The HLA-C*12:72 Allele, Confirmed by Next-Generation Sequencing in an Indian Individual.
The HLA-C*12:72 allele, differs from HLA-C*12:02:02:01, by one nonsynonymous substitution, c.312C>A in exon 2.
Humans↗
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Failure to confirm allelic association between markers at the CAPON gene locus and schizophrenia in a British sample.
BACKGROUND: Linkage studies have confirmed that chromosome 1q23.3 is a susceptibility locus for schizophrenia. It was then claimed that markers at the carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON) gene showed allelic association with schizophrenia in Canadian families. A second Chinese study found a base pair polymorphism at the CAPON gene also associated with schizophrenia. METHODS: We attempted replication using eight markers from the Canadian study in a UK based sample of 450 cases and 450 supernormal controls. RESULTS: We found no evidence for allelic or haplotypic association with schizophrenia for any of the markers found to be associated in the Canadian sample. CONCLUSIONS: The negative results might reflect genetic heterogeneity between the Canadian, Chinese and UK samples or be due to methodological problems. The present finding weakens the evidence that mutations or variation in the CAPON gene are causing genetic susceptibility to schizophrenia in European populations.
Adaptor Proteins, Signal Transducing↗
Oto-facio-cervical (OFC) syndrome is a contiguous gene deletion syndrome involving EYA1: molecular analysis confirms allelism with BOR syndrome and further narrows the Duane syndrome critical region to 1 cM.
Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder involving hearing loss, branchial defects, ear pits and renal abnormalities. Oto-facio-cervical (OFC) syndrome is clinically similar to BOR syndrome, with clinical features in addition to those of BOR syndrome. Mutations in the EYA1 gene (localised to 8q13.3) account for nearly 70% of BOR syndrome cases exhibiting at least three of the major features. Small intragenic deletions of the 3' region of the gene have also been reported in patients with BOR syndrome. We have developed a fluorescent quantitative multiplex polymerase chain reaction for three 3' exons (7, 9 and 13) of the EYA1 gene. This dosage assay, combined with microsatellite marker analysis, has identified de novo deletions of the EYA1 gene and surrounding region in two patients with complex phenotypes involving features of BOR syndrome. One patient with OFC syndrome carried a large deletion of the EYA1 gene region, confirming that OFC syndrome is allelic with BOR syndrome. Microsatellite analysis has shown that comparison of the boundaries of this large deletion with other reported rearrangements of the region reduces the critical region for Duane syndrome (an eye movement disorder) to between markers D8S553 and D8S1797, a genetic distance of approximately 1 cM.
Abnormalities, Multiple↗
Bone marrow donor routine HLA typing identified a novel B*07 allele, B*0734, confirmed by allele-specific DNA cycle sequencing.
In this article, we report the identification of a new human leukocyte antigen-B allele in a sample that was tested in our routine typing for bone marrow donors. This novel allele officially designed B*0734 was found in a female donor of Bavarian Caucasoid origin (Laboratory code 121036). The search for unrelated bone marrow donors was initiated by the Aktion Knochenmarkspende Bayern. In comparison to the common B*070201, B*0734 differs at four nucleotide positions, 412 (G-->A), 539 (G-->T), 559 (G-->A) and 560 (A-->C) causing three amino acid substitutions, at postion 138 Asp-->Asn, at position 180 Arg-->Leu and at position 187 Glu-->Thr.
Adult↗
Bone marrow donor routine HLA typing identified a novel B*55 allele, B*5517, confirmed by allele-specific DNA cycle sequencing.
In this article, we report the identification of a new human leukocyte antigen-B allele in a sample that was tested in our routine typing for volunteer bone marrow donors. This novel allele officially designed B*5517 was found in a male donor of Bavarian Caucasoid origin (Laboratory code 150113). The search for unrelated bone marrow donors was initiated by the Aktion Knochenmarkspende Bayern. In comparison with the common B*5501 allele, B*5517 differs at three nucleotide positions all located in exon 3, at position 379 (C-->G), 419 (T-->A), and 420 (A-->C), resulting in two amino acid substitutions at codons 127 and 140. The amino acid 127, leucine, is changed to valine, and the amino acid 140, also a leucine, is replaced by tyrosine in B*5517.
Alleles↗
Novel QTLs for HDL levels identified in mice by controlling for Apoa2 allelic effects: confirmation of a chromosome 6 locus in a congenic strain.
Atherosclerosis is a complex disease resulting from the interaction of multiple genes, including those causing dyslipidemia. Relatively few of the causative genes have been identified. Previously, we identified Apoa2 as a major determinant of high-density lipoprotein cholesterol (HDL-C) levels in the mouse model. To identify additional HDL-C level quantitative trait loci (QTLs), while controlling for the effect of the Apoa2 locus, we performed linkage analysis in 179 standard diet-fed F(2) mice derived from strains BALB/cJ and B6.C-H25(c) (a congenic strain carrying the BALB/c Apoa2 allele). Three significant QTLs and one suggestive locus were identified. A female-specific locus mapping to chromosome 6 (Chr 6) also exhibited effects on plasma non-HDL-C, apolipoprotein AII (apoAII), apoB, and apoE levels. A Chr 6 QTL was independently isolated in a related congenic strain (C57BL/6J vs. B6.NODc6: P = 0.003 and P = 0.0001 for HDL-C and non-HDL-C levels, respectively). These data are consistent with polygenic inheritance of HDL-C levels in the mouse model and provide candidate loci for HDL-C and non-HDL-C level determination in humans.
Alleles↗
Simple tandem repeat allelic deletions confirm the preferential loss of distal chromosome 6q in melanoma.
Karyotypic analysis, loss of somatic heterozygosity, microcell fusion and cDNA transfection studies have provided compelling evidence that at least one tumour suppressor gene for melanoma resides on chromosome 6. In an attempt to further define the regions to which these putative suppressor genes map, we have carried out loss of heterozygosity (LOH) studies on DNA from 25 fresh melanoma tumours for 9 simple tandem repeat (STR) polymorphism markers spanning chromosome 6. Four samples displayed LOH or homozygosity for all markers studied, indicating that they had lost one homologue of chromosome 6. An additional 3 samples showed LOH for all markers on 6q. Furthermore, 30 melanoma cell lines, for which there were no matching somatic DNA samples, were analyzed for hemizygosity of markers on 6q. One cell line had a homozygous deletion of all markers tested and a further 12 cell lines displayed only one allele for 3 or 4 contiguous markers, indicating that most, if not all of these samples were hemizygous for the region of 6q distal to D6S87. Overall, the rate of LOH on 6q in the 55 melanoma DNAs was 35%, and there were no losses of markers on 6p without concomitant loss of markers on 6q. Two of 5 samples derived from primary melanomas showed LOH, which indicates that LOH for the melanoma suppressor gene on 6q, which maps to a region that contains the SOD2 locus, is a frequent and early event in melanoma tumorigenesis.
Alleles↗
Cadherin-based resistance to Bacillus thuringiensis cotton in hybrid strains of pink bollworm: fitness costs and incomplete resistance.
Recessive resistance to Bacillus thuringiensis (Bt) cotton, Gossypium hirsutum L., in laboratory-selected strains of pink bollworm, Pectinophora gossypiella (Saunders), is associated with three resistance alleles (r1, r2, and r3) of a cadherin gene. Previous experiments based on measurement of fitness components in Bt-resistant and Bt-susceptible strains revealed that fitness costs and incomplete resistance are associated with resistance. Here, we used two hybrid strains of pink bollworm, each containing a mixture of susceptible and resistant individuals, and polymerase chain reaction (PCR) amplifications to test the association between cadherin genotype and fitness components for individuals sharing a common genetic background. All survivors on Bt cotton had two r alleles, confirming that recessive cadherin alleles are tightly linked with resistance to Bt cotton. On non-Bt cotton, significantly greater developmental time for rr than ss larvae indicated a recessive fitness cost, but costs did not affect survival or pupal weight. Incomplete resistance was manifested as longer developmental time, lower survival, and smaller pupal weight in rr individuals developing on Bt cotton compared with non-Bt cotton. As in previous experiments, no significant variation in performance on Bt cotton was detected among rr genotypes. However, a meta-analysis of data from seven experiments revealed that survival on Bt cotton relative to non-Bt cotton was lower in r2r3 and higher in r1r2 compared with the other rr genotypes. Assessment of fitness components associated with cadherin genotypes in hybrid strains of pink bollworm confirms that recessive resistance to Bt cotton is associated with recessive fitness costs and incomplete resistance.
Animals↗
Allelic variation in the DR subregion of the human major histocompatibility complex.
