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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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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
Koda, Y., Soejima, M., Kimura, H.: The polymorphisms of fucosyltransferases. Leg. Med. 3, 2–14 (2001)
Soejima, M., Nakajima, T., Fujihara, J., Takeshita, H., Koda, Y.: Genetic variation of FUT2 in Ovambos, Turks, and Mongolians. Transfusion 48, 1423–1431 (2008)
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)
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)
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)
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)
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)
Stephens, M., Donnelly, P.: A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am. J. Hum. Genet. 73, 1162–1169 (2003)
Bandelt, H.J., Forster, P., Röhl, A.: Median-joining networks for inferring intraspecific phylogenies. Mol. Biol. Evol. 16, 37–48 (1999)
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)
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)
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)
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)
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)
Soejima, M., Koda, Y.: Molecular mechanisms of Lewis antigen expression. Leg. Med. 7, 266–269 (2005)
Soejima, M., Koda, Y.: Denaturing high-performance liquid chromatography-based genotyping and genetic variation of FUT2 in Sri Lanka. Transfusion 45, 1934–1939 (2005)
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)
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)
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)
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)
Garrigan, D., Hammer, M.F.: Reconstructing human origins in the genomic era. Nat. Rev. Genet. 7, 669–680 (2006)
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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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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DOI: https://doi.org/10.1007/s10719-009-9255-8