Biased Polyphenism in Polydactylous Cats Carrying a Single Point Mutation: The Hemingway Model for Digit Novelty
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Point mutations in a cis-regulatory element of Sonic Hedgehog are frequently associated with preaxial polydactyly in humans, mice, and cats. The Hemingway mutant in the Maine Coon cat exhibits polyphenic effects of polydactyly that are not equally distributed. A statistical analysis of a comprehensive data base of Hemingway mutants reveals a biased and discontinuous distribution of extra digits. Further biases exist in the difference of effects in fore- versus hind-limbs and in left–right asymmetry. These non-equally distributed phenotypic effects cannot be explained by the point mutation alone. We propose a double mapping model, termed the Hemingway Model, to account for the biased distribution of supernumerary digits. The model is based on the random bistability of individual cells in the limb area affected by the mutation and on the application of the Central Limit Theorem. It proposes two kinds of mapping events that (a) transform a mutational effect of single additive changes into a continuous distribution, and (b) transform the continuous distribution into discrete character states via developmental threshold effects. The threshold widths for the occurrence of discrete extra digits are specified as units of standard deviations of the continuous variable. This makes it possible to specify the generation of empirical developmental variables (the liability of quantitative genetics) as a result of developmental parameters that give rise to biased morphological patterns and phenotypic novelty.
KeywordsPolydactyly Polyphenism Limb development Central Limit Theorem Developmental thresholds Evolutionary innovation Phenotypic novelty
We thank the PolyTrak team, especially K. Bussard, USA, and V. Bode, Netherlands, for technical assistance with using PolyTrak. We also thank the experienced Maine Coon breeders, M. Roth and P. Nagl in Germany and S. Otten-Boult in the Netherlands, for their valuable support and patience in answering our questions. P. Shevtsova, a Maine Coon breeder in Moscow, provided the picture of the Hemingway mutant. The X-rays are reproduced with kind permission from S. Otten-Boult. We also express our thanks to two anonymous reviewers for their valuable comments and to Tim Peterson for help with the elements of style.
- Adams, W. J. (2009). The life and times of the central limit theorem, Vol. 35. American Mathematical Society. History of Mathematics.Google Scholar
- Christley, S. (2008). Modeling and simulation of vertebrate limb development and algorithms for comparative genomics. Dissertation http://etd.nd.edu/ETD-db/theses/available/etd-04162008-120704/unrestricted/ChristleyS042008.pdf. Accessed October 01, 2012.
- Dahte, K. (2009). Molekulare Ursachen isolierter Handfehlbildungen am Beispiel des BMP-Signalwegs und von SHH. Habilitationsschrift. http://www.diss.fu-berlin.de/diss/servlets/MCRFileNodeServlet/FUDISS_derivate_000000008148/Habilitationsschrift_Dathe_final.pdf?hosts=.
- Driess, S. J. (2005). Punktmutationsanalysen bei GLI3-assoziierten Krankheitsbildern: Greig Cephalopolysyndaktylie-Syndrom, Pallister-Hall-Syndrom und isolierte Polydaktylien. Dissertation, University of Marburg.Google Scholar
- Falconer, D. S. (1989). Introduction to quantitative genetics. New York: Longman Scientific & Technical.Google Scholar
- Farooq, M., Troelsen, J. E., Boyd, M., Eiberg, H., Hansen, L., Hussain, M. S., et al. (2010). Preaxial polydactylous/triphalangeal thumb is associated with changed transcription factor-binding affinity in a family with a novel point mutation in the long range cis-regulator element ZRS. European Journal of Human Genetics, 18(6), 733–736.PubMedCentralPubMedCrossRefGoogle Scholar
- Fischer, H. (2011). A History of the central limit theorem. From classical to modern probability theory. New York: Springer.Google Scholar
- Hamelin, A. (2011). La Polydactylousie du Maine Coon. École Nationale Vétérinaire d’Alfort. Dissertation http://theses.vet-alfort.fr/telecharger.php?id=1334. Accessed October 01, 2012.
- Kuss, P., Villavicencio-Lorini, P., Witte, F., Klose, J., Albrecht, A. N., Seemann, P., et al. (2009). Mutant Hoxd13 induces extra digits in a mouse model of synpolydactyly directly and by decreasing retonic acid synthesis. The Journal of Clinical Investigation, 119(1), 146–156.PubMedCentralPubMedGoogle Scholar
- Li, J. (2011). The evolutionary implication of gene expression variation in eukaryotes: From yeast to human. Dissertation, University of Toronto.Google Scholar
- Nijhout, H. F. (2004). Stochastic gene expression: Dominance, thresholds and boundaries. In R. A. Veitia (Ed.), The biology of genetic dominance. Austin: Landes Bioscience.Google Scholar
- Patterson, V. L., Damrau, C., Paudyal, A., Reeve, B., Grimes, D. T., Stewart, M. E., et al. (2009). Mouse hitchhiker mutants have spina bifida, dorso-ventral patterning defects and polydactyly: Identification of Tulp3 as a novel negative regulator of the Sonic hedgehog pathway. Human Molecular Genetics, 18(19), 1719–1739.PubMedCentralPubMedCrossRefGoogle Scholar
- Pigliucci, M., & Müller, G. B. (Eds.). (2010). Evolution—The extended synthesis. Cambridge: MIT Press.Google Scholar
- Saunders, J. W., & Gasseling, M. T. (1968). Ectodermal-mesenchymal interactions in the origin of limb symmetry. In R. E. Fleischmajer & R. Billingham (Eds.), Epithelial-mesenchymal interactions (pp. 78–97). Baltimore: Lippincott Williams & Wilkins.Google Scholar
- Semerci, C. N., Demirkan, F., Özdemir, M., Biskin, E., Akin, B., Bagci, H., et al. (2009). Homozygous feature of isolated triphalangeal thumb—Preaxial polydactyly linked to 7q36: No phenotypic difference between homozygotes and heterozygotes. Clinical Genetics, 76(1), 85–90.PubMedCrossRefGoogle Scholar
- Shapiro, M. D., Bell, M. A., & Kingsley, D. M. (2006). Parallel genetic origins of pelvic reduction in vertebrates. Proceedings of the National Academy of Sciences, 103, 3753–13758.Google Scholar
- Wieczorek, D., Pawlik, B., Li, Y., Akarsu, N. A., Caliebe, N. A., May, K. J. W., et al. (2010). A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS duplications underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or without triphalangeal thumb. Human Mutation, 31(1), 81–89.PubMedCrossRefGoogle Scholar
- Zhu, J., Zhang, Y.-T., Alber, M. S., & Newman, S. A. (2010). Bare bones patterning formation: A core regulatory network in varying geometrics reproduces major features of vertebrate limb development and evolution. PLoS ONE, 5(5), e10892. doi: 10.1371/journal.pone.0010892.PubMedCentralPubMedCrossRefGoogle Scholar