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Infection-associated FUT2 (Fucosyltransferase 2) genetic variation and impact on functionality assessed by in vivo studies

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Abstract

The secretor (Se)/nonsecretor (se) histo-blood group variation depends on the action of the FUT2 enzyme and has major implications for human susceptibility to infections. To characterize the functionality of FUT2 variants, we assessed the correlation between saliva phenotypes and sequence variation at the FUT2 gene in sixty seven individuals from northern Portugal. While most non-secretor haplotypes were found to carry the 428G > A nonsense mutation in association with a 739G > A missense substitution, we have also identified a recombinant haplotype carrying the 739*A allele together with the efficient 428*G variant in individuals with the Se phenotype. This finding suggested, in contrast to previous results, that the 739*A allele encodes an efficient Se allele. To test this hypothesis we evaluated the in vivo enzyme activity of full coding expression constructs in transient transfection of CHO-K1 cells using FACS (fluorescence-activated cell sorting) analysis and expression of type 2 and type 3 chain H structures as read out. We detected FUT2 activity for the 739*A expression construct, demonstrating that the 739G > A substitution is indeed not inactivating. In accordance with the hypothesis that FUT2 is under long standing balancing selection, we estimated that the time depth of FUT2 global genetic variation is as old as 3 million years. Age estimates of specific variants suggest that the 428G > A mutation occurred at least 1.87 million years ago while the 739G > A substitution is about 816,000 years old. The 385A > T missense mutation underlying the non-secretor phenotype in East Asians appears to be more recent and is likely to have occurred about 256,000 years ago.

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References

  1. Marionneau, S., Cailleau-Thomas, A., Rocher, J., Le Moullac-Vaidye, B., Ruvoën-Clouet, N., Clément, M., Le Pendu, J.: ABH and Lewis histo-blood group antigens, a model for the meaning of oligosaccharide diversity in the face of a changing world. Biochimie 83, 565–573 (2001)

    Article  CAS  PubMed  Google Scholar 

  2. Lindesmith, L., Moe, C., Marionneau, S., Ruvoen, N., Jiang, X., Lindblad, L., Stewart, P., Le Pendu, J., Baric, R.: Human susceptibility and resistance to Norwalk virus infection. Nat. Med. 9, 548–553 (2003)

    Article  CAS  PubMed  Google Scholar 

  3. Hutson, A.M., Airaud, F., Le Pendu, J., Estes, M.K., Atmar, R.L.: Norwalk virus infection associates with secretor status genotyped from sera. J. Med. Virol. 77, 116–120 (2005)

    Article  CAS  PubMed  Google Scholar 

  4. Thorven, M., Grahn, A., Hedlund, K.O., Johansson, H., Wahlfrid, C., Larson, G., Svensson, L.: A homozygous nonsense mutation (428G > A) in the human FUT2 gene provides resistance to symptomatic norovirus (GGII) infections. J. Virol. 79, 15351–15355 (2005)

    Article  CAS  PubMed  Google Scholar 

  5. Kindberg, E., Akerlind, B., Johnsen, C., Knudsen, J.D., Heltberg, O., Larson, G., Böttinger, B., Svensson, L.: Host genetic resistance to symptomatic norovirus (GGII.4) infections in Denmark. J. Clin. Microbiol. 45, 2720–2722 (2007)

    Article  CAS  PubMed  Google Scholar 

  6. Stapleton, A., Hooton, T.M., Fennell, C., Roberts, P.L., Stamm, W.E.: Effect of secretor status on vaginal and rectal colonization with fimbriated Escherichia coli in women with and without recurrent urinary tract infection. J. Infect. Dis. 171, 717–720 (1995)

    CAS  PubMed  Google Scholar 

  7. Azevedo, M., Eriksson, S., Mendes, N., Serpa, J., Figueiredo, C., Resende, L.P., Ruvoën-Clouet, N., Haas, R., Borén, T., Le Pendu, J., David, L.: Infection by Helicobacter pylori expressing the BabA adhesin is influenced by the secretor phenotype. J. Pathol. 215, 308–316 (2008)

    Article  CAS  PubMed  Google Scholar 

  8. Lindén, S., Mahdavi, J., Semino-Mora, C., Olsen, C., Carlstedt, I., Borén, T., Dubois, A.: Role of ABO secretor status in mucosal innate immunity and H. pylori infection. PLoS Pathog. 4, e2 (2008)

    Article  PubMed  Google Scholar 

  9. Koda, Y., Tachida, H., Pang, H., Liu, Y., Soejima, M., Ghaderi, A.A., Takenaka, O., Kimura, V.: Contrasting patterns of polymorphisms at the ABO-secretor gene (FUT2) and plasma alpha(1, 3)fucosyltransferase gene (FUT6) in human populations. Genetics 158, 747–756 (2001)

