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Yoshiro Koda - One of the best experts on this subject based on the ideXlab platform.
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high resolution melting analysis for detection of fusion allele of FUT2
Electrophoresis, 2021Co-Authors: Mikiko Soejima, Yoshiro KodaAbstract:The secretor status of ABH antigens, determined by FUT2 polymorphisms, affects susceptibility to various infectious diseases. In addition to many SNPs responsible for the nonsecretor phenotype, five nonfunctional alleles (se) resulting from copy number variations have been reported. One of the five alleles generated by an unequal crossover between FUT2 and a pseudogene (SEC1), is sefus . This allele may be misidentified as a functional allele if only common inactivating SNPs are genotyped because it contains the 3' region of the functional FUT2. Therefore, accurate detection of sefus is desirable. For this purpose, a high-resolution melting (HRM) analysis is developed for detection of sefus in which a 284bp fragment of SEC1 and sefus but not FUT2, are amplified. This HRM analysis detected sefus reliably. Thus, an initial screening or prescreening for sefus using HRM analysis seems to be useful for association studies of FUT2.
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FUT2 polymorphism in latin american populations
Clinica Chimica Acta, 2020Co-Authors: Mikiko Soejima, Yoshiro KodaAbstract:Abstract Background The secretor type α(1,2)fucosyltransferase gene (FUT2) is known to be rich in population-specific polymorphisms. However, genetic variations of FUT2 have not been well examined in Latin American populations in which nonsecretors are rare. Methods Conventional polymerase chain reactions and direct sequencing were performed to detect single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) of FUT2 in Mexicans including Americans of Mexican ancestry, Puerto Ricans, Caribbeans, and Colombians. FUT2 alleles were determined by cloning into plasmids or PHASE software. The impact of uncharacterized missense SNPs on the enzyme activity were examined by transient transfection assays and estimated by several software programs. Results Three alleles, Se357, Se, and se428, were common, and the frequency of nonsecretors was relatively low in the studied populations. We also encountered several alleles specific to Africans, Europeans, and South and East Asians including a South Asian-specific sedel. In contrast to the in silico prediction, a transient expression study suggested that both of two missense SNPs, 235G > A and 304G > A, did not impair the enzyme activity. Conclusions The allelic polymorphism of FUT2 suggests that the modern Latin American populations were formed via genetic admixture among Native Americans and populations whose ancestors migrated from other continents. In this study, we have observed a discrepancy between in silico and functional analyses for FUT2 for the first time. Therefore, experimental functional analysis is required for evaluation of SNPs of FUT2.
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taqman real time polymerase chain reaction for detection of sec1 FUT2 hybrid alleles identification of novel hybrid allele
Clinica Chimica Acta, 2013Co-Authors: Mikiko Soejima, Yoshiro KodaAbstract:Abstract Background Two hybrid alleles between the secretor type α(1,2)fucosyltransferase gene (FUT2) and a pseudogene of FUT2 (SEC1) have been reported so far; parts of the SEC1 and FUT2 sequences are suggested to be susceptible to recombination. The sefus, one of the two hybrid alleles, is found in Japanese populations at relative high frequencies. Methods A TaqMan assay to distinguish SEC1 and SEC1-FUT2 hybrid alleles was designed for the purpose of dealing with large number of samples. Results The results of the present method were fully consistent with those of the previous method for detection of sefus in the Japanese population. In addition, a novel SEC1-FUT2-SEC1 hybrid allele, which contains a 35-bp sequence (between positions 418 and 452) that is identical to the FUT2 sequence including a 13-bp FUT2-specific region (between positions 436 and 448), was encountered in an individual of European descent. Conclusions The present TaqMan assay is a reliable and powerful method for the large scale association study between disease susceptibility and FUT2 genotypes especially in the Japanese populations because of relative high frequency of sefus. In addition, this method is a useful tool to find novel SEC1-FUT2 hybrid alleles.
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TaqMan-based real-time polymerase chain reaction for detection of FUT2 copy number variations: identification of novel Alu-mediated deletion.
