The genetics and evolution of complex traits

The genetics and evolution of complex traits

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Complex traits are features whose properties are controlled by many genes and whose inheritance does not follow the simple rules of Mendelian genetics. The principal reasons complex traits do not follow Mendelian inheritance is that the relationship between genetic variation and phenotypic variation is non-linear, and the relevant genes do not interact additively.

We are developing methods of computing complex phenotypes by writing differential equation models for known developmental and physiological processes and examining how such systems behave under genetic variation. We have shown that the non-linear and non-additive properties of gene-trait relationships result in a variable and context-dependent correlation between genetic variation and phenotypic variation. Alleles that have a major effect on a trait in one genetic background can be without effect in a different genetic background. This context-dependency of the effects of genetic variation provides a mechanistic explanation of the variable expressivity and incomplete penetrance that are common features of the genetics of complex traits.

We are currently working on methods for analyzing and predicting, through mathematical modeling and computer simulation, the association between genetic variation and phenotypic variation in complex traits. We are particularly interested in how genetic variation affects the development and evolution of complex traits and in the evolution of developmental stability.

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Selected Publications on the Development, Genetics and Evolution of Complex Traits

Anderson, D., Mattingly, J., Nijhout, H. F., and Reed, M.C. 2007. Propagation of fluctuations in biochemical systems, I. Linear SSC networks. Bull. Math. Biol. 69: 1791-1813.

Leduc, D., Escartin, F., Nijhout, H.F., Reed, M.C., Liebl, U., Skouloubris, S. and Myllykallio, H. 2007. Flavin-dependent thymidylate synthase ThyX activity: Implications for the folate cycle in bacteria. J. Bacteriol. 189: 8537-8545.

Nijhout, H.F., Reed, M.C. and Ulrich, C.M. 2007. A day in the life of cell metabolism. Biological Theory 2: 124-127.

Brandon, R.N. and Nijhout, H.F. 2007. The empirical non-equivalence of genic and genotypic models of selection: A decisive refutation of genic selectionism and pluralistic genic selectionism. Philosophy of Science 73: 277-297.

Veitia, R. and Nijhout, H.F. 2006. The robustness of the transcriptional response to alterations in morphogenetic gradients. BioEssays 28: 282-289.

Nijhout, H. F., Reed, M., Anderson, D., Mattingly, J., James, S. J., and Ulrich, C. M. 2006. Long-range allosteric interactions between the folate and methionine cycles stabilize DNA methylation rate. Epigenetics 1: 81-87.

Ulrich , C.M., Nijhout , H.F. and Reed, M.C. 2006. Mathematical modeling: epidemiology meets systems biology. Cancer Epidemiol. Biomarkers Prev. 15: 827-829.

Reed, M.C., Nijhout, H.F., Neuhouser, M.L., Gregory J.F. III., Shane, B., James, S.J., Boynton, A. and Ulrich, C.M. 2006. A mathematical model gives insights into nutritional and genetic aspects of folate-mediated one-carbon metabolism. J. Nutr. 136: 2653-2661.

Nijhout, H.F., Davidowitz, G. and Roff, D.A. 2006. A quantitative analysis of the mechanism that controls body size in Manduca sexta. Journal of Biology 5:16 1-16.

Boyles, A.L. Billups, A.V., Deak, K.L., Siegel, D.G., Mehltretter, L., Slifer, S.H. Bassuk, A.G., Kessler, J.A., Reed, M.C. Nijhout, H.F. George, T.M., Enterline, D.S., Gilbert, J.R., Speer, M.C., and the NTD Collaborative Group. 2006. Neural tube defects and folate pathway genes: family-based association tests of gene–gene and gene–environment interactions. Environ. Health Perspect. 114:1547–1552.

Nijhout, H.F., Reed, M.C., Lam, S-L., Shane, B., Gregory, J.F., and Ulrich, C.M. 2006. In silico experimentation with a model of hepatic mitochondrial folate metabolism. Theoretical Biology and Medical Modelling 3: 40ff.

Edgar, B.A. and Nijhout, H.F. 2004. Growth and cell cycle control in Drosophila. In: Cell Growth: Control of Cell Size (Hall, M.N., Raff, M. and Thomas, G., eds.), pp. 23-83. ColdSpring Harbor Laboratory press, Cold Spring Harbor, NY.

Davidowitz, G., D'Amico, L.J. and Nijhout, H.F. 2004. The effects of environmental variation on a mechanism that controls insect body size. Evolutionary Ecology Research 6: 49-62. (Ask)

Nijhout, H.F. 2004. Stochastic gene expression: dominance, thresholds, and boundaries. In: The Biology of Genetic Dominance (R. Veitia, ed.). Landes Biosciences. (preprint).

Nijhout, H.F. and Davidowitz, G. 2003. Developmental perspectives on phenotypic variation, canalization, and fluctuating asymmetry. In: Developmental Instability: Causes and Consequences (M. Polak, ed.), pp. 3-13. Oxford University Press, Oxford, UK.

Nijhout, H.F. 2003. The control of body size in insects. Developmental Biology 261: 1-9.(PDF)

Nijhout, H.F. 2003. The control of growth. Development 130: 5863-5867.(PDF)

Nijhout, H.F. 2003. The importance of context in genetics. American Scientist 91: 416-423. (Ask).

Reed, M.C., Nijhout, H.F., Sparks, R. and Ulrich, C.M. 2003. A mathematical model of the methionine cycle. Journal of Theoretical Biology 226: 33-43. (PDF)

Nijhout, H.F. & Davidowitz, G.2003. Developmental perspectives on phenotypic variation, canalization, and fluctuating asymmetry. In: Developmental Instability: Causes and Consequences (M. Polak, ed.), pp. 3-13. Oxford Univ. Press.

Berg, A.M., Gibson, W.T. and Nijhout, H.F. 2003. A mechanistic study of evolvability using the mitogen activated protein kinase cascade. Evolution & Development 5: 281-294.(PDF)

Nijhout, H.F. 2002. The nature of robustness in development. BioEssays 24: 553-563.(PDF)

Nijhout, H.F. 2002. Gradients, diffusion and genes in pattern formation. In: Origination of Organismal Form (G. Müller and S. Newman, eds.), pp. 165-181. MIT Press.

Nijhout, H.F. 2002. Genetic regulatory networks. In: Encyclopedia of Evolution. Oxford University Press.

Nijhout, H.F. 2001. The ontogeny of phenotypes. In: Cycles of Contingency (S. Oyama, P. Griffiths and R. Gray eds.), pp. 129-140. MIT Press.

Gilchrist, M.A. and H.F. Nijhout. 2001. Non-linear developmental processes as sources of dominance. Genetics 159: 423-432. (PDF)

Emlen, D.J. and H.F. Nijhout. 2000. The development and evolution of exaggerated morphologies in insects. Ann. Rev. Entomol. 45: 661-708.(PDF)

Klingenberg, C.P. and H.F. Nijhout. 1999. Genetics of fluctuating asymmetry: A developmental model of developmental instability. Evolution 53: 358-375.(PDF)

Nijhout, H.F. 1999. When developmental pathways diverge. Proc. Natl. Acad. Sci. 96: 5348-5350.

Klingenberg, C. and H.F. Nijhout. 1998. Competition among growing organs and developmental control of morphological asymmetry. Proc. Roy. Soc. London B 265: 1135-1139.(PDF)

Nijhout, H.F. and D. Emlen. 1998. Competition among body parts in the development and evolution of insect morphology. Proc. Nat. Acad. Sci. 95: 3685-3689. (PDF)

Nijhout, H.F. and S.M. Paulsen. 1997. Developmental models and polygenic characters. Amer. Nat. 149: 394-405.(PDF)

Nijhout, H.F. 1996. Pattern and Process. In: Pattern Formation in the Physical and Biological Sciences. Santa Fe Institute Studies in the Science of Complexity. (H.F. Nijhout, L. Nadel, and D. Stein eds.). Addison-Wesley. New York.

Nijhout, H.F. and D.E. Wheeler. 1995. Growth models of complex allometries in holometabolous insects. Amer. Nat. 148:40-56.(PDF)

Paulsen, S.M. and H.F. Nijhout, 1993. Phenotypic correlation structure among elements of the color pattern in Precis coenia (Lepidoptera: Nymphalidae). Evolution 47: 593-618.

Nijhout, H.F., 1990. Metaphors and the role of genes in development. BioEssays 12:44-446. (PDF)

Nijhout, H.F., 1990. A comprehensive model for color pattern formation in butterflies. Proc. Roy. Soc. B239:81-113.

Nijhout, H.F., G.A. Wray, C. Kremen and C.K. Teragawa, 1986. Ontogeny, phylogeny and evolution of form: An algorithmic approach. Syst. Zool. 35:445-457.