    CAS  PubMed  Google Scholar 

  10. Walsh, E.C., Sabeti, P., Hutcheson, H.B., Fry, B., Schaffner, S.F., de Bakker, P.I.W., Varilly, P., Palma, A.A., Roy, J., Cooper, R., Winkler, C., Zeng, Y., de The, G., Lander, E.S., O’Brien, S., Altshuler, D.: Searching for signals of evolutionary selection in 168 genes related to immune function. Hum. Genet. 119, 92–102 (2006)

    Article  CAS  PubMed  Google Scholar 

  11. Fumagalli, M., Cagliani, R., Pozzoli, U., Riva, S., Comi, G., Menozzi, G., Bresolin, N., Sironi, M.: Widespread balancing selection and pathogen-driven selection at blood group antigen genes. Genome Res. 19, 199–212 (2009)

    Article  CAS  PubMed  Google Scholar 

  12. Kelly, R.J., Rouquier, S., Giorgi, D., Lennon, G.G., Lowe, J.B.: Sequence and expression of a candidate for the human secretor blood group α(1, 2)fucosyltransferase gene (FUT2). J. Biol. Chem. 270, 4640–4649 (1995)

    Article  CAS  PubMed  Google Scholar 

  13. Liu, Y., Koda, Y., Soejima, M., Pang, H., Schlaphoff, T., du Toit, E.D., Kimura, H.: Extensive polymorphism of the FUT2 gene in an African (Xhosa) population of South Africa. Hum. Genet. 103, 204–210 (1998)

    Article  CAS  PubMed  Google Scholar 

  14. Koda, Y., Soejima, M., Kimura, H.: The polymorphisms of fucosyltransferases. Leg. Med. 3, 2–14 (2001)

    Article  CAS  Google Scholar 

  15. Soejima, M., Nakajima, T., Fujihara, J., Takeshita, H., Koda, Y.: Genetic variation of FUT2 in Ovambos, Turks, and Mongolians. Transfusion 48, 1423–1431 (2008)

    Article  CAS  PubMed  Google Scholar 

  16. Blumenfeld, O.O., Patnaik, S.K.: Allelic genes of blood group antigens: a source of human mutations and cSNPs documented in the blood group antigen gene mutation database. Hum. Mutat. 23, 8–16 (2004)

    Article  CAS  PubMed  Google Scholar 

  17. Serpa, J., Mendes, N., Reis, C.A., Santos Silva, L.F., Almeida, R., Le Pendu, J., David, L.: Two new FUT2 (fucosyltransferase 2 gene) missense polymorphisms, 739G→A and 839 T→C, are partly responsible for non-secretor status in a Caucasian population from Northern Portugal. Biochem. J. 383, 469–474 (2004)

    Article  CAS  PubMed  Google Scholar 

  18. Nogueira, C., Figueiredo, C., Carneiro, F., Gomes, A.T., Barreira, R., Figueira, P., Salgado, C., Belo, L., Peixoto, A., Bravo, J.C., Bravo, L.E., Realpe, J.L., Plaisier, A.P., Quint, W.G., Ruiz, B., Correa, P., van Doorn, L.J.: Helicobacter pylori genotypes may determine gastric histopathology. Am. J. Pathol. 158, 647–654 (2001)

    CAS  PubMed  Google Scholar 

  19. Peleteiro, B., Lunet, N., Figueiredo, C., Carneiro, F., David, L., Barros, H.: Smoking, Helicobacter pylori virulence, and type of intestinal metaplasia in Portuguese males. Cancer Epidemiol. Biomarkers Prev. 16, 322–326 (2007)

    Article  CAS  PubMed  Google Scholar 

  20. Stephens, M., Smith, N.J., Donnely, P.: A new statistical method for haplotype reconstruction from population data. Am. J. Hum. Genet. 68, 978–989 (2001)

    Article  CAS  PubMed  Google Scholar 

  21. Stephens, M., Donnelly, P.: A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am. J. Hum. Genet. 73, 1162–1169 (2003)

    Article  CAS  PubMed  Google Scholar 

  22. Bandelt, H.J., Forster, P., Röhl, A.: Median-joining networks for inferring intraspecific phylogenies. Mol. Biol. Evol. 16, 37–48 (1999)

    CAS  PubMed  Google Scholar 

  23. Griffiths, R.C., Tavaré, S.: Sampling theory for neutral alleles in a varying environment. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 344, 403–410 (1994)

    Article  CAS  PubMed  Google Scholar 

  24. Rozas, J., Sánchez-DelBarrio, J.C., Messeguer, X., Rozas, R.: DnaSP, DNA polymorphism analyses by the coalescent and other methods. Bioinformatics. 19, 2496–2497 (2003)

    Article  CAS  PubMed  Google Scholar 

  25. Patterson, N., Richter, D.J., Gnerre, S., Lander, E.S., Reich, D.: Genetic evidence for complex speciation of humans and chimpanzees. Nature 441, 1103–1108 (2006)