Transfusion, 2010Co-Authors: Mikiko Soejima, Yoshiro KodaAbstract:BACKGROUND: The human FUT2 locus, which encodes a secretor-type α(1,2)fucosyltransferase, is known to be highly polymorphic. In addition to many single-nucleotide polymorphisms, three recombination alleles with a deletion of complete or partial FUT2 coding region have been reported. STUDY DESIGN AND METHODS: To detect copy number variations (CNVs) of the FUT2 gene including three recombinant alleles by a high-throughput system, we developed a triplex TaqMan real-time polymerase chain reaction (PCR) method. The relative number of copies of two regions of the FUT2 gene, the 5′ flanking (FUT2-5′) and FUT2-promoter (Prom) regions, were determined by comparing the number of threshold cycles (Ct) to those of the albumin gene (ALB) as the internal control (ΔCt). RESULTS: The mean 2−ΔΔCt values (FUT2-5′/ALB or Prom/ALB) obtained from 237 samples with known FUT2 copy numbers clearly differentiated two nonoverlapping intervals that corresponded to the one-copy-number samples ranging from 0.42 to 0.59 and two-copy-number samples ranging from 0.81 to 1.19; no FUT2-5′ signal for recombination alleles was detected in homozygotes. Using this assay, we detected an individual in a Chinese population with a loss of one copy of the FUT2-5′ region resulting from a novel Alu-mediated FUT2 deletion (approx. 4 kb). CONCLUSIONS: The TaqMan real-time PCR method was able to detect the number of copies of FUT2 and distinguish different kinds of known CNVs. This system is robust, fast, and suitable for high-throughput analysis.
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sec1 FUT2 sec1 hybrid allele generated by interlocus gene conversion
Transfusion, 2008Co-Authors: Mikiko Soejima, Junko Fujihara, Haruo Takeshita, Yoshiro KodaAbstract:BACKGROUND: Many single-nucleotide polymorphisms have been identified in the coding region of the FUT2 locus, which encodes secretor type α(1,2)fucosyltransferase. In addition, three recombination alleles have been reported. Of these recombination alleles, a fusion gene generated by an unequal crossing over between Sec1, a pseudogene that locates 23 kb upstream to and has high sequence homology with FUT2 and FUT2, was identified as a Japanese-specific nonsecretor allele (sefus). STUDY DESIGN AND METHODS: During the screening of the sefus in Mongolians (n = 118), a hybrid allele of Sec1-FUT2-Sec1 was found. RESULTS: The DNA sequence suggested that the Sec1-FUT2-Sec1 allele contains a 275-bp sequence (between positions 259 and 533) that is identical to the FUT2 sequence including a 54-bp FUT2-specific region (between positions 417 and 470) and that might have been generated by an interlocus gene conversion. CONCLUSION: Because the recombination region of sefus and the upstream recombination region of Sec1-FUT2-Sec1 are almost identical, this sequence stretch is likely to be the breakpoint for different kinds of recombinations that occur in this family of genes.
Mikiko Soejima - One of the best experts on this subject based on the ideXlab platform.
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high resolution melting analysis for detection of fusion allele of FUT2
Electrophoresis, 2021Co-Authors: Mikiko Soejima, Yoshiro KodaAbstract:The secretor status of ABH antigens, determined by FUT2 polymorphisms, affects susceptibility to various infectious diseases. In addition to many SNPs responsible for the nonsecretor phenotype, five nonfunctional alleles (se) resulting from copy number variations have been reported. One of the five alleles generated by an unequal crossover between FUT2 and a pseudogene (SEC1), is sefus . This allele may be misidentified as a functional allele if only common inactivating SNPs are genotyped because it contains the 3' region of the functional FUT2. Therefore, accurate detection of sefus is desirable. For this purpose, a high-resolution melting (HRM) analysis is developed for detection of sefus in which a 284bp fragment of SEC1 and sefus but not FUT2, are amplified. This HRM analysis detected sefus reliably. Thus, an initial screening or prescreening for sefus using HRM analysis seems to be useful for association studies of FUT2.
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FUT2 polymorphism in latin american populations
Clinica Chimica Acta, 2020Co-Authors: Mikiko Soejima, Yoshiro KodaAbstract:Abstract Background The secretor type α(1,2)fucosyltransferase gene (FUT2) is known to be rich in population-specific polymorphisms. However, genetic variations of FUT2 have not been well examined in Latin American populations in which nonsecretors are rare. Methods Conventional polymerase chain reactions and direct sequencing were performed to detect single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) of FUT2 in Mexicans including Americans of Mexican ancestry, Puerto Ricans, Caribbeans, and Colombians. FUT2 alleles were determined by cloning into plasmids or PHASE software. The impact of uncharacterized missense SNPs on the enzyme activity were examined by transient transfection assays and estimated by several software programs. Results Three alleles, Se357, Se, and se428, were common, and the frequency of nonsecretors was relatively low in the studied populations. We also encountered several alleles specific to Africans, Europeans, and South and East Asians including a South Asian-specific sedel. In contrast to the in silico prediction, a transient expression study suggested that both of two missense SNPs, 235G > A and 304G > A, did not impair the enzyme activity. Conclusions The allelic polymorphism of FUT2 suggests that the modern Latin American populations were formed via genetic admixture among Native Americans and populations whose ancestors migrated from other continents. In this study, we have observed a discrepancy between in silico and functional analyses for FUT2 for the first time. Therefore, experimental functional analysis is required for evaluation of SNPs of FUT2.
