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.

Functional and evolutionary implications of gene orthology

Abstract

Orthologues and paralogues are types of homologous genes that are related by speciation or duplication, respectively. Orthologous genes are generally assumed to retain equivalent functions in different organisms and to share other key properties. Several recent comparative genomic studies have focused on testing these expectations. Here we discuss the complexity of the evolution of gene–phenotype relationships and assess the validity of the key implications of orthology and paralogy relationships as general statistical trends and guiding principles.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Decay of the number of one-to-one orthologues with the increase of the intergenomic evolutionary distance.
Figure 2: Functional divergence versus sequence divergence for orthologues and paralogues.

References

  1. Fitch, W. M. Distinguishing homologous from analogous proteins. Systemat. Zool. 19, 99–106 (1970).

    Article  CAS  Google Scholar 

  2. Fitch, W. M. Homology a personal view on some of the problems. Trends Genet. 16, 227–231 (2000).

    Article  CAS  Google Scholar 

  3. Koonin, E. V. Walter Fitch and the orthology paradigm. Brief. Bioinform. 12, 377–378 (2011).

    Article  Google Scholar 

  4. Baldauf, S. L. Phylogeny for the faint of heart: a tutorial. Trends Genet. 19, 345–351 (2003).

    Article  CAS  Google Scholar 

  5. Sonnhammer, E. L. & Koonin, E. V. Orthology, paralogy and proposed classification for paralog subtypes. Trends Genet. 18, 619–620 (2002).

    Article  CAS  Google Scholar 

  6. Koonin, E. V. Orthologs, paralogs and evolutionary genomics. Annu. Rev. Genet. 39, 309–338 (2005).

    Article  CAS  Google Scholar 

  7. Dolinski, K. & Botstein, D. Orthology and functional conservation in eukaryotes. Annu. Rev. Genet. 41, 465–507 (2007).

    Article  CAS  Google Scholar 

  8. Studer, R. A. & Robinson-Rechavi, M. How confident can we be that orthologs are similar, but paralogs differ? Trends Genet. 25, 210–216 (2009).

    Article  CAS  Google Scholar 

  9. Nehrt, N. L., Clark, W. T., Radivojac, P. & Hahn, M. W. Testing the ortholog conjecture with comparative functional genomic data from mammals. PLoS Comput. Biol. 7, e1002073 (2011).

    Article  CAS  Google Scholar 

  10. Kuzniar, A., van Ham, R. C., Pongor, S. & Leunissen, J. A. The quest for orthologs: finding the corresponding gene across genomes. Trends Genet. 24, 539–551 (2008).

    Article  CAS  Google Scholar 

  11. Gabaldón, T. Large-scale assignment of orthology: back to phylogenetics? Genome Biol. 9, 235 (2008).

    Article  Google Scholar 

  12. Altenhoff, A. M. & Dessimoz, C. Phylogenetic and functional assessment of orthologs inference projects and methods. PLoS Comput. Biol. 5, e1000262 (2009).

    Article  Google Scholar 

  13. Trachana, K. et al. Orthology prediction methods: a quality assessment using curated protein families. Bioessays 33, 769–780 (2011).

    Article  CAS  Google Scholar 

  14. Kristensen, D. M., Wolf, Y. I., Mushegian, A. R. & Koonin, E. V. Computational methods for Gene Orthology inference. Brief. Bioinform. 12, 379–391 (2011).

    Article  Google Scholar 

  15. Gabaldón, T. et al. Joining forces in the quest for orthologs. Genome Biol. 10, 403 (2009).

    Article  Google Scholar 

  16. Dessimoz, C., Gabaldón, T., Roos, D. S., Sonnhammer, E. L. & Herrero, J. Toward community standards in the quest for orthologs. Bioinformatics 28, 900–904 (2012).

    Article  CAS  Google Scholar 

  17. Descorps-Declere, S., Lemoine, F., Sculo, Q., Lespinet, O. & Labedan, B. The multiple facets of homology and their use in comparative genomics to study the evolution of genes, genomes, and species. Biochimie 90, 595–608 (2008).

    Article  CAS  Google Scholar 

  18. Mahmood, K., Webb, G. I., Song, J., Whisstock, J. C. & Konagurthu, A. S. Efficient large-scale protein sequence comparison and gene matching to identify orthologs and co-orthologs. Nucleic Acids Res. 40, e44 (2012).

    Article  CAS  Google Scholar 

  19. Roux, J. & Robinson-Rechavi, M. An ontology to clarify homology-related concepts. Trends Genet. 26, 99–102 (2010).

    Article  CAS  Google Scholar 

  20. Tatusov, R. L., Koonin, E. V. & Lipman, D. J. A genomic perspective on protein families. Science 278, 631–637 (1997).