    Article  CAS  PubMed  Google Scholar 

  26. Chang, J.G., Yang, T.Y., Liu, T.C., Lin, T.P., Hu, C.J., Kao, M.C., Wang, N.M., Tsai, F.J., Peng, C.T., Tsai, C.H.: Molecular analysis of secretor type alpha(1, 2)-fucosyltransferase gene mutations in the Chinese and Thai populations. Transfusion 39, 1013–1017 (1999)

    Article  CAS  PubMed  Google Scholar 

  27. Pang, H., Fujitani, N., Soejima, M., Koda, Y., Islam, M.N., Islam, A.K., Kimura, H.: Two distinct Alu-mediated deletions of the human ABO-Secretor (FUT2) locus in Samoan and Bangladeshi populations. Hum. Mutat. 16, 274 (2000)

    Article  CAS  PubMed  Google Scholar 

  28. Soejima, M., Koda, Y.: Molecular mechanisms of Lewis antigen expression. Leg. Med. 7, 266–269 (2005)

    Article  CAS  Google Scholar 

  29. Soejima, M., Koda, Y.: Denaturing high-performance liquid chromatography-based genotyping and genetic variation of FUT2 in Sri Lanka. Transfusion 45, 1934–1939 (2005)

    Article  CAS  PubMed  Google Scholar 

  30. Mollicone, R., Reguigne, I., Kelly, R.J., Fletcher, A., Watt, J., Chatfield, S., Aziz, A., Cameron, H.S., Weston, B.W., Lowe, J.B.: Molecular basis for Lewis alpha(1, 3/1, 4)-fucosyltransferase gene deficiency (FUT3) found in Lewis-negative Indonesian pedigrees. J. Biol. Chem. 269, 20987–20994 (1994)

    CAS  PubMed  Google Scholar 

  31. Marcos, N.T., Pinho, S., Grandela, C., Cruz, A., Samyn-Petit, B., Harduin-Lepers, A., Almeida, R., Silva, F., Morais, V., Costa, J., Kihlberg, J., Clausen, H., Reis, C.A.: Role of the human ST6GalNAc-I and ST6GalNAc-II in the synthesis of the cancer-associated sialyl-Tn antigen. Cancer Res. 64, 7050–7057 (2004)

    Article  CAS  PubMed  Google Scholar 

  32. Koda, Y., Tachida, H., Soejima, M., Takenaka, O., Kimura, H.: Ancient origin of the null allele se(428) of the human ABO-secretor locus (FUT2). J. Mol. Evol. 50, 243–248 (2000)

    CAS  PubMed  Google Scholar 

  33. Tishkoff, S.A., Verrelli, B.C.: Patterns of human genetic diversity: implications for human evolutionary history and disease. Annu. Rev. Genomics Hum. Genet. 4, 293–340 (2003)

    Article  CAS  PubMed  Google Scholar 

  34. Garrigan, D., Hammer, M.F.: Reconstructing human origins in the genomic era. Nat. Rev. Genet. 7, 669–680 (2006)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We gratefully acknowledge Nuno Ferrand for discussions and help in the use of the GENETREE software. We thank Nuno Mendes for expert technical assistance. This study was supported by Fundação para a Ciência e a Tecnologia (FCT) and Programa Operacional Ciência e Inovação 2010 do Quadro Comunitário de Apoio III (PTDC/SAU-MII64153/2006), by FCT project (PPCDT/BIA-BDE/56654/2004) and by the CIMATH project from the Région des Pays de la Loire. AS Carvalho thanks Fundação para a Ciência e a Tecnologia for post-doctoral fellowship (SFRH/BPD/36912/2007).

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Authors and Affiliations

  1. IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua Dr. Roberto Frias s/n, 4200-465, Porto, Portugal

    Lara M. Silva, Ana S. Carvalho, Susana Seixas, Maria Azevedo, Raquel Almeida, Celso A. Reis, Jorge Rocha & Leonor David

  2. Inserm, Université de Nantes, U892, Nantes, France

    Patrice Guillon, Nathalie Ruvoën-Clouet & Jacques Le Pendu

  3. Medical Faculty of the University of Porto, Porto, Portugal

    Raquel Almeida, Celso A. Reis & Leonor David

  4. Ecole Nationale Vétérinaire de Nantes, Nantes, France

    Nathalie Ruvoën-Clouet

  5. Department of Zoology and Anthropology, Faculty of Sciences, University of Porto, Porto, Portugal

    Jorge Rocha

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  1. Lara M. Silva
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Correspondence to Leonor David.

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Silva, L.M., Carvalho, A.S., Guillon, P. et al. Infection-associated FUT2 (Fucosyltransferase 2) genetic variation and impact on functionality assessed by in vivo studies. Glycoconj J 27, 61–68 (2010). https://doi.org/10.1007/s10719-009-9255-8

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