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Biomedical subjects

U Gyllensten

Publications and source records attributed to U Gyllensten.

At least 55 records · Page 3Linked to original sources

The cotton-top tamarin revisited: Mhc class I polymorphism of wild tamarins, and polymorphism and allelic diversity of the class II DQA1, DQB1, and DRB loci.

Cotton-top tamarins (Saguinus oedipus) in captivity are unusual in that they exhibit low levels of polymorphism and allelic diversity at the major histocompatibility complex (Mhc) class I loci. Since the polymorphism has previously only been examined in captive tamarins, we analyzed the Mhc class I alleles of a population of wild tamarins. These wild tamarins, like their captive counterparts, exhibited limited class I polymorphism. We also assessed the levels of polymorphism and allelic diversity at the Mhc class II DQA1, DQB1, DQB2, and the DRB loci in captive populations of cotton-top tamarins. In contrast to the extensive polymorphism in Old World monkeys, only two alleles were detected at each of DQA1 and DQB1. Also, the DQB2 locus was monomorphic and conserved between New and Old World monkeys. Sequences derived from four putative DRB loci were obtained, and extensive polymorphism was found at all four loci. Phylogenetic analysis did not indicate that any of the tamarin DRB loci, with the possible exception of Saoe-DRB3, were orthologous to the human DRB loci. At three of the DRB loci (Saoe-DRB11, Saoe-DRB*W12, Saoe-DRB*W22), the number of nonsynonymous changes was higher than the number of synonymous changes in the putative antigen recognition sites, indicative of positive selection. We found no support for a restriction on the polymorphism at the cotton-top tamarin class II loci. However, the allelic diversity at some of the Saoe-DRB loci is more limited than for the HLA-DRB1, consistent with a restriction imposed by the bone marrow-chimerical lifestyle.

Alleles↗

A comprehensive polymerase chain reaction-oligonucleotide typing system for the HLA class I A locus.

A comprehensive system for genetic typing of the HLA class I A locus is described, based on PCR amplification and typing with nonradioactively labeled SSO probes. Exons 1-3 of the A locus are amplified and typing is performed with a set of 30 nonradioactively labeled oligonucleotide probes. This system resolves 34 of 39 known alleles and 561 (94%) of 595 possible genotypes. Among a sample of 354 individuals from Sweden and China, 97.5% of the genotypes were resolved. Probes were directed preferentially at replacement substitutions in foreign antigen-binding sites, in order to detect not only the known alleles but also new combinations of polymorphic motifs, indicative of previously unrecognized alleles. Three individuals were found with a new combination of polymorphic motifs, suggesting the presence of at least one previously undescribed allele in the populations sampled. This typing system is useful for disease association studies, tissue typing, and in forensic medicine.

Base Sequence↗

Association of susceptibility to multiple sclerosis in Sweden with HLA class II DRB1 and DQB1 alleles.

The association of MS with HLA class II alleles was studied by PCR-based typing of the DQA1, DQB1, DRB1, and DPB1 loci in 94 Swedish patients with relapses and remissions of the disease. The haplotype DRB1*1501-DQA1*0102-DQB1*0602 was found to be positively associated and three haplotypes were found to be negatively associated with MS. Linkage disequilibrium makes it difficult to assess whether DRB1 or DQB1 plays the primary role in the disease association, while the association with DPB1 and DQA1 appears to be secondary to that of DQB1 and DRB1. Two of the three haplotypes negatively associated with MS carry the DQB1*0301 allele. Also, the negatively associated DRB1*0401-DQA1*0301-DQB1*0301 haplotype differs from those with nonassociated DRB1*0401-DQA1*0301-DQB1*0302 haplotype only at DQB1. These results suggest that DQB1 alleles, as well as some DRB1 alleles, are involved in susceptibility and protection to MS. In searching for sequence motifs in the DR beta chain associated with MS susceptibility, all DRB1 alleles on haplotypes positively associated with MS, including the DRB1*1501, were found to encode a Val at position 86 of the DR beta chain. Also, DRB1 alleles that are negatively associated with MS all encode a Gly at position 86, suggesting that the residue at position 86 may be critical in conferring susceptibility and protection to MS. Finally, when the effect of the DRB1*1501 haplotype was removed there was no support for the hypothesis that MS is associated with a putative DQ-alpha beta heterodimer, encoded for by certain DQA1 and DQB1 alleles.