    Article  CAS  Google Scholar 

  21. Remm, M., Storm, C. E. & Sonnhammer, E. L. Automatic clustering of orthologs and in-paralogs from pairwise species comparisons. J. Mol. Biol. 314, 1041–1052 (2001).

    Article  CAS  Google Scholar 

  22. Koonin, E. V., Aravind, L. & Kondrashov, A. S. The impact of comparative genomics on our understanding of evolution. Cell 101, 573–576 (2000).

    Article  CAS  Google Scholar 

  23. Sjolander, K., Datta, R. S., Shen, Y. & Shoffner, G. M. Ortholog identification in the presence of domain architecture rearrangement. Brief. Bioinform. 12, 413–422 (2011).

    Article  Google Scholar 

  24. Forslund, K. & Sonnhammer, E. L. Evolution of protein domain architectures. Methods Mol. Biol. 856, 187–216 (2012).

    Article  CAS  Google Scholar 

  25. Hartmann, B. & Valcarcel, J. Decrypting the genome's alternative messages. Curr. Opin. Cell Biol. 21, 377–386 (2009).

    Article  CAS  Google Scholar 

  26. Irimia, M. & Blencowe, B. J. Alternative splicing: decoding an expansive regulatory layer. Curr. Opin. Cell Biol. 24, 323–332 (2012).

    Article  CAS  Google Scholar 

  27. Basu, M. K., Poliakov, E. & Rogozin, I. B. Domain mobility in proteins: functional and evolutionary implications. Brief. Bioinform. 10, 205–216 (2009).

    Article  CAS  Google Scholar 

  28. Ouzounis, C. Orthology: another terminology muddle. Trends Genet. 15, 445 (1999).

    Article  CAS  Google Scholar 

  29. Theissen, G. Birth, life and death of developmental control genes: new challenges for the homology concept. Theory Biosci. 124, 199–212 (2005).

    Article  CAS  Google Scholar 

  30. Bandyopadhyay, S., Sharan, R. & Ideker, T. Systematic identification of functional orthologs based on protein network comparison. Genome Res. 16, 428–435 (2006).

    Article  CAS  Google Scholar 

  31. Singh, R., Xu, J. & Berger, B. Global alignment of multiple protein interaction networks with application to functional orthology detection. Proc. Natl Acad. Sci. USA 105, 12763–12768 (2008).

    Article  CAS  Google Scholar 

  32. Huynen, M. A. & Bork, P. Measuring genome evolution. Proc. Natl Acad. Sci. USA 95, 5849–5856 (1998).

    Article  CAS  Google Scholar 

  33. Bromham, L. & Penny, D. The modern molecular clock. Nature Rev. Genet. 4, 216–224 (2003).

    Article  CAS  Google Scholar 

  34. Kumar, S. Molecular clocks: four decades of evolution. Nature Rev. Genet. 6, 654–662 (2005).

    Article  CAS  Google Scholar 

  35. Koski, L. B. & Golding, G. B. The closest BLAST hit is often not the nearest neighbor. J. Mol. Evol. 52, 540–542 (2001).

    Article  CAS  Google Scholar 

  36. Hulsen, T., Huynen, M. A., de Vlieg, J. & Groenen, P. M. Benchmarking ortholog identification methods using functional genomics data. Genome Biol. 7, R31 (2006).

    Article  Google Scholar 

  37. Wolf, Y. I. & Koonin, E. V. A tight link between orthologs and bidirectional best hits in bacterial and archaeal genomes. Genome Biol. Evol. 1286–1294 (2012).

  38. Koonin, E. V. Comparative genomics, minimal gene-sets and the last universal common ancestor. Nature Rev. Microbiol. 1, 127–136 (2003).

    Article  CAS  Google Scholar 

  39. Snel, B., Huynen, M. A. & Dutilh, B. E. Genome trees and the nature of genome evolution. Annu. Rev. Microbiol. 59, 191–209 (2005).

    Article  CAS  Google Scholar 

  40. Blomme, T. et al. The gain and loss of genes during 600 million years of vertebrate evolution. Genome Biol. 7, R43 (2006).

    Article  Google Scholar 

  41. Makarova, K. S., Wolf, Y. I., Mekhedov, S. L., Mirkin, B. G. & Koonin, E. V. Ancestral paralogs and pseudoparalogs and their role in the emergence of the eukaryotic cell. Nucleic Acids Res. 33, 4626–4638 (2005).

    Article  CAS  Google Scholar 

  42. Huerta-Cepas, J. & Gabaldón, T. Assigning duplication events to relative temporal scales in genome-wide studies. Bioinformatics 27, 38–45 (2011).

    Article  CAS  Google Scholar 

  43. Forslund, K., Pekkari, I. & Sonnhammer, E. L. Domain architecture conservation in orthologs. BMC Bioinformatics 12, 326 (2011).

    Article  Google Scholar 

  44. Koonin, E. V. et al. A comprehensive evolutionary classification of proteins encoded in complete eukaryotic genomes. Genome Biol. 5, R7 (2004).

