Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285–91. [PMC free article] [PubMed] [Google Scholar]

60. Percival CJ, Marangoni P, Tapaltsyan V, Klein O, Hallgrímsson B. The Interaction of Genetic Background and Mutational Effects in Regulation of Mouse Craniofacial Shape. G3: Genes|Genomes|Genetics. 2017;7(5):1439–1450. [PMC free article] [PubMed] [Google Scholar]

61. Nadeau JH. Modifier genes in mice and humans. Nature Reviews Genetics. 2001;2(3):165. [PubMed] [Google Scholar]

62. Mackay TFC. Epistasis and Quantitative Traits: Using Model Organisms to Study Gene-Gene Interactions. Nature reviews Genetics. 2014;15(1):22–33. [PMC free article] [PubMed] [Google Scholar]

63. Rice S. The evolution of canalization and the breaking of von Baer’s laws: Modeling the evolution of development with epistasis. Evolution. 1998;52(3):647–656. [PubMed] [Google Scholar]

64. Rice SH. Theoretical approaches to the evolution of development and genetic architecture. Annals of the New York Academy of Sciences. 2008;1133:67–86. [PubMed] [Google Scholar]

65. Rutherford SL. Between genotype and phenotype: protein chaperones and evolvability. Nature Reviews Genetics. 2003;4:263. [PubMed] [Google Scholar]

66. Zabinsky RA, Mason GA, Queitsch C, Jarosz DF. It’s not magic - Hsp90 and its effects on genetic and epigenetic variation. Seminars in Cell and Developmental Biology. 2018 In Press. [PMC free article] [PubMed] [Google Scholar]

67. Marques C, Guo W, Pereira P, Taylor A, Patterson C, Evans PC, Shang F. The triage of damaged proteins: degradation by the ubiquitin-proteasome pathway or repair by molecular chaperones. The FASEB Journal. 2006;20(6):741–743. [PMC free article] [PubMed] [Google Scholar]

68. Sangster TA, Salathia N, Undurraga S, Milo R, Schellenberg K, Lindquist S, Queitsch C. HSP90 affects the expression of genetic variation and developmental stability in quantitative traits. Proc Natl Acad Sci U S A. 2008;105(8):2963–8. [PMC free article] [PubMed] [Google Scholar]

69. Samakovli D, Thanou A, Valmas C, Hatzopoulos P. Hsp90 canalizes developmental perturbation. J Exp Bot. 2007;58(13):3513–24. [PubMed] [Google Scholar]

70. Debat V, Milton CC, Rutherford S, Klingenberg CP, Hoffmann AA. Hsp90 and the quantitative variation of wing shape in Drosophila melanogaster. Evolution. 2006;60(12):2529–38. [PubMed] [Google Scholar]

71. Geiler-Samerotte KA, Zhu YO, Goulet BE, Hall DW, Siegal ML. Selection Transforms the Landscape of Genetic Variation Interacting with Hsp90. PLOS Biology. 2016;14(10):e2000465. [PMC free article] [PubMed] [Google Scholar]

72. Calof AL, Kawauchi S, Santos R, Lopez-Burks ME, Hoang MP, Kitzes LM, Lao T, Lechner MS, Hallgrimsson B, Daniel JA, Nussenzweig A, Lander AD. Insights Into Cornelia de Lange Syndrome From the Nipbl-Mutant Mouse. American Journal of Medical Genetics Part A. 2010;152A(7):1633–1633. [Google Scholar]

73. Kawauchi S, Calof AL, Santos R, Lopez-Burks ME, Young CM, Hoang MP, Chua A, Lao T, Lechner MS, Daniel JA. Multiple organ system defects and transcriptional dysregulation in the Nipbl+/− mouse, a model of Cornelia de Lange Syndrome. PLoS Genet. 2009;5(9):e1000650. [PMC free article] [PubMed] [Google Scholar]

