, Volume 70, Issue 10, pp 681–687 | Cite as

Cetacea are natural knockouts for IL20

  • Mónica Lopes-Marques
  • André M. Machado
  • Susana Barbosa
  • Miguel M. Fonseca
  • Raquel RuivoEmail author
  • L. Filipe C. CastroEmail author
Short Communication


The Cetacea infraorder comprises a very unique group within the mammalian lineage. While sharing common ancestors with terrestrial mammals, their exclusive dependence on aquatic environments makes them attractive models to explore the landscape of molecular shifts in radical habitat transitions. Among their diverse anatomical and physiological solutions, we find detectable genetic remodeling of the immune system. In agreement, here we show that the gene sequence of interleukin-20 (IL20) displays unambiguous signs of inactivation with several disruptive mutations, including stop codons, insertions, and a conserved trans-species mutation abolishing a canonical splice site, in nine analyzed cetacean genomes. Considering the suggested role of IL20 in skin immunity processes, including inflammation, epithelization, and remodeling, we propose that gene inactivation follows specific adaptations of cetacean skin to the aquatic environment, in frame with the less-is-more hypothesis.


Cetacea Immune system IL20 Gene loss Skin 


Funding information

This work was supported by Norte2020 and FEDER (Coral - Sustainable Ocean Exploitation - Norte-01-0145-FEDER-000036).

