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PubMed1997

Polymorphism of the h allele and the population frequency of sporadic nonfunctional alleles.

BACKGROUND: Current polymerase chain reaction-based strategies for phenotype prediction often fail when sporadic nonfunctional alleles are encountered. The population frequency of such mutations was not known for any gene under low selection pressure and may be best examined in blood groups systems lacking prevalent nonfunctional alleles. The frequency of the very rare Bombay blood group (Oh, genotype hh sese) was recently determined in a systematic survey of more than 600,000 white individuals. STUDY DESIGN AND METHODS: With this survey used in conjunction with additional blood samples, the population frequency of nonfunctional alleles of the gene encoding the alpha (1,2)fucosyltransferase (H or FUT1) was determined. RESULTS: Seven different h alleles were found in five unrelated individuals, three of whom were homozygous for unique alleles. There was no prevalent h allele. Five missense and one frameshift mutations were observed, that were the presumptive causes of the null phenotype; the coding sequence of one h allele was identical to the H sequence. The average inbreeding factor alpha was 0.00116. The frequency of nonfunctional alleles at the H gene locus was calculated as 1 in 347 in a large white population (95% CI: 1:185-1:824). CONCLUSION: The Bombay blood group phenotype in white is due to diverse, sporadic, nonfunctional alleles without any prevalent allele. Assuming similar rates of nonfunctional alleles in glycosyltransferase genes like ABO, current genotyping strategies may fail as often as once in about 300 individuals of blood group O. Sporadic neutral alleles may also pose a serious obstacle for population-wide screening of many disease-associated genes.

Alleles↗
PubMed1999

Analysis and interpretation of short tandem repeat microvariants and three-banded allele patterns using multiple allele detection systems.

The Palm Beach County Sheriffs Office (PBSO) Crime Laboratory and the Alabama Department of Forensic Sciences (ADFS) have validated and implemented analysis of short tandem repeat (STR) sequences on casework using silver staining kit and SYBR Green I detection systems and are presently validating fluorescently tagged STR alleles using the Hitachi FMBIO 100 instrument. Concurrently, the Broward County Sheriff's Office (BSO) Crime Laboratory is validating the ABI Prism310 Genetic Analyzer capillary electrophoresis STR detection system (ABI CE310) from Perkin Elmer Applied BioSystems. During the course of analyzing over 10,000 individuals for the STR loci CSF1PO, TPOX and THO1 (CTT) using silver staining for allele detection, 42 samples demonstrated alleles that were "off ladder," contained three-banded patterns at a single locus, or exhibited an apparent THO1 "9.3,10" allele pattern. PBSO, ADFS and BSO Crime Laboratories have collaborated on the verification of the allele patterns observed in these 42 samples using the following allele detection systems: (1) manual silver staining, (2) SYBR Green I staining, and/or (3) fluorescently tagged amplified products separated by polyacrylamide gel electrophoresis or capillary electrophoresis followed by laser detection. Regardless of the CTT allele detection system utilized, concordant results were obtained for 41 of the 42 samples. The only exception was a sample in which a wide band within the THO1 locus was identified as a THO1 "9.3, 10" genotype by silver staining kit and SYBR Green I staining but was verified to be a THO1 "9.3" homozygote by all other allele detection systems. Manual allele detection could readily identify microvariants, as a visual assessment of stained gels clearly shows that alleles do not migrate coincident with well-characterized allele size standards. As would be predicted, however, the manual detection systems did not provide adequate resolution to approximate the basepair size for off-ladder variants. All fluorescent software program systems were consistent in designating alleles "not in range" or "off ladder," thereby indicating true microvariants. All single-locus three-banded patterns were detected using all of the STR multiplex systems. In addition, individual locus-specific primers verified multiplexed amplified products were specific for the locus in question.

Alleles↗
PubMed2004

Assignment of allelic configuration in polyploids using the MAC-PR (microsatellite DNA allele counting-peak ratios) method.