74. Santos R, Kawauchi S, Jacobs RE, Lopez-Burks ME, Choi H, Wikenheiser J, Hallgrimsson B, Jamniczky HA, Fraser SE, Lander AD, Calof AL. Conditional Creation and Rescue of Nipbl-Deficiency in Mice Reveals Multiple Determinants of Risk for Congenital Heart Defects. PLoS Biol. 2016;14(9):e2000197. [PMC free article] [PubMed] [Google Scholar]

75. Harmacek L, Watkins-Chow DE, Chen J, Jones KL, Pavan WJ, Salbaum JM, Niswander L. A unique missense allele of BAF155, a core BAF chromatin remodeling complex protein, causes neural tube closure defects in mice. Dev Neurobiol. 2014;74(5):483–97. [PMC free article] [PubMed] [Google Scholar]

76. Green RM, Fish JL, Young NM, Smith FJ, Roberts B, Dolan K, Choi I, Leach CL, Gordon P, Cheverud JM, Roseman CC, Williams TJ, Marcucio RS, Hallgrimsson B. Developmental nonlinearity drives phenotypic robustness. Nat Commun. 2017;8(1):1970. [PMC free article] [PubMed] [Google Scholar]

77. Green RM, Feng W, Phang T, Fish JL, Li H, Spritz RA, Marcucio RS, Hooper J, Jamniczky H, Hallgrímsson B, Williams T. Tfap2a-dependent changes in mouse facial morphology result in clefting that can be ameliorated by a reduction in Fgf8 gene dosage. Dis Model Mech. 2015;8(1):31–43. [PMC free article] [PubMed] [Google Scholar]

78. Hallgrimsson B, Brown JJ, Ford-Hutchinson AF, Sheets HD, Zelditch ML, Jirik FR. The brachymorph mouse and the developmental-genetic basis for canalization and morphological integration. Evol Dev. 2006;8(1):61–73. [PubMed] [Google Scholar]

79. Richardson JB, Uppendahl LD, Traficante MK, Levy SF, Siegal ML. Histone Variant HTZ1 Shows Extensive Epistasis with, but Does Not Increase Robustness to, New Mutations. PLOS Genetics. 2013;9(8):e1003733. [PMC free article] [PubMed] [Google Scholar]

80. Forsberg SK, Andreatta ME, Huang XY, Danku J, Salt DE, Carlborg O. The Multi-allelic Genetic Architecture of a Variance-Heterogeneity Locus for Molybdenum Concentration in Leaves Acts as a Source of Unexplained Additive Genetic Variance. PLoS Genet. 2015;11(11):e1005648. [PMC free article] [PubMed] [Google Scholar]

81. Shen X, Pettersson M, Rönnegård L, Carlborg Ö. Inheritance Beyond Plain Heritability: Variance-Controlling Genes in Arabidopsis thaliana. PLOS Genetics. 2012;8(8):e1002839. [PMC free article] [PubMed] [Google Scholar]

82. Wilkins JF. Genomic imprinting and methylation: epigenetic canalization and conflict. Trends in Genetics. 2005;21(6):356–365. [PubMed] [Google Scholar]

83. Pujadas E, Feinberg AP. Regulated noise in the epigenetic landscape of development and disease. Cell. 2012;148(6):1123–31. [PMC free article] [PubMed] [Google Scholar]

84. Faulk C, Barks A, Dolinoy DC. Phylogenetic and DNA methylation analysis reveal novel regions of variable methylation in the mouse IAP class of transposons. BMC Genomics. 2013;14:48–48. [PMC free article] [PubMed] [Google Scholar]

85. Morgan HD, Sutherland HGE, Martin DIK, Whitelaw E. Epigenetic inheritance at the agouti locus in the mouse. Nature Genetics. 1999;23:314. [PubMed] [Google Scholar]

86. Juriloff DM, Harris MJ, Mager DL, Gagnier L. Epigenetic mechanism causes Wnt9b deficiency and nonsyndromic cleft lip and palate in the A/WySn mouse strain. Birth Defects Res A Clin Mol Teratol. 2014;100(10):772–88. [PubMed] [Google Scholar]