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taqman real time polymerase chain reaction for detection of sec1 FUT2 hybrid alleles identification of novel hybrid allele
Clinica Chimica Acta, 2013Co-Authors: Mikiko Soejima, Yoshiro KodaAbstract:Abstract Background Two hybrid alleles between the secretor type α(1,2)fucosyltransferase gene (FUT2) and a pseudogene of FUT2 (SEC1) have been reported so far; parts of the SEC1 and FUT2 sequences are suggested to be susceptible to recombination. The sefus, one of the two hybrid alleles, is found in Japanese populations at relative high frequencies. Methods A TaqMan assay to distinguish SEC1 and SEC1-FUT2 hybrid alleles was designed for the purpose of dealing with large number of samples. Results The results of the present method were fully consistent with those of the previous method for detection of sefus in the Japanese population. In addition, a novel SEC1-FUT2-SEC1 hybrid allele, which contains a 35-bp sequence (between positions 418 and 452) that is identical to the FUT2 sequence including a 13-bp FUT2-specific region (between positions 436 and 448), was encountered in an individual of European descent. Conclusions The present TaqMan assay is a reliable and powerful method for the large scale association study between disease susceptibility and FUT2 genotypes especially in the Japanese populations because of relative high frequency of sefus. In addition, this method is a useful tool to find novel SEC1-FUT2 hybrid alleles.
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TaqMan-based real-time polymerase chain reaction for detection of FUT2 copy number variations: identification of novel Alu-mediated deletion.
Transfusion, 2010Co-Authors: Mikiko Soejima, Yoshiro KodaAbstract:BACKGROUND: The human FUT2 locus, which encodes a secretor-type α(1,2)fucosyltransferase, is known to be highly polymorphic. In addition to many single-nucleotide polymorphisms, three recombination alleles with a deletion of complete or partial FUT2 coding region have been reported. STUDY DESIGN AND METHODS: To detect copy number variations (CNVs) of the FUT2 gene including three recombinant alleles by a high-throughput system, we developed a triplex TaqMan real-time polymerase chain reaction (PCR) method. The relative number of copies of two regions of the FUT2 gene, the 5′ flanking (FUT2-5′) and FUT2-promoter (Prom) regions, were determined by comparing the number of threshold cycles (Ct) to those of the albumin gene (ALB) as the internal control (ΔCt). RESULTS: The mean 2−ΔΔCt values (FUT2-5′/ALB or Prom/ALB) obtained from 237 samples with known FUT2 copy numbers clearly differentiated two nonoverlapping intervals that corresponded to the one-copy-number samples ranging from 0.42 to 0.59 and two-copy-number samples ranging from 0.81 to 1.19; no FUT2-5′ signal for recombination alleles was detected in homozygotes. Using this assay, we detected an individual in a Chinese population with a loss of one copy of the FUT2-5′ region resulting from a novel Alu-mediated FUT2 deletion (approx. 4 kb). CONCLUSIONS: The TaqMan real-time PCR method was able to detect the number of copies of FUT2 and distinguish different kinds of known CNVs. This system is robust, fast, and suitable for high-throughput analysis.
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sec1 FUT2 sec1 hybrid allele generated by interlocus gene conversion
Transfusion, 2008Co-Authors: Mikiko Soejima, Junko Fujihara, Haruo Takeshita, Yoshiro KodaAbstract:BACKGROUND: Many single-nucleotide polymorphisms have been identified in the coding region of the FUT2 locus, which encodes secretor type α(1,2)fucosyltransferase. In addition, three recombination alleles have been reported. Of these recombination alleles, a fusion gene generated by an unequal crossing over between Sec1, a pseudogene that locates 23 kb upstream to and has high sequence homology with FUT2 and FUT2, was identified as a Japanese-specific nonsecretor allele (sefus). STUDY DESIGN AND METHODS: During the screening of the sefus in Mongolians (n = 118), a hybrid allele of Sec1-FUT2-Sec1 was found. RESULTS: The DNA sequence suggested that the Sec1-FUT2-Sec1 allele contains a 275-bp sequence (between positions 259 and 533) that is identical to the FUT2 sequence including a 54-bp FUT2-specific region (between positions 417 and 470) and that might have been generated by an interlocus gene conversion. CONCLUSION: Because the recombination region of sefus and the upstream recombination region of Sec1-FUT2-Sec1 are almost identical, this sequence stretch is likely to be the breakpoint for different kinds of recombinations that occur in this family of genes.
Nathalie Ruvoenclouet - One of the best experts on this subject based on the ideXlab platform.
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histo blood group antigen binding specificities of human rotaviruses are associated with gastroenteritis but not with in vitro infection
Scientific Reports, 2018Co-Authors: Laure Barbe, Johan Nordgren, Lennart Svensson, Beatrice Le Moullacvaidye, Nathalie Ruvoenclouet, K Echasserieau, Karine Bernardeau, Thomas Carton, Nicolai V BovinAbstract:Human strains of rotavirus A (RVAs) recognize fucosylated glycans belonging to histo-blood group antigens (HBGAs) through their spike protein VP8*. Lack of these ligands due to genetic polymorphisms is associated with resistance to gastroenteritis caused by P[8] genotype RVAs. With the aim to delineate the contribution of HBGAs in the process, we analyzed the glycan specificity of VP8* proteins from various P genotypes. Binding to saliva of VP8* from P[8] and P[4] genotypes required expression of both FUT2 and FUT3 enzymes, whilst binding of VP8* from the P[14] genotype required FUT2 and A enzymes. We further defined a glycan motif, GlcNAcβ3Galβ4GlcNAc, recognized by P[6] clinical strains. Conversion into Lewis antigens by the FUT3 enzyme impaired recognition, explaining their lower binding to saliva of Lewis positive phenotype. In addition, the presence of neutralizing antibodies was associated with the presence of the FUT2 wild type allele in sera from young healthy adults. Nonetheless, in vitro infection of transformed cell lines was independent of HBGAs expression, indicating that HBGAs are not human RV receptors. The match between results from saliva-based binding assays and the epidemiological data indicates that the polymorphism of human HBGAs controls susceptibility to RVAs, although the exact mechanism remains unclear.
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infection associated FUT2 fucosyltransferase 2 genetic variation and impact on functionality assessed by in vivo studies
Glycoconjugate Journal, 2010Co-Authors: Lara M Silva, Nathalie Ruvoenclouet, Patrice Guillon, Ana Sofia Carvalho, Susana Seixas, Maria Azevedo, Raquel Almeida, Celso A. ReisAbstract: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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association between expression of the h histo blood group antigen α1 2fucosyltransferases polymorphism of wild rabbits and sensitivity to rabbit hemorrhagic disease virus
Glycobiology, 2008Co-Authors: Patrice Guillon, Beatrice Le Moullacvaidye, Nathalie Ruvoenclouet, Stephane Marchandeau, Jacques Le PenduAbstract:RHDV (rabbit hemorrhagic disease virus) is a highly virulent calicivirus that has become a major cause of mortality in wild rabbit populations (Oryctolagus cuniculus). It binds to the histo-blood group antigen (HBGA) H type 2 which requires an alpha1,2fucosyltransferase for its synthesis. In rabbit, three alpha1,2fucosyltransferases genes are known, Fut1, FUT2, and Sec1. Nonfunctional alleles at any of these loci could potentially confer resistance to RHDV, similar to human FUT2 alleles that determine the nonsecretor phenotype and resistance to infection by various NoV strains. In this study, we looked for the presence of H type 2 on buccal epithelial cells of wild rabbits from two geographic areas under RHDV pressure and from one RHDV-free area. Some animals with diminished H type 2 expression were found in the three populations (nonsecretor-like phenotype). Their frequency markedly increased according to the RHDV impact, suggesting that outbreaks selected survivors with low expression of the virus ligand. Polymorphisms of the Fut1, FUT2, and Sec1 coding regions were determined among animals that either died or survived outbreaks. The FUT2 and Sec1 genes presented a high polymorphism and the frequency of one Sec1 allele was significantly elevated, over 6-fold, among survivors. Sec1 enzyme variants showed either moderate, low, or undetectable catalytic activity, whereas all variant FUT2 enzymes showed strong catalytic activity. This functional analysis of the enzymes encoded by each FUT2 and Sec1 allele suggests that the association between one Sec1 allele and survival might be explained by a deficit of alpha1,2fucosyltransferase expression rather than by impaired catalytic activity.