Alleles↗

PCR-based DNA typing of saliva on stamps and envelopes.

In forensic cases involving mail bombs, extortion, kidnapping or threatening letters, biological evidence such as the saliva used to attach the stamp and seal the envelope could be used for genetic analysis. We have developed a highly sensitive semi-nested PCR method for the HLA-DRB1 locus; suitable for the analyses of very limited amounts of DNA. When applied to a set of stamps and envelopes with saliva from control individuals, typing results were consistent with those obtained using hairs drawn from the same individuals. No interference was found due to DNA from the fingerprints of people handling the letters. The system was applied to three forensic cases with threatening letters. The first case resulted in an exclusion of the suspect. In the second case, the suspect could not be excluded (probability of identical genotype by chance > 0.01). These results demonstrate that biological evidence in cases with threatening letters is amenable to genetic typing.

Base Sequence↗

Association of insulin-dependent diabetes mellitus in Taiwan with HLA class II DQB1 and DRB1 alleles.

The allelic constitution at HLA class II DRB1, DQB1, DQA1, and DPB1 loci of IDDM patients from Taiwan was compared with that of ethnically matched nondiabetic individuals by PCR-based DNA typing. Of the three haplotypes found to be positively associated with IDDM in Taiwan, two (DRB1*0301-DQA1*0501-DQB1*0201 and DR4-DQA1*0301-DQB1*0302) appear to be identical to the susceptible haplotypes in Caucasian and black populations, whereas the third haplotype (DR4-DQA1*0301-DQB1*04) has been reported to be positively associated with IDDM only in the Japanese population. The three haplotypes, DRB1*1502-DQA1*0102-DQB1*0601 and DRB1*1201 (or 1202)-DQA1*0501-DQB1*0301 and DRB1*0803-DQA1*0103-DQB1*0601, were negatively associated with IDDM in Taiwan; a protective effect of the last haplotype has not been reported previously. Neither DQ beta non-Asp-57 nor DQA1*0301 alone appears sufficient to account for the HLA-associated susceptibility to IDDM in Taiwan. Also, the DQ alpha beta heterodimer encoded by the alleles DQA1*0301/DQB1*0201, DQA1*0301/DQB1*0302, or DQA1*0501/DQB1*0201 does not explain the susceptibility of a larger fraction of the IDDM patients than the residue at position 57 of the DQ beta chain or DQA1*0301. Finally, the DRB1 alleles appear to affect IDDM susceptibility, although for most haplotypes the effect of individual loci cannot be assessed due to the linkage disequilibrium between the DQ and the DR region.

Adult↗

Intrafamilial variation in Leber hereditary optic neuropathy revealed by direct mutation analysis.

Leber hereditary optic neuropathy (LHON) has been associated with a mitochondrial mutation at position 11,778 in the ND4 gene in about 50% of families. Individuals from six Swedish families with LHON were investigated for the presence of this mutation using allele-specific oligonucleotides and a sensitive chemoluminescent detection system. The point mutation was seen in mitochondrial DNA extracted from leukocytes in five families, four of which showed a homoplasmic pattern. One family showed a heteroplasmic pattern and one family was negative for the mutation. Six adults without impaired vision from three LHON families were detected as carriers with a degree of mutated mitochondrial DNA similar to that in affected relatives. The results show that the penetrance of LHON varies remarkably among carriers of the 11,778 mutation within families. We conclude that the prognosis for carriers should be stated cautiously when interpreting results from mutation analysis of mitochondrial DNA in leukocytes.

Adult↗

Genetic typing of HLA class II genes in Swedish populations: application to forensic analysis.