    Article  Google Scholar 

  45. Peterson, M. E. et al. Evolutionary constraints on structural similarity in orthologs and paralogs. Protein Sci. 18, 1306–1315 (2009).

    Article  CAS  Google Scholar 

  46. Mushegian, A. R. & Koonin, E. V. A minimal gene set for cellular life derived by comparison of complete bacterial genomes. Proc. Natl Acad. Sci. USA 93, 10268–10273 (1996).

    Article  CAS  Google Scholar 

  47. Galperin, M. Y., Walker, D. R. & Koonin, E. V. Analogous enzymes: independent inventions in enzyme evolution. Genome Res. 8, 779–790 (1998).

    Article  CAS  Google Scholar 

  48. Omelchenko, M. V., Galperin, M. Y., Wolf, Y. I. & Koonin, E. V. Non-homologous isofunctional enzymes: a systematic analysis of alternative solutions in enzyme evolution. Biol. Direct 5, 31 (2010).

    Article  Google Scholar 

  49. Lynch, V. J. & Wagner, G. P. Resurrecting the role of transcription factor change in developmental evolution. Evolution 62, 2131–2154 (2008).

    Article  CAS  Google Scholar 

  50. Casci, T. Functional genomics: Degrees of similarity. Nature Rev. Genet. 12, 522 (2011).

    Article  CAS  Google Scholar 

  51. Thomas, P. D., Wood, V., Mungall, C. J., Lewis, S. E. & Blake, J. A. On the use of gene ontology annotations to assess functional similarity among orthologs and paralogs: a short report. PLoS Comput. Biol. 8, e1002386 (2012).

    Article  CAS  Google Scholar 

  52. Altenhoff, A. M., Studer, R. A., Robinson-Rechavi, M. & Dessimoz, C. Resolving the ortholog conjecture: orthologs tend to be weakly, but significantly, more similar in function than paralogs. PLoS Comput. Biol. 8, e1002514 (2012).

    Article  CAS  Google Scholar 

  53. Huerta-Cepas, J., Dopazo, J., Huynen, M. A. & Gabaldón, T. Evidence for short-time divergence and long-time conservation of tissue-specific expression after gene duplication. Brief. Bioinform. 12, 442–448 (2011).

    Article  CAS  Google Scholar 

  54. Chen, X. & Zhang, J. The ortholog conjecture is untestable by the current gene ontology but is supported by RNA sequencing data. PLoS Comput. Biol. 8, e1002784 (2012).

    Article  CAS  Google Scholar 

  55. Mohd-Padil, H., Mohd-Adnan, A. & Gabaldón, T. Phylogenetic analyses uncover a novel clade of transferring in non-mammalian vertebrates. Mol. Biol. Evol. 30, 894–905 (2013).

    Article  CAS  Google Scholar 

  56. Huerta-Cepas, J. et al. PhylomeDB v3.0: an expanding repository of genome-wide collections of trees, alignments and phylogeny-based orthology and paralogy predictions. Nucleic Acids Res. 39, D556–D560 (2011).

    Article  CAS  Google Scholar 

  57. Altschul, S. F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

T.G. is supported by funds from the European Research Council and the Spanish Ministry of Economy and Competitiveness. E.V.K. is supported by intramural funds of the US Department of Health and Human Services (to the US National Library of Medicine).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Toni Gabaldón or Eugene V. Koonin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

PowerPoint slides

Glossary

Alternative transcription

The expression of multiple transcripts with different structures from the same gene locus.

Bidirectional best hit

(BBH). A pair of genes that show the greatest sequence similarity to each other in a complete, reciprocal comparison of the gene (protein) sequences from a pair of compared genomes.

Co-orthologue

A gene in a species (or group of species) that is jointly orthologous to the same gene (or genes) in another species (or group of species).

Domain accretion

In evolution, the addition of sequences encoding extra structural domains to protein-coding genes.

Gene Ontology

(GO). A collaborative bioinformatic project aiming at providing an ontology of defined terms representing gene product properties.

In-paralogues

Paralogous genes that originate from a lineage-specific duplication that postdates that reference ancestral species.

Non-homologous and isofunctional

When referring to proteins, these are proteins that in different species carry out equivalent biological functions but are not homologous.

Orthologues

Homologous genes related by speciation.

Orthologous groups

Sets of genes that are inferred to have evolved from a single ancestral gene in the reference ancestral species.

Out-paralogues

Paralogous genes that originate from a duplication that antedates that reference ancestral species.

Paralogues

Homologous genes related by duplication.

Xenologues

Homologous genes that originate from horizontal gene transfer.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gabaldón, T., Koonin, E. Functional and evolutionary implications of gene orthology. Nat Rev Genet 14, 360–366 (2013). https://doi.org/10.1038/nrg3456

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg3456

This article is cited by

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