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Cited by 106Evolution and Genetic DynamicsDevelopmental Biology and Gene RegulationMorphological variations and asymmetry

Developmental nonlinearity drives phenotypic robustness

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Green, Rebecca M., Fish, Jennifer L., Young, Nathan M., Smith, Francis J., Roberts, Benjamin, Dolan, Katie, Choi, Irene, Leach, Courtney L. +6 more·2017·Nature Communications
DOI 10.1038/s41467-017-02037-7PMC PMC5719035
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Abstract

Robustness to perturbation is a fundamental feature of complex organisms. Mutations are the raw material for evolution, yet robustness to their effects is required for species survival. The mechanisms that produce robustness are poorly understood. Nonlinearities are a ubiquitous feature of development that may link variation in development to phenotypic robustness. Here, we manipulate the gene dosage of a signaling molecule, Fgf8, a critical regulator of vertebrate development. We demonstrate that variation in Fgf8 expression has a nonlinear relationship to phenotypic variation, predicting levels of robustness among genotypes. Differences in robustness are not due to gene expression variance or dysregulation, but emerge from the nonlinearity of the genotype–phenotype curve. In this instance, embedded features of development explain robustness differences. How such features vary in natural populations and relate to genetic variation are key questions for unraveling the origin and evolvability of this feature of organismal development.

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  • There is a lack of strong correlation between the magnitude of PICALM alteration and its functional effects in CRISPR-engineered iMGs.

    “We acknowledge a lack of strong correlation between the magnitude of PICALM alteration and its functional effects in CRISPR-engineered iMGs, probably due to technical variations in iMG differentiation and/or the nonlinear relationship between gene expression and cellular phenotypes due to epistasis and systems buffering54,55.”

    From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [54]

    The Introduction describes nonlinear relationships in which variation in gene expression can be buffered before it affects phenotype, supporting the proposed explanation in general. But the paper studies Fgf8 and craniofacial morphology, not PICALM in CRISPR-engineered iMGs; its Discussion also describes developmental nonlinearity as a cause, rather than a consequence, of epistasis. The iMG correlation is the citing authors’ own observation, not a finding attributed to this source. (LLM, conf=0.83)

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References 77 · Cited by 106

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  1. [2]Waddington CH Genetic assimilation of the bithorax phenotype Evolution 1956 10 1 13 10.1111/j.1558-5646.1956.tb02824.x · DOI
  2. [4]Rendel, J. M. Canalization and Gene Control (Logos Press, London, 1967).
  3. [5]Mather K Genetical control of stability in development Heredity 1953 7 297 336 10.1038/hdy.1953.41 · DOI
  4. [6]Thoday J Homeostasis in a selection experiment Heredity 1958 12 401 415 10.1038/hdy.1958.41 · DOI
  5. [7]Scharloo W Mutant expression and canalization Nature 1964 203 1095 1096 10.1038/2031095b0 14223104 · DOI
  6. [8]de Visser JA Perspective: evolution and detection of genetic robustness Evolution 2003 57 1959 1972 14575319
  7. [9]Siegal ML Leu JY On the nature and evolutionary impact of phenotypic robustness mechanisms Annu. Rev. Ecol. Evol. Syst. 2014 45 496 517 10.1146/annurev-ecolsys-120213-091705 26034410 PMC4448758 · DOI
  8. [10]Wagner GP Booth G Bagheri-Chaichian H A population genetic theory of canalization Evolution 1997 51 329 347 10.1111/j.1558-5646.1997.tb02420.x 28565347 · DOI
  9. [11]Rutherford SL From genotype to phenotype: buffering mechanisms and the storage of genetic information Bioessays 2000 22 1095 1105 10.1002/1521-1878(200012)22:12<1095::AID-BIES7>3.0.CO;2-A 11084625 · DOI
  10. [13]Sangster TA HSP90 affects the expression of genetic variation and developmental stability in quantitative traits Proc. Natl. Acad. Sci. USA 2008 105 2963 2968 10.1073/pnas.0712200105 18287065 PMC2268568 · DOI · Paper page
  11. [14]Queitsch C Sangster TA Lindquist S Hsp90 as a capacitor of phenotypic variation Nature 2002 417 618 624 10.1038/nature749 12050657 · DOI · Paper page
  12. [15]Hornstein E Shomron N Canalization of development by microRNAs Nat. Genet. 2006 38 S20 S24 10.1038/ng1803 16736020 · DOI · Paper page
  13. [16]Klingenberg CP Nijhout HF Genetics of fluctuating asymmetry: a developmental model of developmental instability Evolution 1999 53 358 375 10.1111/j.1558-5646.1999.tb03772.x 28565420 · DOI
  14. [17]Hallgrimsson B Deciphering the palimpsest: studying the relationship between morphological integration and phenotypic covariation Evol. Biol. 2009 36 355 376 10.1007/s11692-009-9076-5 23293400 PMC3537827 · DOI
  15. [18]Hallgrimsson B The brachymorph mouse and the developmental-genetic basis for canalization and morphological integration Evol. Dev. 2006 8 61 73 10.1111/j.1525-142X.2006.05075.x 16409383 · DOI
  16. [19]Siegal ML Bergman A Waddington’s canalization revisited: developmental stability and evolution Proc. Natl. Acad. Sci. USA 2002 99 10528 10532 10.1073/pnas.102303999 12082173 PMC124963 · DOI
  17. [20]Bergman A Siegal ML Evolutionary capacitance as a general feature of complex gene networks Nature 2003 424 549 552 10.1038/nature01765 12891357 · DOI
  18. [21]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 e0153295 10.1371/journal.pone.0153295 27082741 PMC4833316 · DOI
  19. [22]Kaufmann, S. The Origins of Order (Oxford University Press, New York, 1993).
  20. [23]ten Tusscher KH Hogeweg P The role of genome and gene regulatory network canalization in the evolution of multi-trait polymorphisms and sympatric speciation BMC Evol. Biol. 2009 9 159 10.1186/1471-2148-9-159 19589138 PMC3224660 · DOI
  21. [24]Felix MA Barkoulas M Pervasive robustness in biological systems Nat. Rev. Genet. 2015 16 483 496 10.1038/nrg3949 26184598 · DOI
  22. [25]Gonze D Abou-Jaoudé W The Goodwin model: behind the Hill function PLoS ONE 2013 8 e69573 10.1371/journal.pone.0069573 23936338 PMC3731313 · DOI
  23. [26]Frank, T. D., Cavadas, M. A. S, Nguyen, L. K. & Cheong, A. in Nonlinear Dynamics in Biological Systems. (eds Carballido-Landeira, J. & Escribano, B.) Vol 7 (Springer, Chicago, IL, USA, 2016).
  24. [27]Lander AD Nie Q Wan FY Do morphogen gradients arise by diffusion? Dev. Cell 2002 2 785 796 10.1016/S1534-5807(02)00179-X 12062090 · DOI
  25. [28]Hallgrimsson B Mio W Marcucio RS Spritz R Let’s face it–complex traits are just not that simple PLoS Genet. 2014 10 e1004724 10.1371/journal.pgen.1004724 25375250 PMC4222688 · DOI
  26. [29]Lewontin, R. C. The Genetic Basis of Evolutionary Change Vol. 560 (Columbia University Press, New York and London, 1974).
  27. [30]Hansen TF Measuring gene interactions Methods Mol. Biol. 2015 1253 115 143 10.1007/978-1-4939-2155-3_7 25403530 · DOI
  28. [31]Falahati-Anbaran M Development of microsatellite markers for the neotropical vine Dalechampia scandens (Euphorbiaceae) Appl. Plant Sci. 2013 1 1200492 10.3732/apps.1200492 PMC4105026 25202553 · DOI
  29. [32]Alberch P From genes to phenotype: dynamical systems and evolvability Genetica 1991 84 5 11 10.1007/BF00123979 1874440 · DOI · Paper page
  30. [33]Rice S A general population genetic theory for the evolution of developmental interactions PNAS 2002 99 15518 15523 10.1073/pnas.202620999 12438697 PMC137749 · DOI
  31. [34]Morrissey MB Evolutionary quantitative genetics of nonlinear developmental systems Evolution 2015 69 2050 2066 10.1111/evo.12728 26174586 · DOI
  32. [35]Rice S The evolution of canalization and the breaking of von Baer’s laws: Modeling the evolution of development with epistasis Evolution 1998 52 647 656 10.1111/j.1558-5646.1998.tb03690.x 28565257 · DOI
  33. [36]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 3405 3409 10.1242/dev.052340 20826528 PMC2947484 · DOI
  34. [37]Crossley PH Martin GR The mouse Fgf8 gene encodes a family of polypeptides and is expressed in regions that direct outgrowth and patterning in the developing embryo Development 1995 121 439 451 7768185
  35. [38]Lewandoski, M., Meyers, E. & Martin, G. in Cold Spring Harbor Symposia on Quantitative Biology 159–168 (Cold Spring Harbor Laboratory Press, New York, 1997). 9598348
  36. [39]Hu D Marcucio RS A SHH-responsive signaling center in the forebrain regulates craniofacial morphogenesis via the facial ectoderm Development 2009 136 107 116 10.1242/dev.026583 19036802 PMC2685963 · DOI
  37. [40]Abu-Issa R Smyth G Smoak I Yamamura Ki Meyers EN Fgf8 is required for pharyngeal arch and cardiovascular development in the mouse Development 2002 129 4613 4625 12223417
  38. [41]Creuzet S Schuler B Couly G Le Douarin NM Reciprocal relationships between Fgf8 and neural crest cells in facial and forebrain development Proc. Natl. Acad. Sci. USA 2004 101 4843 4847 10.1073/pnas.0400869101 15041748 PMC387336 · DOI
  39. [42]Kawauchi S Fgf8 expression defines a morphogenetic center required for olfactory neurogenesis and nasal cavity development in the mouse Development 2005 132 5211 5223 10.1242/dev.02143 16267092 · DOI
  40. [43]Trumpp A Depew MJ Rubenstein JL Bishop JM Martin GR Cre-mediated gene inactivation demonstrates that FGF8 is required for cell survival and patterning of the first branchial arch Genes Dev. 1999 13 3136 3148 10.1101/gad.13.23.3136 10601039 PMC317178 · DOI
  41. [44]Fish JL Satb2, modularity, and the evolvability of the vertebrate jaw Evol. Dev. 2011 13 549 564 10.1111/j.1525-142X.2011.00511.x 23016939 · DOI
  42. [45]Hu D Marcucio RS Unique organization of the frontonasal ectodermal zone in birds and mammals Dev. Biol. 2009 325 200 210 10.1016/j.ydbio.2008.10.026 19013147 PMC2662765 · DOI
  43. [46]Meyers EN Lewandoski M Martin GR An Fgf8 mutant allelic series generated by Cre- and Flp-mediated recombination Nat. Genet. 1998 18 136 141 10.1038/ng0298-136 9462741 · DOI
  44. [47]Reid BS Yang H Melvin VS Taketo MM Williams T Ectodermal Wnt/beta-catenin signaling shapes the mouse face Dev. Biol. 2011 349 261 269 10.1016/j.ydbio.2010.11.012 21087601 PMC3057077 · DOI
  45. [48]Mitteroecker P Gunz P Advances in geometric morphometrics Evol. Biol. 2009 36 235 247 10.1007/s11692-009-9055-x · DOI
  46. [49]Zelditch, M. L., Swiderski, D. L. & Sheets, H. D. Geometric Morphometrics for Biologists: A Primer (Elsevier Academic Press, New York and London, 2012).
  47. [50]Percival CJ Green R Marcucio R Hallgrimsson B Surface landmark quantification of embryonic mouse craniofacial morphogenesis BMC Dev. Biol. 2014 14 31 10.1186/1471-213X-14-31 25059626 PMC4222779 · DOI
  48. [51]Collyer ML Adams DC Otarola-Castillo E Sherratt E A method for analysis of phenotypic change for phenotypes described by high-dimensional data Heredity 2015 115 357 365 10.1038/hdy.2014.75 25204302 PMC4815463 · DOI
  49. [52]Lerner, I. M. Genetic Homeostasis (Wiley & Sons, New York, 1954).
  50. [53]Griffin JN Fgf8 dosage determines midfacial integration and polarity within the nasal and optic capsules Dev. Biol. 2013 374 185 197 10.1016/j.ydbio.2012.11.014 23201021 PMC4086262 · DOI
  51. [55]Shaffer JR Genome-wide association study reveals multiple loci influencing normal human facial morphology PLoS Genet. 2016 12 e1006149 10.1371/journal.pgen.1006149 27560520 PMC4999139 · DOI
  52. [56]Cole JB Genomewide association study of African children identifies association of SCHIP1 and PDE8A with facial size and shape PLoS Genet. 2016 12 e1006174 10.1371/journal.pgen.1006174 27560698 PMC4999243 · DOI
  53. [57]Zhang YT Alber MS Newman SA Mathematical modeling of vertebrate limb development Math. Biosci. 2013 243 1 17 10.1016/j.mbs.2012.11.003 23219575 · DOI
  54. [58]Hansen TF Evolution of genetic architecture under directional selection Evolution 2006 60 1523 1536 10.1111/j.0014-3820.2006.tb00498.x 17017054 · DOI
  55. [59]Hartl DL Dykhuizen DE Dean AM Limits of adaptation: the evolution of selective neutrality Genetics 1985 111 655 674 3932127 PMC1202663
  56. [60]Wright, S. Evolution and the Genetics of Populations, Volume 3: Experimental Results and Evolutionary Deductions (University of Chicago Press, Chicago, IL, USA, 1977).
  57. [61]Wolf JB Developmental interactions and the constituents of quantitative variation Evol. Int. J. Org. Evol. 2001 55 232 245 10.1111/j.0014-3820.2001.tb01289.x 11308082 · DOI
  58. [62]Cheverud JM Quantitative genetics and developmental constraints on evolution by selection J. Theor. Biol. 1984 110 155 171 10.1016/S0022-5193(84)80050-8 6492829 · DOI
  59. [63]Wagner GP Altenberg L Complex adaptations and the evolution of evolvability Evolution 1996 50 967 976 10.1111/j.1558-5646.1996.tb02339.x 28565291 · DOI
  60. [64]Hendrikse JL Parsons TE Hallgrimsson B Evolvability as the proper focus of evolutionary developmental biology Evol. Dev. 2007 9 393 401 10.1111/j.1525-142X.2007.00176.x 17651363 · DOI
  61. [65]Sailer ZR Harms MJ Detecting high-order epistasis in nonlinear genotype-phenotype maps Genetics 2017 205 1079 1088 10.1534/genetics.116.195214 28100592 PMC5340324 · DOI
  62. [66]Hermisson J Hansen TF Wagner GP Epistasis in polygenic traits and the evolution of genetic architecture under stabilizing selection Am. Nat. 2003 161 708 734 10.1086/374204 12858280 · DOI
  63. [67]Mackay TFC Epistasis and quantitative traits:using model organisms to study gene-gene interactions Nat. Rev. Genet. 2014 15 22 33 10.1038/nrg3627 24296533 PMC3918431 · DOI
  64. [68]Brewer S Williams T Loss of AP-2α impacts multiple aspects of ventral body wall development and closure Dev. Biol. 2004 267 399 417 10.1016/j.ydbio.2003.11.021 15013802 · DOI
  65. [69]Zhang W Genome-wide association mapping of quantitative traits in outbred mice G3 (Bethesda) 2012 2 167 174 10.1534/g3.111.001792 22384395 PMC3284324 · DOI
  66. [71]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 154 544 553 10.1002/ajpa.22545 24888714 PMC4425270 · DOI
  67. [73]Adams DC Otarola-Castillo E Geomorph: an R package for the collection and analysis of geometric morphometric shape data Methods Ecol. Evol. 2013 4 393 399 10.1111/2041-210X.12035 · DOI
  68. [75]Parsons TE Epigenetic integration of the developing brain and face Dev. Dyn. 2011 240 2233 2244 10.1002/dvdy.22729 21901785 PMC3246636 · DOI
  69. [76]Smith FJ Divergence of craniofacial developmental trajectories among avian embryos Dev. Dyn. 2015 244 1158 1167 10.1002/dvdy.24262 PMC4544654 25703037 · DOI
  70. [77]Fish JL Sklar RS Woronowicz KC Schneider RA Multiple developmental mechanisms regulate species-specific jaw size Development 2014 141 674 684 10.1242/dev.100107 24449843 PMC3899819 · DOI
  71. [78]Livak KJ Schmittgen TD Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method Methods 2001 25 402 408 10.1006/meth.2001.1262 11846609 · DOI · Paper page
  72. [79]Vandesompele J Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes Genome Biol. 2002 3 research0034.1 research0034.11 10.1186/gb-2002-3-7-research0034 12184808 PMC126239 · DOI · Paper page
  73. [80]Adams DC Collyer ML Permutation tests for phylogenetic comparative analyses of high-dimensional shape data: what you shuffle matters Evolution 2015 69 823 829 10.1111/evo.12596 25641367 · DOI

