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Gene duplication and the adaptive evolution of a classic genetic switch

Abstract

How gene duplication and divergence contribute to genetic novelty and adaptation has been of intense interest, but experimental evidence has been limited. The genetic switch controlling the yeast galactose use pathway includes two paralogous genes in Saccharomyces cerevisiae that encode a co-inducer (GAL3) and a galactokinase (GAL1). These paralogues arose from a single bifunctional ancestral gene as is still present in Kluyveromyces lactis. To determine which evolutionary processes shaped the evolution of the two paralogues, here we assess the effects of precise replacement of coding and non-coding sequences on organismal fitness. We suggest that duplication of the ancestral bifunctional gene allowed for the resolution of an adaptive conflict between the transcriptional regulation of the two gene functions. After duplication, previously disfavoured binding site configurations evolved that divided the regulation of the ancestral gene into two specialized genes, one of which ultimately became one of the most tightly regulated genes in the genome.

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Figure 1: GAL3 + encodes the best co-inducer.
Figure 2: Most adaptive divergence between GAL1 and GAL3 occurred in the promoters.
Figure 3: Adaptive conflict in the configuration of Gal4 binding sites.
Figure 4: Model of the evolution of the GAL genetic switch.

References

  1. Ohno, S. Evolution by Gene Duplication (Springer, New York, 1970)

    Book  Google Scholar 

  2. Taylor, J. S. & Raes, J. Duplication and divergence: the evolution of new genes and old ideas. Annu. Rev. Genet. 38, 615–643 (2004)

    Article  CAS  Google Scholar 

  3. Irwin, D. M., Prager, E. M. & Wilson, A. C. Evolutionary genetics of ruminant lysozymes. Anim. Genet. 23, 193–202 (1992)

    Article  CAS  Google Scholar 

  4. Yokoyama, S. Molecular evolution of color vision in vertebrates. Gene 300, 69–78 (2002)

    Article  CAS  Google Scholar 

  5. Zhang, J., Zhang, Y. P. & Rosenberg, H. F. Adaptive evolution of a duplicated pancreatic ribonuclease gene in a leaf-eating monkey. Nature Genet. 30, 411–415 (2002)

    Article  CAS  Google Scholar 

  6. Prince, V. E. & Pickett, F. B. Splitting pairs: the diverging fates of duplicated genes. Nature Rev. Genet. 3, 827–837 (2002)

    Article  CAS  Google Scholar 

  7. van Hoof, A. Conserved functions of yeast genes support the duplication, degeneration and complementation model for gene duplication. Genetics 171, 1455–1461 (2005)

    Article  CAS  Google Scholar 

  8. Scannell, D. R., Byrne, K. P., Gordon, J. L., Wong, S. & Wolfe, K. H. Multiple rounds of speciation associated with reciprocal gene loss in polyploid yeasts. Nature 440, 341–345 (2006)

    Article  ADS  CAS  Google Scholar 

  9. Schilke, B. et al. Evolution of mitochondrial chaperones utilized in Fe–S cluster biogenesis. Curr. Biol. 16, 1660–1665 (2006)

    Article  CAS  Google Scholar 

  10. Piatigorsky, J. Gene Sharing and Evolution: The Diversity of Protein Functions (Harvard Univ. Press, Cambridge, Massachusetts, 2007)

    Book  Google Scholar 

  11. Force, A. et al. Preservation of duplicate genes by complementary, degenerative mutations. Genetics 151, 1531–1545 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Tumpel, S., Cambronero, F., Wiedemann, L. M. & Krumlauf, R. Evolution of cis elements in the differential expression of two Hoxa2 coparalogous genes in pufferfish (Takifugu rubripes). Proc. Natl Acad. Sci. USA 103, 5419–5424 (2006)

    Article  ADS  CAS  Google Scholar 

  13. Piatigorsky, J. & Wistow, G. The recruitment of crystallins: new functions precede gene duplication. Science 252, 1078–1079 (1991)

    Article  ADS  CAS  Google Scholar 

  14. Hughes, A. L. The evolution of functionally novel proteins after gene duplication. Proc. Biol. Sci. 256, 119–124 (1994)

    Article  CAS  Google Scholar 

  15. Hughes, A. L. Adaptive Evolution of Genes and Genomes (Oxford Univ. Press, Oxford, 1999)

    Google Scholar 

  16. Johnston, M. A model fungal gene regulatory mechanism: the GAL genes of Saccharomyces cerevisiae . Microbiol. Rev. 51, 458–476 (1987)

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Bhat, P. J. & Murthy, T. V. Transcriptional control of the GAL/MEL regulon of yeast Saccharomyces cerevisiae: mechanism of galactose-mediated signal transduction. Mol. Microbiol. 40, 1059–1066 (2001)

