Genetic characteristics and polymorphisms in the chicken interferon-induced transmembrane protein (IFITM3) gene

  • Yong-Chan Kim
  • Min-Ju Jeong
  • Byung-Hoon JeongEmail author
Original Article


The interferon-induced transmembrane protein 3 (IFITM3) gene is classified as a small interferon-stimulated gene and is associated with a broad spectrum of antiviral functions against several fatal enveloped viruses, including influenza A viruses (IAVs). The rs12252 single nucleotide polymorphism (SNP) of the IFITM3 gene in humans was associated with susceptibility to H1N1 influenza in a 2009 pandemic. In addition, overexpression of the IFITM3 protein potently inhibits the highly pathogenic avian influenza H5N1 virus in ducks and chickens. Although chickens are a major host of influenza viruses and the IFITM3 gene participates in the host antiviral system, studies on chicken IFITM3 gene are very rare. To investigate the genetic characteristics of the chicken IFITM3 gene, we performed direct sequencing and alignment in 108 Dekalb White and 72 Ross breeds. We also investigated the genotype and haplotype frequencies and linkage disequilibrium of the IFITM3 gene polymorphisms and evaluated whether the non-synonymous SNPs are deleterious. We found significantly different genotype, allele and haplotypes frequencies between two chicken breeds, Dekalb White and Ross. Furthermore, we compared and analyzed the promoter structure of the chicken IFITM3 gene with that of several species. We found that birds have a long C-terminal domain and inverted topology of the IFITM3 protein compared to mammals. We also identified fourteen genetic polymorphisms in the chicken IFITM3 gene. L100 M and N125H were predicted as ‘probably damaging’ and L100 M can alter the length of its conserved intracellular loop (CIL). Furthermore, chickens, but not mammals, contain CpG islands (CGIs) in this promoter region.


Chickens Interferon-stimulated gene IFITM3 Promoter SNP Topology 



This research was supported by the Basic Science Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science and Technology (2015R1D1A1A01059945; 2018R1D1A1B07048711). This research was also supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2017R1A6A1A03015876). Mr. Yong-Chan Kim and Ms. Min-Ju Jeong were supported by the BK21 Plus program in the Department of Bioactive Material Sciences.

Compliance with ethical standards

Conflict of interest

The authors declared no conflict of interest.