87. Plamondon JA, Harris MJ, Mager DL, Gagnier L, Juriloff DM. The clf2 gene has an epigenetic role in the multifactorial etiology of cleft lip and palate in the A/WySn mouse strain. Birth Defects Research Part A: Clinical and Molecular Teratology. 2011;91(8):716–727. [PubMed] [Google Scholar]

88. Parsons TE, Kristensen E, Hornung L, Diewert VM, Boyd SK, German RZ, Hallgrimsson B. Phenotypic variability and craniofacial dysmorphology: increased shape variance in a mouse model for cleft lip. Journal of Anatomy. 2008;212(2):135–43. [PMC free article] [PubMed] [Google Scholar]

89. Nichols JT, Blanco-Sanchez B, Brooks EP, Parthasarathy R, Dowd J, Subramanian A, Nachtrab G, Poss KD, Schilling TF, Kimmel CB. Ligament versus bone cell identity in the zebrafish hyoid skeleton is regulated by mef2ca. Development. 2016;143(23):4430–4440. [PMC free article] [PubMed] [Google Scholar]

91. Bosia C, Osella M, Baroudi ME, Cora D, Caselle M. Gene autoregulation via intronic microRNAs and its functions. BMC Syst Biol. 2012;6:131. [PMC free article] [PubMed] [Google Scholar]

92. Ebert MS, Sharp PA. Roles for microRNAs in conferring robustness to biological processes. Cell. 2012;149(3):515–24. [PMC free article] [PubMed] [Google Scholar]

93. Masel J, Siegal ML. Robustness: mechanisms and consequences. Trends in genetics. 2009;25(9):395–403. [PMC free article] [PubMed] [Google Scholar]

94. Choi WY, Giraldez AJ, Schier AF. Target protectors reveal dampening and balancing of Nodal agonist and antagonist by miR-430. Science. 2007;318(5848):271–4. [PubMed] [Google Scholar]

95. Kasper DM, Moro A, Ristori E, Narayanan A, Hill-Teran G, Fleming E, Moreno-Mateos M, Vejnar CE, Zhang J, Lee D, Gu M, Gerstein M, Giraldez A, Nicoli S. MicroRNAs Establish Uniform Traits during the Architecture of Vertebrate Embryos. Dev Cell. 2017;40(6):552–565 e5. [PMC free article] [PubMed] [Google Scholar]

96. Cassidy JJ, Jha AR, Posadas DM, Giri R, Venken KJ, Ji J, Jiang H, Bellen HJ, White KP, Carthew RW. miR-9a minimizes the phenotypic impact of genomic diversity by buffering a transcription factor. Cell. 2013;155(7):1556–67. [PMC free article] [PubMed] [Google Scholar]

97. Goulart LF, Bettella F, Sønderby IE, Schork AJ, Thompson WK, Mattingsdal M, Steen VM, Zuber V, Wang Y, Dale AM, Andreassen OA, Djurovic S. MicroRNAs enrichment in GWAS of complex human phenotypes. BMC Genomics. 2015;16(1):304. [PMC free article] [PubMed] [Google Scholar]

98. Aubin D. Forms of explanation in the catastrophe theory of René Thom: topology, morphogenesis, and the structuralism, Growing explanations: Historical perspectives on recent science. Duke Univ. Press; 2004. pp. 95–130. [Google Scholar]

99. Newman SA, Rice SA. Model for Constraint and Control in Biochemical Networks. Proceedings of the National Academy of Sciences. 1971;68(1):92–96. [PMC free article] [PubMed] [Google Scholar]

100. Kauffman S. The large scale structure and dynamics of gene control circuits: An ensemble approach. Journal of Theoretical Biology. 1974;44(1):167–190. [PubMed] [Google Scholar]

101. Xiao Y. A Tutorial on Analysis and Simulation of Boolean Gene Regulatory Network Models. Current Genomics. 2009;10(7):511–525. [PMC free article] [PubMed] [Google Scholar]

