Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Exposing the fitness contribution of duplicated genes

Nature Genetics volume 40, pages 676–681 (2008)Cite this article

This article has been updated

Abstract

Duplicate genes from the whole-genome duplication (WGD) in yeast are often dispensable—removing one copy has little or no phenotypic consequence1,2. It is unknown, however, whether such dispensability reflects insignificance of the ancestral function or compensation from paralogs3,4,5,6,7. Here, using precise competition-based measurements of the fitness cost of single and double deletions, we estimate the exposed fitness contribution of WGD duplicate genes in metabolism and bound the importance of their ancestral pre-duplication function. We find that the functional overlap between paralogs sufficiently explains the apparent dispensability of individual WGD genes. Furthermore, the lower bound on the fitness value of the ancestral function, which is estimated by the degree of synergistic epistasis, is at least as large as the average fitness cost of deleting single non-WGD genes. These results suggest that most metabolic functions encoded by WGD genes are important today and were also important at the time of duplication.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Measuring the extent of paralogous compensation.
Figure 2: Competition-based high-resolution fitness profiling of single and double deletions.
Figure 3: Dispensability of WGD genes is explained by paralogous compensation.
Figure 4: Exposed fitness of duplicated genes and bounds on fitness contribution of ancestral function.
Figure 5: Synergistic epistasis between WGD pairs correlates with conservation of amino acid sequence and protein interaction partners.
Figure 6: High occurrence of synergy between WGD gene pairs with at least one highly expressed member.

Similar content being viewed by others

Change history

  • 30 April 2008

    The HTML version of the manuscript originally contained several errors in the reference list. These errors have been corrected in the HTML version of the manuscript.

References

  1. Gu, Z.L. et al. Role of duplicate genes in genetic robustness against null mutations. Nature 421, 63–66 (2003).

    Article  CAS  Google Scholar 

  2. Seoighe, C. & Wolfe, K.H. Yeast genome evolution in the post-genome era. Curr. Opin. Microbiol. 2, 548–554 (1999).

    Article  CAS  Google Scholar 

  3. Wagner, A. Robustness against mutations in genetic networks of yeast. Nat. Genet. 24, 355–361 (2000).

    Article  CAS  Google Scholar 

  4. Papp, B., Pal, C. & Hurst, L.D. Metabolic network analysis of the causes and evolution of enzyme dispensability in yeast. Nature 429, 661–664 (2004).

    Article  CAS  Google Scholar 

  5. Kafri, R., Bar-Even, A. & Pilpel, Y. Transcription control reprogramming in genetic backup circuits. Nat. Genet. 37, 295–299 (2005).

    Article  CAS  Google Scholar 

  6. Kuepfer, L., Sauer, U. & Blank, L.M. Metabolic functions of duplicate genes in Saccharomyces cerevisiae. Genome Res. 15, 1421–1430 (2005).

    Article  CAS  Google Scholar 

  7. He, X.L. & Zhang, J.Z. Higher duplicability of less important genes in yeast genomes. Mol. Biol. Evol. 23, 144–151 (2006).

    Article  CAS  Google Scholar 

  8. Tong, A.H.Y. et al. Global mapping of the yeast genetic interaction network. Science 303, 808–813 (2004).

    Article  CAS  Google Scholar 

  9. Segre, D., DeLuna, A., Church, G.M. & Kishony, R. Modular epistasis in yeast metabolism. Nat. Genet. 37, 77–83 (2005).

    Article  CAS  Google Scholar 

  10. Schuldiner, M. et al. Exploration of the function and organization of the yeast early secretory pathway through an epistatic miniarray profile. Cell 123, 507–519 (2005).

    Article  CAS  Google Scholar 

  11. St Onge, R.P. et al. Systematic pathway analysis using high-resolution fitness profiling of combinatorial gene deletions. Nat. Genet. 39, 199–206 (2007).

    Article  CAS  Google Scholar 

  12. Hegreness, M., Shoresh, N., Hartl, D. & Kishony, R. An equivalence principle for the incorporation of favorable mutations in asexual populations. Science 311, 1615–1617 (2006).

    Article  CAS  Google Scholar 

  13. Thatcher, J.W., Shaw, J.M. & Dickinson, W.J. Marginal fitness contributions of nonessential genes in yeast. Proc. Natl. Acad. Sci. USA 95, 253–257 (1998).

    Article  CAS  Google Scholar 

  14. Deutscher, D., Meilijson, I., Kupiec, M. & Ruppin, E. Multiple knockout analysis of genetic robustness in the yeast metabolic network. Nat. Genet. 38, 993–998 (2006).

