Sequence homology



Identity, similarity, and conservation









Databases of orthologous genes


  • eggNOG[7]
  • GreenPhylDB[8] for plants
  • InParanoid[9] focuses on pairwise ortholog relationships
  • OHNOLOGS[10][11] is a repository of the genes retained from whole genome duplications in the vertebrate genomes including human and mouse.
  • OMA
  • OrthoDB[12] appreciates that the orthology concept is relative to different speciation points by providing a hierarchy of orthologs along the species tree.
  • OrthoInspector[13] is a repository of orthologous genes for 4753 organisms covering the three domains of life
  • OrthologID[14]
  • OrthoMaM[15] for mammals
  • OrthoMCL[16]
  • Roundup[17]




Paralogous genes are genes that are related via duplication events in the last common ancestor (LCA) of the species being compared. They result from the mutation of duplicated genes during separate speciation events. When descendants from the LCA share mutated homologs of the original duplicated genes then those genes are considered paralogs.[1]

As an example, in the LCA, one gene (gene A) may get duplicated to make a separate similar gene (gene B), those two genes will continue to get passed to subsequent generations. During speciation, one environment will favor a mutation in gene A (gene A1), producing a new species with genes A1 and B. Then in a separate speciation event, one environment will favor a mutation in gene B (gene B1) giving rise to a new species with genes A and B1. The descendants’ genes A1 and B1 are paralogous to each other because they are homologs that are related via a duplication event in the last common ancestor of the two species.[1]

Additional classifications of paralogs include alloparalogs (out-paralogs) and symparalogs (in-paralogs). Alloparalogs are paralogs that evolved from gene duplications that preceded the given speciation event. In other words, alloparalogs are paralogs that evolved from duplication events that happened in the LCA of the organisms being compared. The example above is an example alloparalogy. Symparalogs are paralogs that evolved from gene duplication of paralogous genes in subsequent speciation events. From the example above, if the descendant with genes A1 and B underwent another speciation event where gene A1 duplicated, the new species would have genes B, A1a, and A1b. In this example, genes A1a and A1b are symparalogs.[1]

Paralogous genes can shape the structure of whole genomes and thus explain genome evolution to a large extent. Examples include the Homeobox (Hox) genes in animals. These genes not only underwent gene duplications within chromosomes but also whole genome duplications. As a result, Hox genes in most vertebrates are clustered across multiple chromosomes with the HoxA-D clusters being the best studied.[23]


It is often asserted that orthologs are more functionally similar than paralogs of similar divergence, but several papers have challenged this notion.[24][25][26]



Paralogous chromosomal regions

Sometimes, large regions of chromosomes share gene content similar to other chromosomal regions within the same genome.[28] They are well characterised in the human genome, where they have been used as evidence to support the 2R hypothesis. Sets of duplicated, triplicated and quadruplicated genes, with the related genes on different chromosomes, are deduced to be remnants from genome or chromosomal duplications. A set of paralogy regions is together called a paralogon.[29] Well-studied sets of paralogy regions include regions of human chromosome 2, 7, 12 and 17 containing Hox gene clusters, collagen genes, keratin genes and other duplicated genes,[30] regions of human chromosomes 4, 5, 8 and 10 containing neuropeptide receptor genes, NK class homeobox genes and many more gene families,[31][32][33] and parts of human chromosomes 13, 4, 5 and X containing the ParaHox genes and their neighbors.[34] The Major histocompatibility complex (MHC) on human chromosome 6 has paralogy regions on chromosomes 1, 9 and 19.[35] Much of the human genome seems to be assignable to paralogy regions.[36]



Ohnologous genes are paralogous genes that have originated by a process of whole-genome duplication. The name was first given in honour of Susumu Ohno by Ken Wolfe.[37] Ohnologues are useful for evolutionary analysis because all ohnologues in a genome have been diverging for the same length of time (since their common origin in the whole genome duplication). Ohnologues are also known to show greater association with cancers, dominant genetic disorders, and pathogenic copy number variations.[38][39][40][41][42]






Gametology denotes the relationship between homologous genes on non-recombining, opposite sex chromosomes. The term was coined by García-Moreno and Mindell.[43] 2000. Gametologs result from the origination of genetic sex determination and barriers to recombination between sex chromosomes. Examples of gametologs include CHDW and CHDZ in birds.[43]