102. Soulé ME. Allomeric variation 1.: The theory and some consequences. The American Naturalist. 1982;120(6):751–764. [Google Scholar]

103. Barbaric I, Miller G, Dear TN. Appearances can be deceiving: phenotypes of knockout mice. Briefings in Functional Genomics. 2007;6(2):91–103. [PubMed] [Google Scholar]

104. Wagner A. Evolution of gene networks by gene duplications: a mathematical model and its implications on genome organization. Proceedings of the National Academy of Sciences of the United States of America. 1994;91(10):4387–4391. [PMC free article] [PubMed] [Google Scholar]

105. Morishita Y, Iwasa Y. Accuracy of positional information provided by multiple morphogen gradients with correlated noise. Physical Review E. 2009;79(6):061905. [PubMed] [Google Scholar]

106. Levy SF, Siegal ML. Network Hubs Buffer Environmental Variation in Saccharomyces cerevisiae. PLOS Biology. 2008;6(11):e264. [PMC free article] [PubMed] [Google Scholar]

107. Geiler Samerotte K, Sartoria FMO, Siegal ML. Decanalizing thinking on Canalization. Seminars in Cell and Developmental Biology. In Press. [PMC free article] [PubMed] [Google Scholar]

108. White RJ, Nie Q, Lander AD, Schilling TF. Complex Regulation of cyp26a1 Creates a Robust Retinoic Acid Gradient in the Zebrafish Embryo. PLOS Biology. 2007;5(11):e304. [PMC free article] [PubMed] [Google Scholar]

109. Paulsen M, Legewie S, Eils R, Karaulanov E, Niehrs C. Negative feedback in the bone morphogenetic protein 4 (BMP4) synexpression group governs its dynamic signaling range and canalizes development. Proceedings of the National Academy of Sciences. 2011;108(25):10202–10207. [PMC free article] [PubMed] [Google Scholar]

110. Nelson RM, Pettersson ME, Li X, Carlborg Ö. Variance Heterogeneity in Saccharomyces cerevisiae Expression Data: Trans-Regulation and Epistasis. PLOS ONE. 2013;8(11):e79507. [PMC free article] [PubMed] [Google Scholar]

111. von Dassow M, Davidson LA. Physics and the canalization of morphogenesis: a grand challenge in organismal biology. Phys Biol. 2011;8(4):045002. [PMC free article] [PubMed] [Google Scholar]

112. Lerner IM. Genetic Homeostasis. Wiley & Sons; New York: 1954. [Google Scholar]

113. Hartl GB, Suchentrunk F, Willing R, Petznek R. Allozyme heterozygosity and fluctuating asymmetry in the brown hare (L epus europaeus): A test of the developmental homeostasis hypothesis. Philos Trans R Soc Lond [Biol] 1995;350:313–323. [Google Scholar]

114. Suchentrunk F. Variability of minor tooth traits and allozymic diversity in brown hare Lepus europaeus populations. Acta Theriologica. 1993;38(Suppl 2):59–69. [Google Scholar]

115. Mitton JB. Enzyme heterozygosity, metabolism, and developmental stability. Genetica. 1993;89:47–65. [Google Scholar]

116. Livshits G, Kobyliansky E. Fluctuating asymmetry as a possible measure of developmental homeostasis in humans: a review. Human Biology. 1991;63(4):441–466. [PubMed] [Google Scholar]

117. Bader RS. Fluctuating Asymmetry in the dentition if the house mouse. Growth. 1965;29:291–300. [PubMed] [Google Scholar]

118. Clarke GM. The genetic basis of developmental stability. I. Relationships between stability, heterozygosity and genomic coadaptation. Genetica. 1993;89:15–23. [Google Scholar]

119. Alibert P, Renaud S, Dod B, Bonhomme F, Auffray JC. Fluctuating asymmetry in the Mus musculus hybrid zone: a heterotic effect in disrupted co-adapted genomes. Proceedings of the Royal Society of London B. 1994;258(1351):53–9. [PubMed] [Google Scholar]

120. Auffray JC, Fontanillas P, Catalan J, Britton-Davidian J. Developmental stability in house mice heterozygous for single Robertsonian fusions. J Hered. 2001;92(1):23–9. [PubMed] [Google Scholar]

121. Graham JH. Genomic coadaptation and developmental stability in hybrid zones. Acta Zoologica Fennica. 1992;191:121–131. [Google Scholar]

122. Leary RF, Allendorf FW, Knudsen KL, Thorgaard GH. Heterozygosity and developmental stability in gynogenetic diploid and triploid rainbow trout. Heredity (Edinburgh) 1985;54(Pt 2):219–25. [PubMed] [Google Scholar]

123. Roff D. Evolutionary quantitative genetics: Are we in danger of throwing out the baby with the bathwater? Annales Zoologici Fennici, JSTOR. 2003:315–320. [Google Scholar]

124. Magnus P, Berg K, Bjerkedal T. Association of parental consanguinity with decreased birth weight and increased rate of early death and congenital malformations. Clinical Genetics. 1985;28(4):335–342. [PubMed] [Google Scholar]

125. Bittles AH, Black ML. Consanguinity, human evolution, and complex diseases. Proceedings of the National Academy of Sciences. 2010;107(suppl 1):1779–1786. [PMC free article] [PubMed] [Google Scholar]

126. Stinchcombe JR, Kirkpatrick M. Genetics and evolution of function-valued traits: understanding environmentally responsive phenotypes. Trends in Ecology & Evolution. 2012;27(11):637–647. [PubMed] [Google Scholar]

127. Rice S. A general population genetic theory for the evolution of developmental interactions. PNAS. 2002;99(24):15518–15523. [PMC free article] [PubMed] [Google Scholar]

128. Morrissey MB. Evolutionary quantitative genetics of nonlinear developmental systems. Evolution. 2015;69(8):2050–66. [PubMed] [Google Scholar]

129. Klingenberg CP, Nijhout HF. Genetics of fluctuating asymmetry: A developmental model of developmental instability. Evolution. 1999;53(2):358–375. [PubMed] [Google Scholar]

130. Ramler D, Mitteroecker P, Shama LN, Wegner KM, Ahnelt H. Nonlinear effects of temperature on body form and developmental canalization in the threespine stickleback. J Evol Biol. 2014 [PubMed] [Google Scholar]

131. Hartl DL, Dykhuizen DE, Dean AM. Limits of adaptation: the evolution of selective neutrality. Genetics. 1985;111(3):655–74. [PMC free article] [PubMed] [Google Scholar]

132. Wright S. Evolution and the Genetics of Populations, Volume 3: Experimental results and evolutionary deductions. University of Chicago Press; Chicago: 1977. [Google Scholar]

133. Badyaev AV, Foresman KR. Extreme environmental change and evolution: stress-induced morphological variation is strongly concordant with patterns of evolutionary divergence in shrew mandibles. Proc R Soc Lond B Biol Sci. 2000;267(1441):371–7. [PMC free article] [PubMed] [Google Scholar]

134. Steiner UK, van Buskirk J. Environmental stress and the costs of whole-organism phenotypic plasticity in tadpoles. J Evol Biol. 2008;21(1):97–103. [PubMed] [Google Scholar]

135. Hill AV. The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. J Physiol. 1910;40:4–7. [Google Scholar]

136. Weiss JN. The Hill equation revisited: uses and misuses. The FASEB Journal. 1997;11(11):835–841. [PubMed] [Google Scholar]

137. Steinacher A, Bates DG, Akman OE, Soyer OS. Nonlinear Dynamics in Gene Regulation Promote Robustness and Evolvability of Gene Expression Levels. PLOS ONE. 2016;11(4):e0153295. [PMC free article] [PubMed] [Google Scholar]

138. Zarai Y, Margaliot M, Tuller T. Optimal Down Regulation of mRNA Translation. Scientific Reports. 2017;7:41243. [PMC free article] [PubMed] [Google Scholar]