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influence of the combined abo FUT2 and fut3 polymorphism on susceptibility to norwalk virus attachment
The Journal of Infectious Diseases, 2005Co-Authors: Severine Marionneau, Nathalie Ruvoenclouet, Nicolai V Bovin, Jacques Le Pendu, Fabrice AiraudAbstract:4 Shemyakin Institute of Bioorganic Chemistry, Moscow, Russia The binding of Norwalk virus (NV) recombinant capsids was tested in a panel of saliva samples collected from 96 donors with different ABO, secretor, and Lewis phenotypes. As previously reported, binding occurred specifically to saliva from secretors, regardless of their Lewis phenotype status. Blood group B saliva was poorly recognized, whereas binding to blood group O saliva was higher and binding to blood group A saliva was highest. Transfection of either blood group A or B enzyme into H epitope-expressing cells showed that masking of H epitopes by the A and B antigens blocked the attachment of NV capsids. The high level of binding to blood group A secretor saliva could be explained by an optimal H type 1 ligand density, which was lower than that in blood group O saliva and much higher than that in blood group B saliva. Indeed, despite a higher ligand density, saliva from homozygotes with 2 functional FUT2 alleles was less strongly recognized than saliva from heterozygotes with 1 functional and 1 inactivated FUT2 allele. Partial fucosidase treatment of duodenal tissue sections and binding to a synthetic probe with varying densities of H type 1 trisaccharide indicated that optimal attachment occurred at medium ligand density.
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influence of the combined abo FUT2 and fut3 polymorphism on susceptibility to norwalk virus attachment
The Journal of Infectious Diseases, 2005Co-Authors: Severine Marionneau, Nathalie Ruvoenclouet, Nicolai V Bovin, Jacques Le Pendu, Fabrice AiraudAbstract:The binding of Norwalk virus (NV) recombinant capsids was tested in a panel of saliva samples collected from 96 donors with different ABO, secretor, and Lewis phenotypes. As previously reported, binding occurred specifically to saliva from secretors, regardless of their Lewis phenotype status. Blood group B saliva was poorly recognized, whereas binding to blood group O saliva was higher and binding to blood group A saliva was highest. Transfection of either blood group A or B enzyme into H epitope-expressing cells showed that masking of H epitopes by the A and B antigens blocked the attachment of NV capsids. The high level of binding to blood group A secretor saliva could be explained by an optimal H type 1 ligand density, which was lower than that in blood group O saliva and much higher than that in blood group B saliva. Indeed, despite a higher ligand density, saliva from homozygotes with 2 functional FUT2 alleles was less strongly recognized than saliva from heterozygotes with 1 functional and 1 inactivated FUT2 allele. Partial fucosidase treatment of duodenal tissue sections and binding to a synthetic probe with varying densities of H type 1 trisaccharide indicated that optimal attachment occurred at medium ligand density.
Hiroshi Kimura - One of the best experts on this subject based on the ideXlab platform.
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a novel tetrameric short tandem repeat located in the 3 flanking region of the human abo secretor gene FUT2 and association between FUT2 and FUT2 01 loci
Human Biology, 2004Co-Authors: Hao Pang, Mikiko Soejima, Yoshiro Koda, Hiroshi KimuraAbstract:We found a novel polymorphic short tandem repeat (FUT2/01), 3.8 kb downstream of the coding region of FUT2. Seventeen length and 33 sequence variants were identified in 300 individuals representing three major human populations. Africans (Xhosa) and Europeans were characterized by high microvariation, and Japanese were characterized by a simple repeat structure. All exhibited high haplotype diversity.
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polymorphism of the human abo secretor locus FUT2 in four populations in asia indication of distinct asian subpopulations
Annals of Human Genetics, 2001Co-Authors: Hao Pang, Mikiko Soejima, Yoshiro Koda, Noboru Fujitani, T Ogaki, Atsushi Saito, T Kawasaki, Hiroshi KimuraAbstract:The polymorphic alleles of the human ABO-Secretor locus ( FUT2 or Se ) show high heterogeneity and overt ethnic specificity. To provide additional data for analysis to elucidate the origins of populations, we have investigated the allelic polymorphism of FUT2 in 40 unrelated Tibetan and 53 Tamang individuals from Nepal, 42 Indonesian individuals from Surabaya, and 55 Uygur individuals from Urumqi, using DNA sequencing. In Tibetan, Tamang and Indonesian populations, the frequency of a nonfunctional allele, se 357,385 , which is found only in Asian populations, was 0·638, 0·509 and 0·631, respectively. In Uygur, the se 428 , which is common in Caucasian populations, and the se 357,385 consisting of two common nonfunctional FUT2 alleles, had frequencies of 0·3 and 0·145, respectively. The fixation index ( F ST ) based on genetic differentiation was obtained pairwise among the four populations in this study and six populations in our previous studies. The results suggested that genetic differentiation among Tibetan, Tamang, Indonesian and East Asian populations is very low, while the distribution feature of the FUT2 alleles in the Uygur population implied an admixture of European with Asian. The distribution of nonfunctional alleles at the FUT2 locus provided further evidence of human migration among the Asian populations.