    Article  CAS  Google Scholar 

  18. Ptashne, M. & Gann, A. Genes and Signals (Cold Spring Harbor Laboratory Press, Woodbury, New York, 2001)

    Google Scholar 

  19. Wolfe, K. H. & Shields, D. C. Molecular evidence for an ancient duplication of the entire yeast genome. Nature 387, 708–713 (1997)

    Article  ADS  CAS  Google Scholar 

  20. Dietrich, F. S. et al. The Ashbya gossypii genome as a tool for mapping the ancient Saccharomyces cerevisiae genome. Science 304, 304–307 (2004)

    Article  ADS  CAS  Google Scholar 

  21. Kellis, M., Birren, B. W. & Lander, E. S. Proof and evolutionary analysis of ancient genome duplication in the yeast Saccharomyces cerevisiae . Nature 428, 617–624 (2004)

    Article  ADS  CAS  Google Scholar 

  22. Hittinger, C. T., Rokas, A. & Carroll, S. B. Parallel inactivation of multiple GAL pathway genes and ecological diversification in yeasts. Proc. Natl Acad. Sci. USA 101, 14144–14149 (2004)

    Article  ADS  CAS  Google Scholar 

  23. Scannell, D. R. et al. Independent sorting-out of thousands of duplicated gene pairs in two yeast species descended from a whole-genome duplication. Proc. Natl Acad. Sci. USA 104, 8397–8402 (2007)

    Article  ADS  CAS  Google Scholar 

  24. Johnston, M. & Davis, R. W. Sequences that regulate the divergent GAL1GAL10 promoter in Saccharomyces cerevisiae. . Mol. Cell. Biol. 4, 1440–1448 (1984)

    Article  CAS  Google Scholar 

  25. West, R. W., Yocum, R. R. & Ptashne, M. Saccharomyces cerevisiae GAL1GAL10 divergent promoter region: location and function of the upstream activating sequence UASG . Mol. Cell. Biol. 4, 2467–2478 (1984)

    Article  CAS  Google Scholar 

  26. Bajwa, W., Torchia, T. E. & Hopper, J. E. Yeast regulatory gene GAL3: carbon regulation; UASGal elements in common with GAL1, GAL2, GAL7, GAL10, GAL80, and MEL1; encoded protein strikingly similar to yeast and Escherichia coli galactokinases. Mol. Cell. Biol. 8, 3439–3447 (1988)

    Article  CAS  Google Scholar 

  27. Zenke, F. T. et al. Activation of Gal4p by galactose-dependent interaction of galactokinase and Gal80p. Science 272, 1662–1665 (1996)

    Article  ADS  CAS  Google Scholar 

  28. Yano, K. & Fukasawa, T. Galactose-dependent reversible interaction of Gal3p with Gal80p in the induction pathway of Gal4p-activated genes of Saccharomyces cerevisiae . Proc. Natl Acad. Sci. USA 94, 1721–1726 (1997)

    Article  ADS  CAS  Google Scholar 

  29. Platt, A. & Reece, R. J. The yeast galactose genetic switch is mediated by the formation of a Gal4p-Gal80p-Gal3p complex. EMBO J. 17, 4086–4091 (1998)

    Article  CAS  Google Scholar 

  30. Peng, G. & Hopper, J. E. Gene activation by interaction of an inhibitor with a cytoplasmic signaling protein. Proc. Natl Acad. Sci. USA 99, 8548–8553 (2002)

    Article  ADS  CAS  Google Scholar 

  31. Meyer, J., Walker-Jonah, A. & Hollenberg, C. P. Galactokinase encoded by GAL1 is a bifunctional protein required for induction of the GAL genes in Kluyveromyces lactis and is able to suppress the gal3 phenotype in Saccharomyces cerevisiae . Mol. Cell. Biol. 11, 5454–5461 (1991)

    Article  CAS  Google Scholar 

  32. Rubio-Texeira, M. A comparative analysis of the GAL genetic switch between not-so-distant cousins: Saccharomyces cerevisiae versus Kluyveromyces lactis . FEMS Yeast Res. 5, 1115–1128 (2005)

    Article  CAS  Google Scholar 

  33. Webster, T. D. & Dickson, R. C. The organization and transcription of the galactose gene cluster of Kluyveromyces lactis . Nucleic Acids Res. 16, 8011–8028 (1988)

    Article  CAS  Google Scholar 

  34. Thoden, J. B., Sellick, C. A., Timson, D. J., Reece, R. J. & Holden, H. M. Molecular structure of Saccharomyces cerevisiae Gal1p, a bifunctional galactokinase and transcriptional inducer. J. Biol. Chem. 280, 36905–36911 (2005)

    Article  CAS  Google Scholar 

  35. Platt, A., Ross, H. C., Hankin, S. & Reece, R. J. The insertion of two amino acids into a transcriptional inducer converts it into a galactokinase. Proc. Natl Acad. Sci. USA 97, 3154–3159 (2000)