139. Lander AD, Nie Q, Wan FY. Do morphogen gradients arise by diffusion? Developmental cell. 2002;2(6):785–796. [PubMed] [Google Scholar]

140. Zhang YT, Alber MS, Newman SA. Mathematical modeling of vertebrate limb development. Mathematical biosciences. 2013;243(1):1–17. [PubMed] [Google Scholar]

141. Le Rouzic A, Alvarez-Castro JM, Hansen TF. The Evolution of Canalization and Evolvability in Stable and Fluctuating Environments. Evolutionary Biology. 2013;40(3):317–340. [Google Scholar]

142. Pelabon C, Hansen TF, Carter AJ, Houle D. Evolution of variation and variability under fluctuating, stabilizing, and disruptive selection. Evolution. 2010;64(7):1912–25. [PubMed] [Google Scholar]

143. Hornstein E, Shomron N. Canalization of development by microRNAs. Nat Genet. 2006;38(Suppl):S20–4. [PubMed] [Google Scholar]

144. Huizinga J, Stanley KO, Clune J. The Emergence of Canalization and Evolvability in an Open-Ended, Interactive Evolutionary System. 2017 arXiv preprint arXiv:1704.05143. [PubMed] [Google Scholar]

145. Kim MS, Kim JR, Kim D, Lander AD, Cho KH. Spatiotemporal network motif reveals the biological traits of developmental gene regulatory networks in Drosophila melanogaster. BMC Systems Biology. 2012;6(1):31. [PMC free article] [PubMed] [Google Scholar]

146. Young NM, Chong HJ, Hu D, Hallgrímsson B, Marcucio RS. Quantitative analyses link modulation of sonic hedgehog signaling to continuous variation in facial growth and shape. Development. 2010;137(20):3405–3409. [PMC free article] [PubMed] [Google Scholar]

147. Lewontin RC. The genetic basis of evolutionary change. Columbia University Press; New York: 1974. [Google Scholar]

148. Xu Q, Jamniczky H, Hu D, Green RM, Marcucio RS, Hallgrimsson B, Mio W. Correlations between the morphology of sonic hedgehog expression domains and embryonic craniofacial shape. Evolutionary biology. 2015;42(3):379–386. [PMC free article] [PubMed] [Google Scholar]

149. Epp JR, Niibori Y, Liz Hsiang HL, Mercaldo V, Deisseroth K, Josselyn SA, Frankland PW. Optimization of CLARITY for Clearing Whole-Brain and Other Intact Organs(1,2,3) eNeuro. 2015;2(3) [PMC free article] [PubMed] [Google Scholar]

150. Martinez-Abadias N, Mateu Estivill R, Sastre Tomas J, Motch Perrine S, Yoon M, Robert-Moreno A, Swoger J, Russo L, Kawasaki K, Richtsmeier J, Sharpe J. Quantification of gene expression patterns to reveal the origins of abnormal morphogenesis. bioRxiv. 2018 [PMC free article] [PubMed] [Google Scholar]

151. Martínez-Abadías N, Mateu R, Niksic M, Russo L, Sharpe J. Geometric Morphometrics on Gene Expression Patterns Within Phenotypes: A Case Example on Limb Development. Systematic Biology. 2016;65(2):194–211. [PMC free article] [PubMed] [Google Scholar]

152. Hu D, Young NM, Xu Q, Jamniczky H, Green RM, Mio W, Marcucio RS, Hallgrimsson B. Signals from the brain induce variation in avian facial shape. Dev Dyn. 2015;244(9):1133–1143. [PMC free article] [PubMed] [Google Scholar]

153. Matamoro-Vidal A, Salazar-Ciudad I, Houle D. Making quantitative morphological variation from basic developmental processes: Where are we? The case of the Drosophila wing. Developmental Dynamics. 2015;244(9):1058–1073. [PMC free article] [PubMed] [Google Scholar]

What does it mean when a trait is deeply canalized?

What is true about canalized traits?

Which term describes the process of many genes acting together to determine a trait?

Which type of research is helpful in clarifying the interaction of genes and environment?