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contrasting patterns of polymorphisms at the abo secretor gene FUT2 and plasma alpha 1 3 fucosyltransferase gene fut6 in human populations
Genetics, 2001Co-Authors: Yoshiro Koda, Mikiko Soejima, Hao Pang, Hidenori Tachida, Yuhua Liu, Abbas Ghaderi, Osamu Takenaka, Hiroshi KimuraAbstract:The coding sequences ( approximately 1 kb) of FUT2 [ABO-Secretor type alpha(1,2)fucosyltransferase] and of FUT6 [plasma alpha(1,3)fucosyltransferase] were analyzed for allelic polymorphism by direct sequencing in five populations. The nucleotide diversities of FUT2 estimated from pairwise sequence differences were 0.0045, 0.0042, 0.0042, 0.0009, and 0.0008 in Africans, European-Africans, Iranians, Chinese, and Japanese, respectively. The nucleotide diversities of FUT6 were 0.0024, 0.0016, 0.0015, 0.0017, and 0.0020 in Africans, European-Africans, Iranians, Chinese, and Japanese, respectively. At FUT2, excesses in pairwise sequence differences compared to the number of polymorphic sites as indicated by a significantly positive Tajima's D were observed in European-Africans and in Iranians. The data do not fit expectations of the equilibrium neutral model with an infinite number of sites. On the other hand, Tajima's D's at FUT6 in each of the five populations and at FUT2 in Africans, Chinese, and Japanese were not significantly different from zero. F(ST) between the Asians and the others measured at FUT2 was higher than at FUT6. These results suggest that natural selection was responsible for the generation of the FUT2 polymorphism in European-Africans and in Iranians.
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two distinct alu mediated deletions of the human abo secretor FUT2 locus in samoan and bangladeshi populations
Human Mutation, 2000Co-Authors: Hao Pang, Mikiko Soejima, Yoshiro Koda, Noboru Fujitani, Mohammed Nasimul Islam, A Shamsul K M Islam, Hiroshi KimuraAbstract:The human secretor α(1,2) fucosyltransferase encoded by the FUT2 determines the production of ABO(H) antigens in secretions. Recent studies demonstrated the presence of several nonfunctional alleles in the FUT2. During the analysis for inactivating mutations at the FUT2 locus from 24 Samoan and 47 Bangladeshi individuals, we found two distinct Alu-mediated deletions of FUT2. The FUT2 deletion in a Bangladeshi population was identical with that found in Indian individuals with the Bombay phenotype (sedel), but not associated with the null allele (T725G) of the H gene (FUT1). The FUT2 deletion in Samoans is a novel null allele (sedel2). The junction region of sedel2 was successfully amplified using the same primers for the sedel amplification. DNA sequencing of the junction region of the sedel2 indicated that there was a 32-bp sequence identity between DNA sequences surrounding the 5′ and 3′ breakpoints. The size of the deletion of the sedel2 was 9.3 kb, including the full coding region of FUT2. The frequency of the sedel in a Bangladeshi population was 0.074, and that of the sedel2 in a Samoan population was 0.104. Hum Mutat 16:274, 2000. © 2000 Wiley-Liss, Inc.
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The Fusion Gene at the ABO-Secretor Locus ( FUT2 ): absence in Chinese populations
Journal of Human Genetics, 1999Co-Authors: Yoshiro Koda, Bao-jie Wang, Heung Bum Oh, Mikiko Soejima, Hao Pang, Hiroshi KimuraAbstract:The fusion gene (sefus) is a null allele of the secretor type α (1, 2) fucosyltransferase gene (FUT2) and was first found in a Japanese population. It has not yet been reported in any other ethnic population. In the present study, we investigated the distribution of the fusion gene of the FUT2 locus in five populations from three ethnic groups in East Asia. The fusion gene was found in two additional Japanese populations with a high frequency (0.0551 in Okinawa and 0.0792 in Akita) and, for the first time outside Japan, in a Korean population, at a very low frequency (0.0063 in Seoul). In contrast, we found no fusion gene in two Chinese populations. These findings showed that the FUT2 fusion gene was ubiquitous in Japanese, but was rare in neighboring populations, suggesting that the FUT2 fusion gene had emerged from within the Japanese. Additionally, a new null allele with a C-to-T substitution at nucleotide 658 was found in one individual native of southern China.
Steven E Domino - One of the best experts on this subject based on the ideXlab platform.