See also


  2. "Clustal FAQ #Symbols". Clustal. Retrieved 8 December 2014.
  3. Fitch WM (June 1970). "Distinguishing homologous from analogous proteins". Systematic Zoology. 19 (2): 99–113. doi:10.2307/2412448. JSTOR 2412448. PMID 5449325.
  4. Falciatore A, Merendino L, Barneche F, Ceol M, Meskauskiene R, Apel K, Rochaix JD (January 2005). "The FLP proteins act as regulators of chlorophyll synthesis in response to light and plastid signals in Chlamydomonas". Genes & Development. 19 (1): 176–187. doi:10.1101/gad.321305. PMC 540235. PMID 15630026.
  6. COGs: Clusters of Orthologous Groups of proteins
  7. eggNOG: evolutionary genealogy of genes: Non-supervised Orthologous Groups
    Muller J, Szklarczyk D, Julien P, Letunic I, Roth A, Kuhn M, Powell S, von Mering C, Doerks T, Jensen LJ, Bork P (January 2010). "eggNOG v2.0: extending the evolutionary genealogy of genes with enhanced non-supervised orthologous groups, species and functional annotations". Nucleic Acids Research. 38 (Database issue): D190–5. doi:10.1093/nar/gkp951. PMC 2808932. PMID 19900971.
  8. GreenPhylDB
    Conte MG, Gaillard S, Lanau N, Rouard M, Périn C (January 2008). "GreenPhylDB: a database for plant comparative genomics". Nucleic Acids Research. 36 (Database issue): D991–8. doi:10.1093/nar/gkm934. PMC 2238940. PMID 17986457.
  9. Inparanoid: Eukaryotic Ortholog Groups
    Ostlund G, Schmitt T, Forslund K, Köstler T, Messina DN, Roopra S, Frings O, Sonnhammer EL (January 2010). "InParanoid 7: new algorithms and tools for eukaryotic orthology analysis". Nucleic Acids Research. 38 (Database issue): D196–203. doi:10.1093/nar/gkp931. PMC 2808972. PMID 19892828.
  10. Singh PP, Arora J, Isambert H (July 2015). "Identification of Ohnolog Genes Originating from Whole Genome Duplication in Early Vertebrates, Based on Synteny Comparison across Multiple Genomes". PLoS Computational Biology. 11 (7): e1004394. doi:10.1371/journal.pcbi.1004394. PMC 4504502. PMID 26181593.
  11. "Vertebrate Ohnologs". Retrieved 2018-10-12.
  12. Zdobnov EM, Tegenfeldt F, Kuznetsov D, Waterhouse RM, Simão FA, Ioannidis P, Seppey M, Loetscher A, Kriventseva EV (January 2017). "OrthoDB v9.1: cataloging evolutionary and functional annotations for animal, fungal, plant, archaeal, bacterial and viral orthologs". Nucleic Acids Research. 45 (D1): D744–D749. doi:10.1093/nar/gkw1119. PMC 5210582. PMID 27899580.
  13. Linard, B; Allot, A; Schneider, R; Morel, C; Ripp, R; Bigler, M; Thompson, JD; Poch, O; Lecompte, O (1 February 2015). "OrthoInspector 2.0: Software and database updates". Bioinformatics. 31 (3): 447–8. doi:10.1093/bioinformatics/btu642. PMID 25273105.
  14. OrthologID
  15. OrthoMaM
    Ranwez V, Delsuc F, Ranwez S, Belkhir K, Tilak MK, Douzery EJ (November 2007). "OrthoMaM: a database of orthologous genomic markers for placental mammal phylogenetics". BMC Evolutionary Biology. 7: 241. doi:10.1186/1471-2148-7-241. PMC 2249597. PMID 18053139.
  16. OrthoMCL: Identification of Ortholog Groups for Eukaryotic Genomes
    Chen F, Mackey AJ, Stoeckert CJ, Roos DS (January 2006). "OrthoMCL-DB: querying a comprehensive multi-species collection of ortholog groups". Nucleic Acids Research. 34 (Database issue): D363–8. doi:10.1093/nar/gkj123. PMC 1347485. PMID 16381887.
  17. Roundup
    Deluca TF, Wu IH, Pu J, Monaghan T, Peshkin L, Singh S, Wall DP (August 2006). "Roundup: a multi-genome repository of orthologs and evolutionary distances". Bioinformatics. 22 (16): 2044–2046. doi:10.1093/bioinformatics/btl286. PMID 16777906.
  18. TreeFam: Tree families database