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  1. Adami C (2002) What is complexity? BioEssays 24:1085–1094. CrossRefPubMedGoogle Scholar
  2. Akdis M, Burgler S, Crameri R, Eiwegger T, Fujita H, Gomez E, Klunker S, Meyer N, O’Mahony L, Palomares O, Rhyner C, Quaked N, Schaffartzik A, van de Veen W, Zeller S, Zimmermann M, Akdis CA (2011) Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases J Allergy Clin Immunol 127:701–721.e770 doi:, 721.e70CrossRefGoogle Scholar
  3. Albalat R, Cañestro C (2016) Evolution by gene loss. Nat Rev Genet 17:379–391., Scholar
  4. Blumberg H, Conklin D, Xu WF, Grossmann A, Brender T, Carollo S, Eagan M, Foster D, Haldeman BA, Hammond A, Haugen H, Jelinek L, Kelly JD, Madden K, Maurer MF, Parrish-Novak J, Prunkard D, Sexson S, Sprecher C, Waggie K, West J, Whitmore TE, Yao L, Kuechle MK, Dale BA, Chandrasekher YA (2001) Interleukin 20: discovery, receptor identification, and role in epidermal function. Cell 104:9–19CrossRefGoogle Scholar
  5. Braun BA, Marcovitz A, Camp JG, Jia R, Bejerano G (2015) Mx1 and Mx2 key antiviral proteins are surprisingly lost in toothed whales. Proc Natl Acad Sci U S A 112:8036–8040. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Emerling CA, Widjaja AD, Nguyen NN, Springer MS (2017) Their loss is our gain: regressive evolution in vertebrates provides genomic models for uncovering human disease loci. J Med Genet 54:787–794. CrossRefPubMedGoogle Scholar
  7. Fickenscher H, Pirzer H (2004) Interleukin-26. Int Immunopharmacol 4:609–613. CrossRefPubMedGoogle Scholar
  8. Go Y, Satta Y, Takenaka O, Takahata N (2005) Lineage-specific loss of function of bitter taste receptor genes in humans and nonhuman primates. Genetics 170:313–326CrossRefGoogle Scholar
  9. He M, Liang P (2010) IL-24 transgenic mice: in vivo evidence of overlapping functions for IL-20, IL-22, and IL-24 in the epidermis. J Immunol 184:1793–1798. CrossRefPubMedGoogle Scholar
  10. Hicks BD, St Aubin DJ, Geraci JR, Brown WR (1985) Epidermal growth in the bottlenose dolphin, Tursiops truncatus. J Invest Dermatol 85:60–63CrossRefGoogle Scholar
  11. Hsu YH, Hsing CH, Li CF, Chan CH, Chang MC, Yan JJ, Chang MS (2012) Anti-IL-20 monoclonal antibody suppresses breast cancer progression and bone osteolysis in murine models. J Immunol 188:1981–1991. CrossRefPubMedGoogle Scholar
  12. Hsu YH, Chiu YS, Chen WY, Huang KY, Jou IM, Wu PT, Wu CH, Chang MS (2016) Anti-IL-20 monoclonal antibody promotes bone fracture healing through regulating IL-20-mediated osteoblastogenesis. Sci Rep 6:24339. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Lachner J, Mlitz V, Tschachler E, Eckhart L (2017) Epidermal cornification is preceded by the expression of a keratinocyte-specific set of pyroptosis-related genes. Sci Rep 7:17446. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Lopes-Marques M, Ruivo R, Fonseca E, Teixeira A, Castro LFC (2017) Unusual loss of chymosin in mammalian lineages parallels neo-natal immune transfer strategies. Mol Phylogenet Evol 116:78–86. CrossRefPubMedGoogle Scholar
  15. Maere S, Van de Peer Y (2010) Duplicate retention after small- and large-scale duplications. In: Evolution after gene duplication. John Wiley & Sons, Inc., pp 31–56. doi: CrossRefGoogle Scholar
  16. McGowen MR, Gatesy J, Wildman DE (2014) Molecular evolution tracks macroevolutionary transitions in Cetacea. Trends Ecol Evol 29:336–346. CrossRefPubMedGoogle Scholar
  17. Morris JJ, Lenski RE, Zinser ER (2012) The Black Queen Hypothesis: evolution of dependencies through adaptive gene loss. mBio 3.
  18. Neves F, Abrantes J, Steinke JW, Esteves PJ (2014) Maximum-likelihood approaches reveal signatures of positive selection in IL genes in mammals. Innate Immun 20:184–191. CrossRefPubMedGoogle Scholar
  19. Olson MV (1999) When less is more: gene loss as an engine of evolutionary change. Am J Hum Genet 64:18–23CrossRefGoogle Scholar
  20. Parada GE, Munita R, Cerda CA, Gysling K (2014) A comprehensive survey of non-canonical splice sites in the human transcriptome. Nucleic Acids Res 42:10564–10578. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Pond SL, Frost SD (2005) Datamonkey: rapid detection of selective pressure on individual sites of codon alignments. Bioinformatics (Oxford, England) 21:2531–2533. CrossRefGoogle Scholar
  22. Pyenson ND (2017) The ecological rise of whales chronicled by the fossil record. Curr Biol: CB 27:R558–r564. CrossRefPubMedGoogle Scholar
  23. Romer J, Hasselager E, Norby PL, Steiniche T, Thorn Clausen J, Kragballe K (2003) Epidermal overexpression of interleukin-19 and -20 mRNA in psoriatic skin disappears after short-term treatment with cyclosporine a or calcipotriol. J Invest Dermatol 121:1306–1311. CrossRefPubMedGoogle Scholar
  24. Rutz S, Wang X, Ouyang W (2014) The IL-20 subfamily of cytokines—from host defence to tissue homeostasis. Nat Rev Immunol 14:783–795. CrossRefPubMedGoogle Scholar
  25. Sadier A et al (2018) Evidence for multifactorial processes underlying phenotypic variation in bat visual opsins bioRxiv.
  26. Sharma V, Elghafari A, Hiller M (2016) Coding exon-structure aware realigner (CESAR) utilizes genome alignments for accurate comparative gene annotation. Nucleic Acids Res 44:e103–e103. CrossRefPubMedPubMedCentralGoogle Scholar
  27. Sharma V, Hecker N, Roscito JG, Foerster L, Langer BE, Hiller M (2018) A genomics approach reveals insights into the importance of gene losses for mammalian adaptations. Nat Commun 9:1215. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Sibley CR, Blazquez L, Ule J (2016) Lessons from non-canonical splicing. Nat Rev Genet 17:407–421. CrossRefPubMedPubMedCentralGoogle Scholar
  29. Sokolov VEE (1982) Mammalian skin. University of California Press, Berkeley and Los AngelesGoogle Scholar
  30. Spearman RI (1972) The epidermal stratum corneum of the whale. J Anat 113:373–381PubMedPubMedCentralGoogle Scholar
  31. Springer MS, Gatesy J (2018) Evolution of the MC5R gene in placental mammals with evidence for its inactivation in multiple lineages that lack sebaceous glands. Mol Phylogenet Evol 120:364–374. CrossRefPubMedGoogle Scholar
  32. Strasser B, Mlitz V, Fischer H, Tschachler E, Eckhart L (2015) Comparative genomics reveals conservation of filaggrin and loss of caspase-14 in dolphins. Exp Dermatol 24:365–369. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Wertheim JO, Murrell B, Smith MD, Kosakovsky Pond SL, Scheffler K (2015) RELAX: detecting relaxed selection in a phylogenetic framework. Mol Biol Evol 32:820–832. CrossRefPubMedGoogle Scholar
  34. Wolk K, Haugen HS, Xu W, Witte E, Waggie K, Anderson M, vom Baur E, Witte K, Warszawska K, Philipp S, Johnson-Leger C, Volk HD, Sterry W, Sabat R (2009) IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-gamma are not. J Mol Med (Berl) 87:523–536. CrossRefGoogle Scholar
  35. Yang Z (1998) Likelihood ratio tests for detecting positive selection and application to primate lysozyme evolution. Mol Biol Evol 15:568–573. CrossRefPubMedGoogle Scholar
  36. Yang Z (2007) PAML 4: phylogenetic analysis by maximum likelihood. Mol Biol Evol 24:1586–1591. CrossRefGoogle Scholar
  37. Yang Z, Nielsen R (1998) Synonymous and nonsynonymous rate variation in nuclear genes of mammals. J Mol Evol 46:409–418CrossRefGoogle Scholar
  38. Yim H-S et al (2013) Minke whale genome and aquatic adaptation in cetaceans. Nat Genet 46(88)., Scholar
  39. Zabka TS, Romano TA (2003) Distribution of MHC II (+) cells in skin of the Atlantic bottlenose dolphin (Tursiops truncatus): an initial investigation of dolphin dendritic cells. Anat Rec A Discov Mol Cell Evol Biol 273:636–647. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Mónica Lopes-Marques
    • 1
  • André M. Machado
    • 1
  • Susana Barbosa
    • 1
  • Miguel M. Fonseca
    • 1
  • Raquel Ruivo
    • 1
    Email author
  • L. Filipe C. Castro
    • 1
    • 2
    Email author
  1. 1.CIIMAR – Interdisciplinary Centre of Marine and Environmental ResearchU. Porto – University of PortoMatosinhosPortugal
  2. 2.Department of Biology, Faculty of SciencesU. Porto - University of PortoPortoPortugal

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