    Article  ADS  CAS  Google Scholar 

  36. Weinreich, D. M., Watson, R. A. & Chao, L. Perspective: sign epistasis and genetic constraint on evolutionary trajectories. Evol. Int. J. Org. Evol. 59, 1165–1174 (2005)

    CAS  Google Scholar 

  37. Kellis, M., Patterson, N., Endrizzi, M., Birren, B. & Lander, E. S. Sequencing and comparison of yeast species to identify genes and regulatory elements. Nature 423, 241–254 (2003)

    Article  ADS  CAS  Google Scholar 

  38. Melcher, K. & Xu, H. E. Gal80–Gal80 interaction on adjacent Gal4p binding sites is required for complete GAL gene repression. EMBO J. 20, 841–851 (2001)

    Article  CAS  Google Scholar 

  39. Wagner, A. Asymmetric functional divergence of duplicate genes in yeast. Mol. Biol. Evol. 19, 1760–1768 (2002)

    Article  CAS  Google Scholar 

  40. Makova, K. D. & Li, W. H. Divergence in the spatial pattern of gene expression between human duplicate genes. Genome Res. 13, 1638–1645 (2003)

    Article  CAS  Google Scholar 

  41. Gu, Z., Rifkin, S. A., White, K. P. & Li, W. H. Duplicate genes increase gene expression diversity within and between species. Nature Genet. 36, 577–579 (2004)

    Article  CAS  Google Scholar 

  42. Huminiecki, L. & Wolfe, K. H. Divergence of spatial gene expression profiles following species-specific gene duplications in human and mouse. Genome Res. 14, 1870–1879 (2004)

    Article  CAS  Google Scholar 

  43. Li, W. H., Yang, J. & Gu, X. Expression divergence between duplicate genes. Trends Genet. 21, 602–607 (2005)

    Article  Google Scholar 

  44. Goodman, M., Moore, G. W. & Matsuda, G. Darwinian evolution in the genealogy of haemoglobin. Nature 253, 603–608 (1975)

    Article  ADS  CAS  Google Scholar 

  45. Gould, A., Morrison, A., Sproat, G., White, R. A. & Krumlauf, R. Positive cross-regulation and enhancer sharing: two mechanisms for specifying overlapping Hox expression patterns. Genes Dev. 11, 900–913 (1997)

    Article  CAS  Google Scholar 

  46. Cohen, B. A., Mitra, R. D., Hughes, J. D. & Church, G. M. A computational analysis of whole-genome expression data reveals chromosomal domains of gene expression. Nature Genet. 26, 183–186 (2000)

    Article  CAS  Google Scholar 

  47. Hartl, D. L. & Clark, A. G. in Principles of Population Genetics 216 (Sinauer Associates, Sunderland, Massachusetts, 1997)

    Google Scholar 

  48. Brachmann, C. B. et al. Designer deletion strains derived from Saccharomyces cerevisiae S288C: a useful set of strains and plasmids for PCR-mediated gene disruption and other applications. Yeast 14, 115–132 (1998)

    Article  CAS  Google Scholar 

  49. Kooistra, R., Hooykaas, P. J. & Steensma, H. Y. Efficient gene targeting in Kluyveromyces lactis . Yeast 21, 781–792 (2004)

    Article  CAS  Google Scholar 

  50. Guldener, U., Heck, S., Fielder, T., Beinhauer, J. & Hegemann, J. H. A new efficient gene disruption cassette for repeated use in budding yeast. Nucleic Acids Res. 24, 2519–2524 (1996)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank B. L. Williams for sharing unpublished data, reagents and the competition assay; J. E. Selegue for technical support; M. Johnston and Washington University in St Louis for access to laboratory space and equipment; Collection de Levures d'Intérêt Biotechnologique for K. lactis strain CLIB210; H. Y. Steensma for the NHEJ-deficient K. lactis strain and transformation protocol; J. H. Hegemann for the kanMX cassette; B. L. Williams, P. M. van Wynsberghe and Carroll laboratory members for technical advice; L. M. Olds for artwork; and B. L. Williams, B. Prud’homme and M. Johnston for critical reading of the manuscript. The Howard Hughes Medical Institute supported this work through an investigatorship (S.B.C.) and predoctoral fellowship (C.T.H.).

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Correspondence to Sean B. Carroll.

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The file contains Supplementary Discussion of Supplementary Tables S1-S4, Supplementary Tables S1-S4, Supplementary Figure S1 with Legend and additional references. (PDF 391 kb)

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Hittinger, C., Carroll, S. Gene duplication and the adaptive evolution of a classic genetic switch. Nature 449, 677–681 (2007). https://doi.org/10.1038/nature06151

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