Authors
Green, R. M., Fish, J. L., Young, N. M., Smith, F. J., Roberts, B., Dolan, K., Choi, I., Leach, C. L., Gordon, P., Cheverud, J. M., Roseman, C. C., Williams, T. J., Marcucio, R. S., & Hallgrímsson, B.
Affiliations
  • University of Calgary (CA)
  • University of Massachusetts Lowell (US)
  • University of California, San Francisco (US)
  • University of Colorado Anschutz (US)
  • Loyola University Chicago (US)
  • University of Illinois Urbana-Champaign (US)
Corresponding author
  • Marcucio, Ralph S.
  • Hallgrímsson, Benedikt
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-12-06
Volume
8
Issue
1
Pages
1970-1970
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-017-02037-7
PMC
PMC5719035
OpenAlex
W2774097669
Cited by
106
References
77
Citations by year
2026: 8 · 2025: 14 · 2024: 9 · 2023: 15 · 2022: 9 · 2021: 16 · 2020: 8 · 2019: 21 · 2018: 6
FWCI
6.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Loyola eCommons (Loyola University of Chicago) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health (NIH-R01)
  • Natural Sciences and Engineering Research Council of Canada (238992, 238992‐17)
  • National Institute of Dental and Craniofacial Research (R01DE019843, R01DE019638)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Physical Sciences › Mathematics › Geometry and Topology › Morphological variations and asymmetry
Keywords
phenotypic robustness, FGF8, gene dosage, genotype-phenotype mapping, developmental variation, vertebrate development, evolvability
MeSH terms
Animals, Computer Simulation, Biological Evolution, Gene Expression Regulation, Genotype, Male, Models, Genetic, Mutation, Phenotype, RNA, Genetic Variation, Gene Expression, Nonlinear Dynamics, Gene Dosage, Evolution, Molecular, Mice, Fibroblast Growth Factor 8, Gene Regulatory Networks

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