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genetically dictated change in host mucus carbohydrate landscape exerts a diet dependent effect on the gut microbiota
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Steven E Domino, Purna C Kashyap, Angela Marcobal, Luke K Ursell, Samuel A Smits, Erica D Sonnenburg, Elizabeth K Costello, Steven K Higginbottom, Susan HolmesAbstract:We investigate how host mucus glycan composition interacts with dietary carbohydrate content to influence the composition and expressed functions of a human gut community. The humanized gnotobiotic mice mimic humans with a nonsecretor phenotype due to knockout of their α1–2 fucosyltransferase (FUT2) gene. The fecal microbiota of FUT2− mice that lack fucosylated host glycans show decreased alpha diversity relative to FUT2+ mice and exhibit significant differences in community composition. A glucose-rich plant polysaccharide-deficient (PD) diet exerted a strong effect on the microbiota membership but eliminated the effect of FUT2 genotype. Additionally fecal metabolites predicted host genotype in mice on a polysaccharide-rich standard diet but not on a PD diet. A more detailed mechanistic analysis of these interactions involved colonization of gnotobiotic FUT2+ and FUT2− mice with Bacteroides thetaiotaomicron, a prominent member of the human gut microbiota known to adaptively forage host mucosal glycans when dietary polysaccharides are absent. Within FUT2− mice, the B. thetaiotaomicron fucose catabolic pathway was markedly down-regulated, whereas BT4241–4247, an operon responsive to terminal β-galactose, the precursor that accumulates in the FUT2− mice, was significantly up-regulated. These changes in B. thetaiotaomicron gene expression were only evident in mice fed a PD diet, wherein B. thetaiotaomicron relies on host mucus consumption. Furthermore, up-regulation of the BT4241–4247 operon was also seen in humanized FUT2− mice. Together, these data demonstrate that differences in host genotype that affect the carbohydrate landscape of the distal gut interact with diet to alter the composition and function of resident microbes in a diet-dependent manner.
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distinct fucosylation of m cells and epithelial cells by fut1 and FUT2 respectively in response to intestinal environmental stress
Biochemical and Biophysical Research Communications, 2011Co-Authors: Kazutaka Terahara, Tomonori Nochi, Masato Yoshida, Yuko Takahashi, Yoshiyuki Goto, Hirotsugu Hatai, Shiho Kurokawa, Myoung Ho Jang, Mina Kweon, Steven E DominoAbstract:Abstract The intestinal epithelium contains columnar epithelial cells (ECs) and M cells, and fucosylation of the apical surface of ECs and M cells is involved in distinguishing the two populations and in their response to commensal flora and environmental stress. Here, we show that fucosylated ECs (F-ECs) were induced in the mouse small intestine by the pro-inflammatory agents dextran sodium sulfate and indomethacin, in addition to an enteropathogen derived cholera toxin. Although F-ECs showed specificity for the M cell-markers, lectin Ulex europaeus agglutinin-1 and our monoclonal antibody NKM 16-2-4, these cells also retained EC-phenotypes including an affinity for the EC-marker lectin wheat germ agglutinin. Interestingly, fucosylation of Peyer’s patch M cells and F-ECs was distinctly regulated by α(1,2)fucosyltransferase Fut1 and FUT2, respectively. These results indicate that FUT2-mediated F-ECs share M cell-related fucosylated molecules but maintain distinctive EC characteristics, Fut1 is, therefore, a reliable marker for M cells.
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gastrointestinal mucins of FUT2 null mice lack terminal fucosylation without affecting colonization by candida albicans
Glycobiology, 2005Co-Authors: Elizabeth A Hurd, Jessica M Holmen, Gunnar C Hansson, Steven E DominoAbstract:Posttranslational modification of apomucins by the sequential action of glycosyltransferases is required to produce mature mucins. The Secretor gene (FUT2) encodes an alpha(1,2)fucosyltransferase (EC 2.4.1.69) that catalyzes addition of terminal alpha(1,2)fucose residues on mucins and other molecules in mucosal epithelium. Mutant mice containing targeted replacement of FUT2 with the bacterial reporter gene lacZ were studied to determine the affect of the loss of FUT2 on glycosylation of mucins in the gastrointestinal tract. By whole organ X-gal staining, lacZ activity is prominently expressed in the foveolar pit and chief cells of the glandular stomach, Brunner's glands of the duodenum, and goblet cells in the large intestine of FUT2-LacZ-null mice. Staining with Aleuria aurantia agglutinin demonstrates loss of L-fucosylated epithelial glycans throughout the gastrointestinal tract of FUT2-LacZ-null mice, however, histologic appearance of the tissues appears normal. Analysis of oligosaccharides released from insoluble colonic mucins, largely Muc2, by mass spectrometry shows complete lack of terminal fucosylation of O-linked oligosaccharides in FUT2-LacZ-null mice. Precursor glycans accumulate with no evidence of compensation by other fucosyltransferases or sialyltransferases on mucin glycosylation. Because Candida albicans has been reported to adhere to intestinal mucins creating a potential reservoir associated with vaginitis, FUT2-LacZ-null and wild-type mice were inoculated by gastric lavage with C. albicans. We observe no difference in colonization between genotypes suggesting mucin terminal fucosylation does not significantly influence C. albicans-host interaction in the intestine, highlighting that infections caused by the same organism at different mucosal surfaces are not equal.