    van der Heijden RT, Snel B, van Noort V, Huynen MA (March 2007). "Orthology prediction at scalable resolution by phylogenetic tree analysis". BMC Bioinformatics. 8: 83. doi:10.1186/1471-2105-8-83. PMC 1838432. PMID 17346331.
  19. TreeFam: Tree families database
    Ruan J, Li H, Chen Z, Coghlan A, Coin LJ, Guo Y, Hériché JK, Hu Y, Kristiansen K, Li R, Liu T, Moses A, Qin J, Vang S, Vilella AJ, Ureta-Vidal A, Bolund L, Wang J, Durbin R (January 2008). "TreeFam: 2008 Update". Nucleic Acids Research. 36 (Database issue): D735–40. doi:10.1093/nar/gkm1005. PMC 2238856. PMID 18056084.
  22. Fulton DL, Li YY, Laird MR, Horsman BG, Roche FM, Brinkman FS (May 2006). "Improving the specificity of high-throughput ortholog prediction". BMC Bioinformatics. 7: 270. doi:10.1186/1471-2105-7-270. PMC 1524997. PMID 16729895.
  23. Zakany J, Duboule D (August 2007). "The role of Hox genes during vertebrate limb development". Current Opinion in Genetics & Development. 17 (4): 359–366. doi:10.1016/j.gde.2007.05.011. PMID 17644373.
  24. Studer RA, Robinson-Rechavi M (May 2009). "How confident can we be that orthologs are similar, but paralogs differ?". Trends in Genetics. 25 (5): 210–216. doi:10.1016/j.tig.2009.03.004. PMID 19368988.
  26. Eisen, Jonathan. "Special Guest Post & Discussion Invitation from Matthew Hahn on Ortholog Conjecture Paper".
  27. Noda-Garcia L, Romero Romero ML, Longo LM, Kolodkin-Gal I, Tawfik DS (July 2017). "Bacilli glutamate dehydrogenases diverged via coevolution of transcription and enzyme regulation". EMBO Reports. 18 (7): 1139–1149. doi:10.15252/embr.201743990. PMC 5494520. PMID 28468957.
  29. Coulier F, Popovici C, Villet R, Birnbaum D (December 2000). "MetaHox gene clusters". The Journal of Experimental Zoology. 288 (4): 345–351. doi:10.1002/1097-010X(20001215)288:4<345::AID-JEZ7>3.0.CO;2-Y. PMID 11144283.
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  32. Larsson TA, Olsson F, Sundstrom G, Lundin LG, Brenner S, Venkatesh B, Larhammar D (June 2008). "Early vertebrate chromosome duplications and the evolution of the neuropeptide Y receptor gene regions". BMC Evolutionary Biology. 8: 184. doi:10.1186/1471-2148-8-184. PMC 2453138. PMID 18578868.
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  34. Mulley JF, Chiu CH, Holland PW (July 2006). "Breakup of a homeobox cluster after genome duplication in teleosts". Proceedings of the National Academy of Sciences of the United States of America. 103 (27): 10369–10372. doi:10.1073/pnas.0600341103. PMC 1502464. PMID 16801555.
  35. Flajnik MF, Kasahara M (September 2001). "Comparative genomics of the MHC: glimpses into the evolution of the adaptive immune system". Immunity. 15 (3): 351–362. doi:10.1016/S1074-7613(01)00198-4. PMID 11567626.
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  41. McLysaght A, Makino T, Grayton HM, Tropeano M, Mitchell KJ, Vassos E, Collier DA (January 2014). "Ohnologs are overrepresented in pathogenic copy number mutations". Proceedings of the National Academy of Sciences of the United States of America. 111 (1): 361–366. doi:10.1073/pnas.1309324111. PMC 3890797. PMID 24368850.
  42. Makino T, McLysaght A (May 2010). "Ohnologs in the human genome are dosage balanced and frequently associated with disease". Proceedings of the National Academy of Sciences of the United States of America. 107 (20): 9270–9274. doi:10.1073/pnas.0914697107. PMC 2889102. PMID 20439718.
  43. García-Moreno J, Mindell DP (December 2000). "Rooting a phylogeny with homologous genes on opposite sex chromosomes (gametologs): a case study using avian CHD". Molecular Biology and Evolution. 17 (12): 1826–1832. doi:10.1093/oxfordjournals.molbev.a026283. PMID 11110898.