Allelic variation in the DR subregion of the human major histocompatibility complex has been analyzed by nucleic acid sequencing of cDNA clones obtained from cell lines homozygous by consanguinity for all the common serological types DR1-9. Two expressed loci were identified in the haplotypes DR2, -3, -4, -7, and -9; one locus being present at a much lower frequency (4-7%) than the other. The low-frequency allele was highly conserved between each of the DRw53 (DR4, -7, -9) and the DRw52 (DR3, -5, -6) haplotypes. Analysis of the variation between alleles confirms the presence of three allelic hypervariable regions. At each variable residue, a limited range of amino acid substitutions are found, distinguishing them from immunoglobulin hypervariable regions. Dinucleotide substitutions are extremely common. Individual hypervariable regions are often shared between haplotypes. Much of the variation in these alleles can be attributed to the shuffling of these regions between haplotypes, possibly by the mechanism of gene conversion.
Alleles↗
Influence of the polymorphism of apolipoprotein E in cerebral vascular disease.
UNLABELLED: The genetic heterogeneity of apolipoprotein E (apo E) has been associated with lipid profile and atherothrombotic stroke, however this association remains inconclusive. OBJECTIVE: To evaluate the relationship between the isoforms of apo E and atherothrombotic stroke, by ascertaining the frequency of its alleles and genotypes associated with the lipid profile in patients with stroke. METHOD: A total of 207 individuals were divided into two groups, consisting of 107 patients with stroke and 100 individuals without clinical symptoms of the disease. Blood samples were taken from patients and controls for molecular investigation of the apo E (epsilon2, epsilon3 and epsilon4 alleles) for the analysis of the lipid profile. RESULTS: The epsilon3 allele was the most common and its prevalence was significantly higher in patients (0.93) compared to the controls (0.86; p=0.024). The epsilon2 allele was rarely seen specifically in patients (0.02 versus 0.05 in controls, p=0.191). The epsilon4 allele was not associated with stroke showing a reduced frequency in patients (0.05) when compared to controls (0.09; p=0.011). Although higher average levels of lipid profile were found in patients when compared to controls, with statistical significance for the values of total cholesterol (TC) (203.6 mg/dL +/- 57.98 and 181.9 mg/dL +/- 68.47 respectively; p=0.003) and low-density lipoprotein cholesterol (LDLc) (131.4mg/dL +/- 52.60 and 116 mg/dL +/- 56.38, respectively; p=0.014), these were independent of the presence of the epsilon4 allele. In control group the higher TC and LDLc values occurred in the absence of the epsilon4 allele, confirming the conflicting effect of the alleles of apo E on the plasmatic lipids and atherothrombotic stroke. CONCLUSION: The isoforms of apo E cannot be regarded as an isolated risk factor for stroke and do not show association with lipid profile in this study.
Aged↗
HLA polymorphism in Bulgarians defined by high-resolution typing methods in comparison with other populations.
In the present study we analyzed for the first time HLA class I and class II polymorphisms defined by high-resolution typing methods in the Bulgarian population. Comparisons with other populations of common historical background were performed. Most HLA-A, -B, -DRB alleles and haplotypes observed in the Bulgarian population are also common in Europe. Alleles and haplotypes considered as Mediterranean are relatively frequent in the Bulgarian population. Observation of Oriental alleles confirms the contribution of Asians to the genetic diversity of Bulgarians. The use of high-resolution typing methods allowed to identify allele variants rare for Europeans that were correlated to specific population groups. Phylogenetic and correspondence analyses showed that Bulgarians are more closely related to Macedonians, Greeks, and Romanians than to other European populations and Middle Eastern people living near the Mediterranean. The HLA-A,-B,-DRB1 allele and haplotype diversity defined by high-resolution DNA methods confirm that the Bulgarian population is characterized by features of southern European anthropological type with some influence of additional ethnic groups. Implementation of high-resolution typing methods allows a significantly wider spectrum of HLA variation to be detected, including rare alleles and haplotypes, and further clarifies the origin of Bulgarians.
Bulgaria↗
HLA-DQA1 genotyping by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and restriction endonuclease digestion in Papua New Guinea.