    Article  CAS  Google Scholar 

  15. Harrison, R., Papp, B., Pál, C., Oliver, S.G. & Delneri, D. Plasticity of genetic interactions in metabolic networks of yeast. Proc. Natl. Acad. Sci. USA 104, 2307–2312 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. 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  CAS  Google Scholar 

  18. Lynch, M. & Force, A. The probability of duplicate gene preservation by subfunctionalization. Genetics 154, 459–473 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. He, X. & Zhang, J. Rapid subfunctionalization accompanied by prolonged and substantial neofunctionalization in duplicate gene evolution. Genetics 169, 1157–1164 (2005).

    Article  Google Scholar 

  20. Tirosh, I. & Barkai, N. Comparative analysis indicates regulatory neofunctionalization of yeast duplicates. Genome Biol. 8, R50 (2007).

    Article  Google Scholar 

  21. Vitkup, D., Kharchenko, P. & Wagner, A. Influence of metabolic network structure and function on enzyme evolution. Genome Biol. 7, R39 (2006).

    Article  Google Scholar 

  22. Conant, G.C. & Wolfe, K.H. Increased glycolytic flux as an outcome of whole-genome duplication in yeast. Mol. Systems Biol. 3, 129 (2007).

    Article  Google Scholar 

  23. Guan, Y., Dunham, M.J. & Troyanskaya, O.G. Functional analysis of gene duplications in Saccharomyces cerevisiae. Genetics 175, 933–943 (2007).

    Article  CAS  Google Scholar 

  24. Presser, A., Elowitz, M.B., Kellis, M. & Kishony, R. The evolutionary dynamics of the Saccharomyces cerevisiae protein interaction network after duplication. Proc. Natl. Acad. Sci. USA 105, 950–954 (2008).

    Article  CAS  Google Scholar 

  25. Makino, T., Suzuki, Y. & Gojobori, T. Differential evolutionary rates of duplicated genes in protein interaction network. Gene 385, 57–63 (2006).

    Article  CAS  Google Scholar 

  26. Wapinski, I., Pfeffer, A., Friedman, N. & Regev, A. Natural history and evolutionary principles of gene duplication in fungi. Nature 449, 54–61 (2007).

    Article  CAS  Google Scholar 

  27. Kafri, R., Levy, M. & Pilpel, Y. The regulatory utilization of genetic redundancy through responsive backup circuits. Proc. Natl. Acad. Sci. USA 103, 11653–11658 (2006).

    Article  CAS  Google Scholar 

  28. Ihmels, J., Collins, S.R., Schuldiner, M., Krogan, N.J. & Weissman, J.S. Backup without redundancy: genetic interactions reveal the cost of duplicate gene loss. Molecular Systems Biology 3, 86 (2007).

    Article  Google Scholar 

  29. Huh, W.-K. et al. Global analysis of protein localization in budding yeast. Nature 425, 686–691 (2003).

    Article  CAS  Google Scholar 

  30. DeLuna, A., Avendano, A., Riego, L. & Gonzalez, A. NADP-glutamate dehydrogenase isoenzymes of Saccharomyces cerevisiae—purification, kinetic properties, and physiological roles. J. Biol. Chem. 276, 43775–43783 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank E. Angelino, N.Q. Balaban, N. Barkai, R. Chait, M. Elowitz, M. Ernebjerg, R. Kafri, E. Mancera, R. Milo, M. Vibranovski, D.R. Wagner, I. Wapinski, R. Ward and P. Yeh for helpful discussions and critical reading of the manuscript, M. Springer for help with flow cytometry, and C. Boone (University of Toronto) and J.S. Weissman (University of California San Francisco) for their gifts of strains and plasmids. This work was supported by a grant from the Human Frontiers Science Program to R.K.; A.D. is a Fellow of the Pew Program in the Biomedical Sciences.

Author information

Authors and Affiliations

  1. Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Alexander DeLuna, Kalin Vetsigian, Noam Shoresh, Matthew Hegreness, Maritrini Colón-González, Sharon Chao & Roy Kishony

  2. School of Engineering and Applied Sciences, Harvard University, Cambridge, 02138, Massachusetts, USA

    Roy Kishony

Authors
  1. Alexander DeLuna
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kalin Vetsigian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Noam Shoresh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Matthew Hegreness
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maritrini Colón-González
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sharon Chao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Roy Kishony
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roy Kishony.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and Supplementary Methods (PDF 3243 kb)

Supplementary Table 1

Complete data set (XLS 269 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

DeLuna, A., Vetsigian, K., Shoresh, N. et al. Exposing the fitness contribution of duplicated genes. Nat Genet 40, 676–681 (2008). https://doi.org/10.1038/ng.123

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.123

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing