The Pleiotropic Structure of the Genotype-phenotype Map: the Evolvability of Complex Organisms

Overview

Journal Nat Rev Genet

Specialty Genetics

Date 2011 Feb 19

PMID 21331091

Citations 308

Authors

Gunter P Wagner

Jianzhi Zhang

Affiliations

Soon will be listed here.

Abstract

It was first noticed 100 years ago that mutations tend to affect more than one phenotypic characteristic, a phenomenon that was called 'pleiotropy'. Because pleiotropy was found so frequently, the notion arose that pleiotropy is 'universal'. However, quantitative estimates of pleiotropy have not been available until recently. These estimates show that pleiotropy is highly restricted and are more in line with the notion of variational modularity than with universal pleiotropy. This finding has major implications for the evolvability of complex organisms and the mapping of disease-causing mutations.

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References

Poon A, Otto S . Compensating for our load of mutations: freezing the meltdown of small populations. Evolution. 2000; 54(5):1467-79. DOI: 10.1111/j.0014-3820.2000.tb00693.x. View

Flint J, Mackay T . Genetic architecture of quantitative traits in mice, flies, and humans. Genome Res. 2009; 19(5):723-33. PMC: 3647534. DOI: 10.1101/gr.086660.108. View

Wagner G, Kenney-Hunt J, Pavlicev M, Peck J, Waxman D, Cheverud J . Pleiotropic scaling of gene effects and the 'cost of complexity'. Nature. 2008; 452(7186):470-2. DOI: 10.1038/nature06756. View

Barton N . Pleiotropic models of quantitative variation. Genetics. 1990; 124(3):773-82. PMC: 1203967. DOI: 10.1093/genetics/124.3.773. View

Hansen T, Houle D . Measuring and comparing evolvability and constraint in multivariate characters. J Evol Biol. 2008; 21(5):1201-19. DOI: 10.1111/j.1420-9101.2008.01573.x. View

Hansen T . Is modularity necessary for evolvability? Remarks on the relationship between pleiotropy and evolvability. Biosystems. 2003; 69(2-3):83-94. DOI: 10.1016/s0303-2647(02)00132-6. View

Tyler A, Asselbergs F, Williams S, Moore J . Shadows of complexity: what biological networks reveal about epistasis and pleiotropy. Bioessays. 2009; 31(2):220-7. PMC: 3159922. DOI: 10.1002/bies.200800022. View

Cordell H . Detecting gene-gene interactions that underlie human diseases. Nat Rev Genet. 2009; 10(6):392-404. PMC: 2872761. DOI: 10.1038/nrg2579. View

Su Z, Zeng Y, Gu X . A preliminary analysis of gene pleiotropy estimated from protein sequences. J Exp Zool B Mol Dev Evol. 2009; 314(2):115-22. DOI: 10.1002/jez.b.21315. View

10.

Brem R, Yvert G, Clinton R, Kruglyak L . Genetic dissection of transcriptional regulation in budding yeast. Science. 2002; 296(5568):752-5. DOI: 10.1126/science.1069516. View

11.

Gu X . Evolutionary framework for protein sequence evolution and gene pleiotropy. Genetics. 2007; 175(4):1813-22. PMC: 1855142. DOI: 10.1534/genetics.106.066530. View

12.

Gu X . Stabilizing selection of protein function and distribution of selection coefficient among sites. Genetica. 2006; 130(1):93-7. DOI: 10.1007/s10709-006-0022-5. View

13.

Chevin L, Martin G, Lenormand T . Fisher's model and the genomics of adaptation: restricted pleiotropy, heterogenous mutation, and parallel evolution. Evolution. 2010; 64(11):3213-31. DOI: 10.1111/j.1558-5646.2010.01058.x. View

14.

Morley M, Molony C, Weber T, Devlin J, Ewens K, Spielman R . Genetic analysis of genome-wide variation in human gene expression. Nature. 2004; 430(7001):743-7. PMC: 2966974. DOI: 10.1038/nature02797. View

15.

Sugio S, Kashima A, Mochizuki S, Noda M, Kobayashi K . Crystal structure of human serum albumin at 2.5 A resolution. Protein Eng. 1999; 12(6):439-46. DOI: 10.1093/protein/12.6.439. View

16.

Tenaillon O, Silander O, Uzan J, Chao L . Quantifying organismal complexity using a population genetic approach. PLoS One. 2007; 2(2):e217. PMC: 1790863. DOI: 10.1371/journal.pone.0000217. View

17.

Foster K, Shaulsky G, Strassmann J, Queller D, Thompson C . Pleiotropy as a mechanism to stabilize cooperation. Nature. 2004; 431(7009):693-6. DOI: 10.1038/nature02894. View

18.

Hodgkin J . Seven types of pleiotropy. Int J Dev Biol. 1998; 42(3):501-5. View

19.

Knott S, Haley C . Multitrait least squares for quantitative trait loci detection. Genetics. 2000; 156(2):899-911. PMC: 1461263. DOI: 10.1093/genetics/156.2.899. View

20.

Orr H, Coyne J . The genetics of adaptation: a reassessment. Am Nat. 2009; 140(5):725-42. DOI: 10.1086/285437. View