We have used PCR-SSCP, a technique based on the conformation of single-stranded DNA, to characterize the HLA-DQA1 gene in four geographically diverse population groups in Papua New Guinea. Among the 294 individuals that were studied from Goroka, north coast of Madang, Kimbe and Wanigela, we detected 5 of the 20 known variants of this gene locus. These included alleles 0101, 0102, 0103, 0301 and 0501. Furthermore, variable mobility shifts observed for alleles 0301 and 0501 from Madang suggested a further 3 variants. All 15 combinations of the 5 confirmed alleles were detected and their respective gene frequencies found to be consistent with the groups' ethnic and linguistic diversity. In respect to their frequencies and the observed overall allelic heterozygosity, the distribution in Kimbe showed some similarity to that in the north coast of Madang while Madang and Goroka were the most different. The distribution of alleles 0102 and 0501 was observed to be similar for Goroka and Wanigela as was 0301 for Madang and Wanigela. Our results, confirmed by endonuclease digestion, show PCR-SSCP to be a highly sensitive technique that can be used to characterize HLA-DQ antigens. In addition, the simplicity of the method provides an opportunity for large-scale typing of HLA antigens.
Alleles↗
Preimplantation genetic diagnosis for beta-thalassaemia using sequencing of single cell PCR products to detect mutations and polymorphic loci.
In order to carry out preimplantation genetic diagnosis (PGD) for beta-thalassaemia, we have applied direct sequencing of single cell PCR products to detect mutations and polymorphic loci within the beta-globin gene. Conventional duplex PCR was used to amplify two regions of the beta-globin gene with an amplification efficiency of 79% for blastomeres. Sequencing data were obtained for 100% of amplified products, with 12% having confirmed allele drop-out (ADO). A double ADO event was observed at least twice, confirming the real risk of such an event during PGD. In one couple, the presence of a polymorphism linked to the female partner's mutation enabled us to eliminate the risk of misdiagnosis due to double ADO without having to amplify both mutations within the same PCR product. We present here the data from eight clinical PGD cycles for three couples resulting in a singleton pregnancy and a twin pregnancy with all babies confirmed to be free from beta-thalassaemia (major).
Embryo Transfer↗
HLA class II DNA typing in Buerger's disease.
To analyze the genetic factors involved in the pathogenesis of Buerger's disease, the polymorphisms of HLA class II genes (HLA-DP, -DQ and -DRB) were investigated in 36 patients using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. HLA class I (B54 and B52) and HLA class II (DQ alleles) genes were also typed by polymerase chain reaction-sequence-specific oligonucleotide probe (PCR SSOP) method to confirm alleles. PCR-RFLP typing revealed that the frequencies of HLA class II genes, DRB1*0405, DQB1*0401, DQA1*03 and DPB1*0501, were significantly increased in the patients with Buerger's disease compared with the healthy controls. Further, DNA typing confirmed that HLA-B54 was associated with Buerger's disease. These results suggested that the haplotype of HLA-B54-DRB1*0405-DQB1*0401- DQA1*03-DPB1*0501 was associated with Buerger's disease in Japanese population.
Adult↗
The original pink-eyed dilution mutation (p) arose in Asiatic mice: implications for the H4 minor histocompatibility antigen, Myod1 regulation and the origin of inbred strains.
Allelic variation of the mouse pink-eyed dilution (p) gene in common laboratory strains and wild mice was examined by Southern blot and by polymerase chain reaction. In these assays the original p mutation allele found in strains SJL/J, 129/J, B10.129(21m), P/J and FS/Ei most closely matches an Asian Mus musculus allele, confirming anecdotal accounts of the Asian origin of this mutation. In contrast, the wild-type allele found in other common laboratory strains was apparently derived from Mus domesticus. Analysis of chromosome 7 loci both proximal and distal to the p locus demonstrates that strains SJL/J, 129/J, B10.129(21M), P/J and FS/Ei contain DNA segments of varying length derived from M. musculus. Strains 129/J and B10.129(21M) contain the largest segment of M. musculus-derived DNA (about 5 cM), including the loci Myod1, p, three clustered GABAA receptor subunit loci (Gabrg3, Gabra5 and Gabrb3), and Snrpn. The difference in the species origin of genes from this region of chromosome 7 may underlie the basis of the antigenicity of the minor histocompatibility antigen H4, defined by the strain B10.129(21M), and may account for the enhanced Myod1 activity observed in SJL/J mice.
Alleles↗
Presymptomatic diagnosis of myotonic dystrophy.