  1. Anafu AA, Bowen CH, Chin CR, Brass AL, Holm GH (2013) Interferon-inducible Transmembrane Protein 3 (IFITM3) Restricts Reovirus Cell Entry. J Biol Chem 288(24):17261–17271Google Scholar
  2. Bailey CC, Kondur HR, Huang IC, Farzan M (2013) Interferon-induced transmembrane protein 3 is a type II transmembrane protein. J Biol Chem 288(45):32184–32193Google Scholar
  3. Bassano I, Ong SH, Lawless N, Whitehead T, Fife M, Kellam P (2017) Accurate characterization of the IFITM locus using MiSeq and PacBio sequencing shows genetic variation in Galliformes. BMC Genomics 30(18):419Google Scholar
  4. Blyth GA, Chan WF, Webster RG, Magor KE (2015) Duck interferon-inducible transmembrane protein 3 mediates restriction of influenza viruses. J Virol 90(1):103–116Google Scholar
  5. Brass AL, Huang IC, Benita Y, John SP, Krishnan MN, Feeley EM, Ryan BJ, Weyer JL, van der Weyden L, Fikrig E, Adams DJ, Xavier RJ, Farzan M, Elledge SJ (2009) The IFITM proteins mediate cellular resistance to influenza a H1N1 virus, West Nile virus, and dengue virus. Cell 139(7):1243–1254Google Scholar
  6. Chen S, Wang L, Chen J, Zhang L, Wang S, Goraya MU, Chi X, Na Y, Shao W, Yang Z, Zeng X, Chen S, Chen JL (2017) Avian interferon-inducible transmembrane protein family effectively restricts avian Tembusu virus infection. Front Microbiol 8:672Google Scholar
  7. Danino YM, Even D, Ideses D, Juven-Gershon T (2015) The core promoter: at the heart of gene expression. Biochim Biophys Acta 1849(8):1116–1131Google Scholar
  8. Diamond MS, Farzan M (2013) The broad-spectrum antiviral functions of IFIT and IFITM proteins. Nat Rev Immunol 13(1):46–57Google Scholar
  9. Everitt AR, Clare S, Pertel T, John SP, Wash RS, Smith SE, Chin CR, Feeley EM, Sims JS, Adams DJ, Wise HM, Kane L, Goulding D, Digard P, Anttila V, Baillie JK, Walsh TS, Hume DA, Palotie A, Xue Y, Colonna V, Tyler-Smith C, Dunning J, Gordon SB, Gen II, Investigators M, Smyth RL, Openshaw PJ, Dougan G, Brass AL, Kellam P (2012) IFITM3 restricts the morbidity and mortality associated with influenza. Nature 484(7395):519–523Google Scholar
  10. Feeley EM, Sims JS, John SP, Chin CR, Pertel T, Chen LM, Gaiha GD, Ryan BJ, Donis RO, Elledge SJ, Brass AL (2011) IFITM3 inhibits influenza a virus infection by preventing cytosolic entry. PLoS Pathog 7(10):e1002337Google Scholar
  11. Friedman RL, Manly SP, McMahon M, Kerr IM, Stark GR (1984) Transcriptional and posttranscriptional regulation of interferon-induced gene expression in human cells. Cell 38(3):745–755Google Scholar
  12. Jeong BH, Kim NH, Choi EK, Lee C, Song YH, Kim JI, Carp RI, Kim YS (2005a) Polymorphism at 3' UTR +28 of the prion-like protein gene is associated with sporadic Creutzfeldt-Jakob disease. Eur J Hum Genet 13(9):1094–1097Google Scholar
  13. Jeong BH, Lee KH, Kim NH, Jin JK, Kim JI, Carp RI, Kim YS (2005b) Association of sporadic Creutzfeldt-Jakob disease with homozygous genotypes at PRNP codons 129 and 219 in the Korean population. Neurogenetics 6(4):229–232Google Scholar
  14. Jia R, Pan Q, Ding S, Rong L, Liu SL, Geng Y, Qiao W, Liang C (2012) The N-terminal region of IFITM3 modulates its antiviral activity by regulating IFITM3 cellular localization. J Virol 86(24):13697–13707Google Scholar
  15. Jia R, Xu F, Qian J, Yao Y, Miao C, Zheng YM, Liu SL, Guo F, Geng Y, Qiao W, Liang C (2014) Identification of an endocytic signal essential for the antiviral action of IFITM3. Cell Microbiol 16(7):1080–1093Google Scholar
  16. John SP, Chin CR, Perreira JM, Feeley EM, Aker AM, Savidis G, Smith SE, Elia AE, Everitt AR, Vora M, Pertel T, Elledge SJ, Kellam P, Brass AL (2013) The CD225 domain of IFITM3 is required for both IFITM protein association and inhibition of influenza a virus and dengue virus replication. J Virol 87(14):7837–7852Google Scholar
  17. Juven-Gershon T, Kadonaga JT (2010) Regulation of gene expression via the core promoter and the basal transcriptional machinery. Dev Biol 339(2):225–229Google Scholar
  18. Kaiser P (2010) Advances in avian immunology--prospects for disease control: a review. Avian Pathol 39(5):309–324Google Scholar
  19. Kim YC, Jeong BH (2017a) Lack of germline mutation at codon 211 of the prion protein gene (PRNP) in Korean native cattle. Acta Vet Hung 65(1):147–152Google Scholar
  20. Kim YC, Jeong BH (2017b) No correlation of the disease severity of influenza a virus infection with the rs12252 polymorphism of the interferon-induced transmembrane protein 3 gene. Intervirology 60(1–2):69–74Google Scholar