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tissue specific loss of fucosylated glycolipids in mice with targeted deletion of alpha 1 2 fucosyltransferase genes
Biochemical Journal, 2004Co-Authors: Masao Iwamori, Steven E DominoAbstract:Glycolipids in epithelial tissues of the gastrointestinal tract act as receptors for enteric bacteria and are implicated in the activation of the intestinal immune system. To clarify the genes involved in the fucosylation of the major glycolipids, substrate glycolipids and fucosylated products were measured in tissues of wild-type and mutant mice lacking alpha(1,2)fucosyltransferase genes FUT1 or FUT2. Quantitative determination was performed by TLC-immunostaining for GA1 (Gg4Cer), FGA1 (fucosyl GA1), GM1 (II3NeuAc-Gg4Cer), FGM1 (fucosyl GM1), and Forssman glycolipids. Both FGM1 and FGA1 completely disappeared from the antrum, cecum, and colon of FUT2-null mice, but not those of FUT1-null and wild-type mice. Precursor glycolipids, GM1 and GA1, accumulated in tissues of FUT2-null mice, indicating that the FUT2-encoded enzyme preferentially participates in the fucosylation of GA1 and GM1 in these tissues. Female reproductive organs were similarly found to utilize FUT2 for the fucosylation of glycolipids FGA1 (uterus and cervix), and FGM1 (ovary), due to their absence in FUT2-null mice. In FUT1-null mice FGA1 was lost from the pancreas, but was present in wild-type and FUT2-null mice, indicating that FUT1 is essential for fucosylation of GA1 in the pancreas. Ulex europaeus agglutinin-I lectin histochemistry for alpha(1,2)fucose residues confirmed the absence of alpha(1,2)fucose residues from the apical surface of pancreatic acinar glands of FUT1-null mice. Ileum, epididymis, and testis retained specific fucosylated glycolipids, irrespective of targeted deletion of either gene, indicating either compensation for or redundancy of the alpha(1,2)fucosyltransferase genes in these tissues.
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lacz expression in FUT2 lacz reporter mice reveals estrogen regulated endocervical glandular expression during estrous cycle hormone replacement and pregnancy
Glycobiology, 2003Co-Authors: Steven E Domino, Elizabeth A HurdAbstract:The “Secretor” gene (FUT2) encodes an α(1,2)fucosyltransferase (E.C. 2.4.1.69) that elaborates α(1,2)fucose residues on mucosal epithelium and secreted mucins. While uterine α(1,2)fucosylated glycans have proposed to be involved in embryo adhesion, mice with a homozygous null mutation of FUT2 displayed normal fertility. To help develop alternative hypotheses for function, the cell type and regulation of FUT2 expression during the estrous cycle, hormone replacement, and pregnancy was examined in FUT2-LacZ reporter mice containing targeted replacement of FUT2 with bacterial lacZ. LacZ expression in the reproductive tract of FUT2-LacZ mice is most prominent in the glandular epithelium of the endocervix during estrus and pregnancy. Nuclear LacZ expression identifies cell specific expression of FUT2 in mucus secreting cells of the endocervix, uterine glands, foveolar pit and chief cells of the stomach, and goblet cells of the colon. In ovariectomized FUT2-LacZ mice, estradiol treatment stimulates X-gal staining in endocervix and uterus, but does not affect expression in stomach and colon. Northern blot analysis in wild type mice shows 15-fold elevations of FUT2 steady-state mRNA with estradiol treatment, while Fut1 varies little. FUT2 levels in the glandular stomach and distal colon remain constant while uterine FUT2 levels vary 8-fold during the estrous cycle. These data represent the first demonstration of a glycosyltransferase gene under tissue-specific hormonal regulation in a LacZ reporter mouse model. Endocervical expression of FUT2 in estrus and pregnancy may modify cervical mucus barrier properties from microbial infection analogous to the potential role of mucosal glycans in humans.