The discovery of an expanded (CTG)n repeat sequence in myotonic dystrophy (DM) has greatly improved our ability to detect DM gene carriers who have few or none of the classical signs of this disorder. We report here our experience with two such groups of gene carriers. We used a PCR based protocol that should be especially sensitive to small increases in CTG triplet number which might escape detection by conventional Southern blot analysis. Our analyses show that on 100 non-DM chromosomes the number of CTG triplets ranged from five to 37. We then studied 17 obligate gene carriers aged 55 years and over who showed no muscle weakness. All of the gene carriers in this group showed a relatively small increase in the number of CTG triplets (52 to 90 CTG triplets) with limited somatic mosaicism. We subsequently studied 11 subjects (aged 19 to 36 years) who had previously been identified as gene carriers by genetic linkage studies, but who lacked diagnostic signs. In this prospectively studied group, nine subjects showed an expanded allele, confirming the earlier prediction from linked genetic markers. The other two subjects had only two normal alleles and no expanded allele. Revision of the clinical data casts doubt on the original diagnosis of DM in their families. Preferential amplification of the normal non-expanded allele was noted in three asymptomatic gene carriers in this study (as well as in two of their clinically affected relatives). We caution that, at least in our hands, the DM mutation can be confidently excluded by this PCR based method only if both normal alleles have been identified.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Huntington's disease: diagnosis by amplification of the CAG repeat.
AIM: To develop and validate a test for the diagnosis of Huntington's disease by the direct detection, and sizing of, expanded CAG triplet repeats within the Huntington gene of affected individuals. METHODS: A polymerase chain reaction-based test which specifically amplifies the CAG repeat was developed using an ultra heat stable polymerase and [alpha 35S] delta ATP incorporation. Amplified alleles were separated on DNA sequencing gels and sized by comparison with a known sequence. RESULTS: Analysis of 10 affected individuals showed abnormal alleles with repeat numbers ranging from 40 to 61. In one case, that had been diagnostically uncertain because there was no family history of Huntington's disease, the demonstration of an expanded allele confirmed the diagnosis. Analysis of this patient's elderly and unaffected father indicated that he had an allele at the extreme end of the normal range. In a second case with atypical neurological features the diagnosis was also established by the demonstration of an expanded allele. CONCLUSIONS: This assay allows improved diagnosis of Huntington's disease including completely accurate presymptomatic and antenatal diagnosis. Easy access to this test has implications for clinical practice but acceptable guidelines for its use will need to be developed.
Adult↗
Resistance gene-analog polymorphism markers co-segregating with the YR5 gene for resistance to wheat stripe rust.
The Yr5 gene confers resistance to all races of the stripe rust pathogen ( Puccinia striiformis f. sp. tritici) of wheat in the United States. To develop molecular markers for Yr5, a BC(7):F(3) population was developed by backcrossing the Yr5 donor ' Triticum spelta album' (TSA) with the recurrent parent 'Avocet Susceptible' (AVS). Seedlings of the Yr5 near-isogenic lines (AVS/6* Yr5), AVS, TSA, and the BC(7):F(3) lines were tested with North American races of P. striiformis f. sp. tritici under controlled greenhouse conditions. The single gene was confirmed by a 1:2:1 segregation ratio for homozygous-resistant, heterozygous and homozygous-susceptible BC(7):F(3) lines. Genomic DNA was extracted from the parents (the Yr5 near-isogenic line and AVS) and 202 BC(7):F(3) lines. The resistance gene-analog polymorphism (RGAP) technique was used to identify molecular markers. The parents and the homozygous-resistant and homozygous-susceptible BC(7):F(3) bulks were used to identify putative RGAP markers for Yr5. Association of the markers with Yr5 was determined using segregation analysis with DNA from the individual BC(7):F(3) lines. Of 16 RGAP markers confirmed by segregation analysis with 109 BC(7):F(3) lines, and nine of the markers confirmed with an additional 93 BC(7):F(3) lines, three markers co-segregated with the resistance allele and three markers co-segregated with the susceptibility allele at the Yr5 locus. The other four markers were tightly linked to the locus. Analysis of a set of Chinese Spring nulli-tetrasomic lines with three markers that co-segregated with, or were linked to, the susceptibility allele confirmed that the Yr5 locus is on chromosome 2B. Of five RGAP markers that were cloned and sequenced, markers Xwgp-17 and Xwgp-18 that co-segregated with the Yr5 locus were co-dominant and had 98% homology with each other in both DNA and translated amino-acid sequences. The two markers had 97% homology with a resistance gene-like sequence from Aegilops ventricosa and had significant homology with many known plant resistance genes, resistance gene analogs and expressed sequence tags (ESTs) from wheat and other plant species. The markers Xwgp-17 and Xwgp-18 also had significant homology with the NB-ARC domain that is in several genes for plant resistance to diseases, nematode cell death and human apoptotic signaling. These markers should be useful to clone Yr5 and combine Yr5 with other genes for durable and superior resistance for the control of stripe rust.
Amino Acid Sequence↗