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Publications Relevant Images Home page		Complex traits are features whose properties are controlled by many genes and whose inheritance does not follow the simple rules of Mendelian genetics. The principal reasons complex traits do not follow Mendelian inheritance is that the relationship between genetic variation and phenotypic variation is non-linear, and the relevant genes do not interact additively. We are developing methods of computing complex phenotypes by writing differential equation models for known developmental and physiological processes and examining how such systems behave under genetic variation. We have shown that the non-linear and non-additive properties of gene-trait relationships result in a variable and context-dependent correlation between genetic variation and phenotypic variation. Alleles that have a major effect on a trait in one genetic background can be without effect in a different genetic background. This context-dependency of the effects of genetic variation provides a mechanistic explanation of the variable expressivity and incomplete penetrance that are common features of the genetics of complex traits. We are currently working on methods for analyzing and predicting, through mathematical modeling and computer simulation, the association between genetic variation and phenotypic variation in complex traits. We are particularly interested in how genetic variation affects the development and evolution of complex traits and in the evolution of developmental stability.


Relevant Images Home page		Selected Publications on the Development, Genetics and Evolution of Complex Traits Anderson, D., Mattingly, J., Nijhout, H. F., and Reed, M.C. 2007. Propagation of fluctuations in biochemical systems, I. Linear SSC networks. Bull. Math. Biol. 69: 1791-1813. Leduc, D., Escartin, F., Nijhout, H.F., Reed, M.C., Liebl, U., Skouloubris, S. and Myllykallio, H. 2007. Flavin-dependent thymidylate synthase ThyX activity: Implications for the folate cycle in bacteria. J. Bacteriol. 189: 8537-8545. Nijhout, H.F., Reed, M.C. and Ulrich, C.M. 2007. A day in the life of cell metabolism. Biological Theory 2: 124-127. Brandon, R.N. and Nijhout, H.F. 2007. The empirical non-equivalence of genic and genotypic models of selection: A decisive refutation of genic selectionism and pluralistic genic selectionism. Philosophy of Science 73: 277-297. Veitia, R. and Nijhout, H.F. 2006. The robustness of the transcriptional response to alterations in morphogenetic gradients. BioEssays 28: 282-289. Nijhout, H. F., Reed, M., Anderson, D., Mattingly, J., James, S. J., and Ulrich, C. M. 2006. Long-range allosteric interactions between the folate and methionine cycles stabilize DNA methylation rate. Epigenetics 1: 81-87. Ulrich , C.M., Nijhout , H.F. and Reed, M.C. 2006. Mathematical modeling: epidemiology meets systems biology. Cancer Epidemiol. Biomarkers Prev. 15: 827-829. Reed, M.C., Nijhout, H.F., Neuhouser, M.L., Gregory J.F. III., Shane, B., James, S.J., Boynton, A. and Ulrich, C.M. 2006. A mathematical model gives insights into nutritional and genetic aspects of folate-mediated one-carbon metabolism. J. Nutr. 136: 2653-2661. Nijhout, H.F., Davidowitz, G. and Roff, D.A. 2006. A quantitative analysis of the mechanism that controls body size in Manduca sexta. Journal of Biology 5:16 1-16. Boyles, A.L. Billups, A.V., Deak, K.L., Siegel, D.G., Mehltretter, L., Slifer, S.H. Bassuk, A.G., Kessler, J.A., Reed, M.C. Nijhout, H.F. George, T.M., Enterline, D.S., Gilbert, J.R., Speer, M.C., and the NTD Collaborative Group. 2006. Neural tube defects and folate pathway genes: family-based association tests of gene–gene and gene–environment interactions. Environ. Health Perspect. 114:1547–1552. Nijhout, H.F., Reed, M.C., Lam, S-L., Shane, B., Gregory, J.F., and Ulrich, C.M. 2006. In silico experimentation with a model of hepatic mitochondrial folate metabolism. Theoretical Biology and Medical Modelling 3: 40ff. Edgar, B.A. and Nijhout, H.F. 2004. Growth and cell cycle control in Drosophila. In: Cell Growth: Control of Cell Size (Hall, M.N., Raff, M. and Thomas, G., eds.), pp. 23-83. ColdSpring Harbor Laboratory press, Cold Spring Harbor, NY. Davidowitz, G., D'Amico, L.J. and Nijhout, H.F. 2004. The effects of environmental variation on a mechanism that controls insect body size. Evolutionary Ecology Research 6: 49-62. (Ask) Nijhout, H.F. 2004. Stochastic gene expression: dominance, thresholds, and boundaries. In: The Biology of Genetic Dominance (R. Veitia, ed.). Landes Biosciences. (preprint). Nijhout, H.F. and Davidowitz, G. 2003. Developmental perspectives on phenotypic variation, canalization, and fluctuating asymmetry. In: Developmental Instability: Causes and Consequences (M. Polak, ed.), pp. 3-13. Oxford University Press, Oxford, UK. Nijhout, H.F. 2003. The control of body size in insects. Developmental Biology 261: 1-9.(PDF) Nijhout, H.F. 2003. The control of growth. Development 130: 5863-5867.(PDF) Nijhout, H.F. 2003. The importance of context in genetics. American Scientist 91: 416-423. (Ask). Reed, M.C., Nijhout, H.F., Sparks, R. and Ulrich, C.M. 2003. A mathematical model of the methionine cycle. Journal of Theoretical Biology 226: 33-43. (PDF) Nijhout, H.F. & Davidowitz, G.2003. Developmental perspectives on phenotypic variation, canalization, and fluctuating asymmetry. In: Developmental Instability: Causes and Consequences (M. Polak, ed.), pp. 3-13. Oxford Univ. Press. Berg, A.M., Gibson, W.T. and Nijhout, H.F. 2003. A mechanistic study of evolvability using the mitogen activated protein kinase cascade. Evolution & Development 5: 281-294.(PDF) Nijhout, H.F. 2002. The nature of robustness in development. BioEssays 24: 553-563.(PDF) Nijhout, H.F. 2002. Gradients, diffusion and genes in pattern formation. In: Origination of Organismal Form (G. Müller and S. Newman, eds.), pp. 165-181. MIT Press. Nijhout, H.F. 2002. Genetic regulatory networks. In: Encyclopedia of Evolution. Oxford University Press. Nijhout, H.F. 2001. The ontogeny of phenotypes. In: Cycles of Contingency (S. Oyama, P. Griffiths and R. Gray eds.), pp. 129-140. MIT Press. Gilchrist, M.A. and H.F. Nijhout. 2001. Non-linear developmental processes as sources of dominance. Genetics 159: 423-432. (PDF) Emlen, D.J. and H.F. Nijhout. 2000. The development and evolution of exaggerated morphologies in insects. Ann. Rev. Entomol. 45: 661-708.(PDF) Klingenberg, C.P. and H.F. Nijhout. 1999. Genetics of fluctuating asymmetry: A developmental model of developmental instability. Evolution 53: 358-375.(PDF) Nijhout, H.F. 1999. When developmental pathways diverge. Proc. Natl. Acad. Sci. 96: 5348-5350. Klingenberg, C. and H.F. Nijhout. 1998. Competition among growing organs and developmental control of morphological asymmetry. Proc. Roy. Soc. London B 265: 1135-1139.(PDF) Nijhout, H.F. and D. Emlen. 1998. Competition among body parts in the development and evolution of insect morphology. Proc. Nat. Acad. Sci. 95: 3685-3689. (PDF) Nijhout, H.F. and S.M. Paulsen. 1997. Developmental models and polygenic characters. Amer. Nat. 149: 394-405.(PDF) Nijhout, H.F. 1996. Pattern and Process. In: Pattern Formation in the Physical and Biological Sciences. Santa Fe Institute Studies in the Science of Complexity. (H.F. Nijhout, L. Nadel, and D. Stein eds.). Addison-Wesley. New York. Nijhout, H.F. and D.E. Wheeler. 1995. Growth models of complex allometries in holometabolous insects. Amer. Nat. 148:40-56.(PDF) Paulsen, S.M. and H.F. Nijhout, 1993. Phenotypic correlation structure among elements of the color pattern in Precis coenia (Lepidoptera: Nymphalidae). Evolution 47: 593-618. Nijhout, H.F., 1990. Metaphors and the role of genes in development. BioEssays 12:44-446. (PDF) Nijhout, H.F., 1990. A comprehensive model for color pattern formation in butterflies. Proc. Roy. Soc. B239:81-113. Nijhout, H.F., G.A. Wray, C. Kremen and C.K. Teragawa, 1986. Ontogeny, phylogeny and evolution of form: An algorithmic approach. Syst. Zool. 35:445-457.

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