  21. Lenhard B, Sandelin A, Carninci P (2012) Metazoan promoters: emerging characteristics and insights into transcriptional regulation. Nat Rev Genet 13(4):233–245Google Scholar
  22. Li K, Markosyan RM, Zheng YM, Golfetto O, Bungart B, Li M, Ding S, He Y, Liang C, Lee JC, Gratton E, Cohen FS, Liu SL (2013) IFITM proteins restrict viral membrane hemifusion. PLoS Pathog 9(1):e1003124Google Scholar
  23. Naderi M, Hashemi M, Abedipour F, Bahari G, Rezaei M, Taheri M (2016) Evaluation of interferon-induced transmembrane protein-3 (IFITM3) rs7478728 and rs3888188 polymorphisms and the risk of pulmonary tuberculosis. Biomed Rep 5(5):634–638Google Scholar
  24. Ranjbar S, Haridas V, Jasenosky LD, Falvo JV, Goldfeld AE (2015) A role for IFITM proteins in restriction of mycobacterium tuberculosis infection. Cell Rep 13(5):874–883Google Scholar
  25. Santhakumar D, Rubbenstroth D, Martinez-Sobrido L, Munir M (2017) Avian interferons and their antiviral effectors. Front Immunol 31(8):49Google Scholar
  26. Savidis G, Perreira JM, Portmann JM, Meraner P, Guo Z, Green S, Brass AL (2016) The IFITMs inhibit Zika virus replication. Cell Rep 15(11):2323–2330Google Scholar
  27. Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, Rice CM (2011) A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472(7344):481–485Google Scholar
  28. Seo GS, Lee JK, Yu JI, Yun KJ, Chae SC, Choi SC (2010) Identification of the polymorphisms in IFITM3 gene and their association in a Korean population with ulcerative colitis. Exp Mol Med 42(2):99–104Google Scholar
  29. Smith SE, Gibson MS, Wash RS, Ferrara F, Wright E, Temperton N, Kellam P, Fife M (2013) Chicken interferon-inducible transmembrane protein 3 restricts influenza viruses and lyssaviruses in vitro. J Virol 87(23):12957–12966Google Scholar
  30. Smith J, Smith N, Yu L, Paton IR, Gutowska MW, Forrest HL, Danner AF, Seiler JP, Digard P, Webster RG, Burt DW (2015) A comparative analysis of host responses to avian influenza infection in ducks and chickens highlights a role for the interferon-induced transmembrane proteins in viral resistance. BMC Genomics 4(16):574Google Scholar
  31. Traub LM, Bonifacino JS (2013) Cargo recognition in clathrin-mediated endocytosis. Cold Spring Harb Perspect Biol 5(11):a016790Google Scholar
  32. Wang A, Sun L, Wang M, Jia R, Zhu D, Liu M, Sun K, Yang Q, Wu Y, Chen X, Cheng A, Chen S (2017) Identification of IFITM1 and IFITM3 in goose: gene structure, expression patterns, and immune Reponses against Tembusu virus infection. Biomed Res Int 2017:5149062Google Scholar
  33. Weidner JM, Jiang D, Pan XB, Chang J, Block TM, Guo JT (2010) Interferon-induced cell membrane proteins, IFITM3 and tetherin, inhibit vesicular stomatitis virus infection via distinct mechanisms. J Virol 84(24):12646–12657Google Scholar
  34. Wu F, Dassopoulos T, Cope L, Maitra A, Brant SR, Harris ML, Bayless TM, Parmigiani G, Chakravarti S (2007) Genome-wide gene expression differences in Crohn's disease and ulcerative colitis from endoscopic pinch biopsies: insights into distinctive pathogenesis. Inflamm Bowel Dis 13(7):807–821Google Scholar
  35. Xuan Y, Wang LN, Li W, Zi HR, Guo Y, Yan WJ, Chen XB, Wei PM (2015) IFITM3 rs12252 T>C polymorphism is associated with the risk of severe influenza: a meta-analysis. Epidemiol Infect 143(14):2975–2984Google Scholar
  36. Xu-Yang Z, Pei-Yu B, Chuan-Tao Y, Wei Y, Hong-Wei M, Kang T, Chun-Mei Z, Ying-Feng L, Xin W, Ping-Zhong W, Chang-Xing H, Xue-Fan B, Ying Z, Zhan-Sheng J (2016) Interferon-induced transmembrane protein 3 inhibits Hantaan virus infection, and its single nucleotide polymorphism rs12252 influences the severity of hemorrhagic fever with renal syndrome. Front Immunol 7:535Google Scholar
  37. Zhang Z, Liu J, Li M, Yang H, Zhang C (2012) Evolutionary dynamics of the interferon-induced transmembrane gene family in vertebrates. PLoS One 7(11):e49265Google Scholar
  38. Zhang YH, Zhao Y, Li N, Peng YC, Giannoulatou E, Jin RH, Yan HP, Wu H, Liu JH, Liu N, Wang DY, Shu YL, Ho LP, Kellam P, McMichael A, Dong T (2013) Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals. Nat Commun 4:1418Google Scholar
  39. Zhu J, He F, Hu S, Yu J (2008) On the nature of human housekeeping genes. Trends Genet 24(10):481–484Google Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Korea Zoonosis Research InstituteChonbuk National UniversityIksanRepublic of Korea
  2. 2.Department of Bioactive Material SciencesChonbuk National UniversityJeonjuRepublic of Korea

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