In an attempt to determine the value of DNA based typing of HLA class II loci to forensic analysis, allele and genotype frequencies at DQA1, DQB1, DPB1, and DRB1 were determined in samples from two Swedish populations using hybridization with sequence specific oligonucleotides to PCR amplified DNA. Significant allele frequency differences were observed at the DQB1 and DRB1 loci between the two populations, as well as between one of the Swedish and a Norwegian population. The average heterozygosity varies between 0.74 to 0.91 and the power of discrimination between 0.90 to 0.98, with the highest values obtained for the DRB1 locus. The probability of genotype identity by chance differs on average 2% between the populations. When applied to a paternity case with one parent deceased and a criminal case, typing of class II loci proved in both cases informative. Analyses of DR and DQ genes does not increase the power of discrimination, due to strong linkage, but offers through the reconstruction of putative haplotypes an internal control for the consistency of the typing results at several loci. Typing of the DRB1 and DPB1 loci was found to result in an approximate combined average probability of genotype identity by chance of one in a thousand.

Alleles↗

Low incidence of human papillomavirus type 16 DNA in bladder tumor detected by the polymerase chain reaction.

Human papillomavirus (HPV) detection was done using the polymerase chain reaction technique on tumor tissue from 44 patients with transitional cell carcinoma of the urinary bladder. Only one of the 44 was associated with HPV infection. The HPV-positive patient was not known to have immunodeficiency or genital warts, and the tumor was not morphologically different from the other tumors. Control experiments excluded the possibility that this finding was caused by contamination of the sample. This study confirms that HPV infection is a rare condition in bladder carcinoma.

Carcinoma, Transitional Cell↗

Paternal inheritance of mitochondrial DNA in mice.

For nearly 20 years it has been assumed on the basis of low-resolution experiments that mitochondrial (mt)DNA, in contrast to the genes in the nucleus, has an exclusively maternal mode of inheritance in animals. Using the polymerase chain reaction, paternally inherited mtDNA molecules have now been detected in mice at a frequency of 10(-4), relative to the maternal contributions. These mice were hybrids between two inbred strains (C57BL/6J and Mus spretus) whose mtDNAs can be distinguished easily. This new mode of inheritance provides a mechanism for generating heteroplasmy and may explain mitochondrial disorders exhibiting biparental transmission.

Animals↗

Genetic diversity at class II DRB loci of the primate MHC.

The evolution of polymorphism at loci encoding the beta-chains of the MHC class II DR Ag was studied in primates by DNA amplification (polymerase chain reaction). Phylogenetic analysis of 63 DRB sequences from the polymorphic second exon (first domain) of nonhuman primates and 53 human sequences indicates the presence of five DRB loci in primates, derived from a DRB1-like ancestral locus over 20 million yr ago. Many of the allelic types at the DRB1 locus predate the divergence of hominoids (5 million yr ago) and some (DR4, DR3, 5, 6) predate the divergence of Old world monkeys and hominoids (20 million yr ago). The DRB3 locus appears to have arisen before the divergence of hominoids on an ancestral DRB1 lineage. The DRB2 and DRB5 loci were generated more than 20 million yr ago and the DRB4 locus more than 5 million yr ago. The DRB2 locus, a pseudogene in humans, is polymorphic in the nonhuman primates.

Amino Acid Sequence↗

HLA class II allelic variation and susceptibility to pemphigus vulgaris.

The autoimmune dermatologic disease pemphigus vulgaris (PV) is associated with the HLA serotypes DR4 and DRw6. Susceptibility to PV could be conferred either by sequences shared between the DR4 and DRw6 haplotypes or by different sequences in these haplotypes. We have examined the distribution of DR and DQ beta-chain and DQ alpha-chain alleles in PV patients and in control subjects by hybridization with oligonucleotide probes and sequence analysis of in vitro amplified DNA. Ninety percent (34/38) of the DR4 haplotypes in patients contain a specific DR beta I sequence present in 36% (16 of 44) of DR4 controls (P = 0.001). This sequence is also found in DRw6 haplotypes. However, it is present in only 25% (6 of 24) of DRw6 patients. The results of our analysis indicate that predisposition to PV is conferred by different sequences in DR4 and DRw6 haplotypes. The DR4 susceptibility is highly associated with the Dw10 DR beta I allele, implicating the polymorphic residues in the third hypervariable region. The DRw6 susceptibility is strongly associated with a rare DQ beta allele (DQB1.3). This allele differs from a common DQ beta allele (DQB1.1) only by a valine----aspartic acid substitution at position 57.

Alleles↗