Polysomic inheritance frequently results in the simultaneous occurrence of several microsatellite DNA alleles on a single locus. The MAC-PR (microsatellite DNA allele counting-peak ratios) method was recently developed for the analysis of polyploid plants and makes use of the quantitative values for microsatellite allele peak areas. To date, this approach has only been used in plants with known genetic relationships. We report here the application of MAC-PR for the first time to random samples of unknown pedigrees. We analysed six microsatellite loci using a set of tetraploid ornamental rose ( Rosa x hybrida L.) varieties. For each locus, all alleles were analysed in pairwise combinations in order to determine their copy number in the individual samples. This was accomplished by calculating the ratios between the peak areas for two alleles in all of the samples where these two alleles occurred together. The allele peak ratios observed were plotted in a histogram, and those histograms that produced at least two well-separated groups were selected for further analysis. Mean allelic peak ratio values for these groups were compared to the relationships expected between alleles in hypothetical configurations of the locus investigated. Using this approach, we were able to assign precise allelic configurations (the actual genotype) to almost all of the varieties analysed for five of the six loci investigated. MAC-PR also appears to be a very effective tool for detecting 'null' alleles in polyploid species.

Alleles↗
PubMed1989

The B allele of the NS gene of avian influenza viruses, but not the A allele, attenuates a human influenza A virus for squirrel monkeys.

The nonstructural (NS) genes of avian influenza A viruses have been divided into two groups on the basis of nucleotide sequence homology, which we have referred to here as alleles A and B. We sequenced the NS genes of eight additional avian influenza A viruses in order to define the differences between these two alleles more thoroughly. Four of the viruses had NS gene sequences which resembled that of A/FPV/Rostock/34 and belonged to allele A while the other four viruses had NS gene sequences more similar to that of A/Duck/Alberta/76 and belonged to allele B. There was approximately 90% sequence homology within alleles and 72% homology between alleles. As previously reported the NS genes of human influenza A viruses belong to allele A. We constructed single gene avian-human reassortant influenza A viruses containing an allele A or B NS gene segment from an avian influenza A virus and all other genes from a human influenza A virus and tested these reassortants for their ability to grow in the respiratory tract of a nonhuman primate. Reassortants containing an avian NS gene segment of allele B were significantly restricted in growth in the respiratory tract of squirrel monkeys while reassortants with an allele A NS gene segment were not. The divergent evolution of the B NS allele in birds may have resulted in gene products which do not function optimally in cooperation with genes from a human virus in viral replication in primate respiratory epithelium.

Alleles↗
PubMed2000

Diversity of alleles encoding HLA-B40: relative frequencies in united states populations and description of five novel alleles.

The frequency of each B*40 allele was determined by DNA sequencing in four major United States populations: Caucasians, African Americans, Asians/Pacific Islanders, and Hispanics. Thirty-two individuals from each ethnic group, who were previously described serologically as B40, B60, or B61, were randomly selected out of a pool of 82,979 unrelated individuals for allele characterization. Out of nine different B*40 alleles identified in this study, B*4001 and B*4002 were the two most frequent B*40 alleles in all the population groups. B*4001 was the primary B*40 allele seen in Caucasians (83%) and African Americans (76%), while B*4002 was found in the majority of Hispanics (62%). The distributions of both alleles were comparable in the Asian/Pacific Islander population. These two alleles were the only B*40 alleles detected in Caucasians while four to five additional B*40 alleles were seen in the other population groups. The other B*40 alleles detected in this study included: B*4003 and B*4010 in Asian/Pacific Islanders; B*4012 and B*4016 in African Americans; and B*4004, B*4006, and B*4027 in Hispanics. Analysis revealed significant differences between Hispanics and all other groups as well as between African Americans and Asian/Pacific Islanders. This report also describes five novel B*40 alleles: B*4019, B*4020, B*4024, B*4027, and B*4028.

Alleles↗
PubMed1996

Rapid detection of the cisAB allele consisting of a chimera of normal A and B alleles by PCR-RFLPs.

DNA samples were analysed from Japanese individuals with the very rare ABO variant phenotype, cisAB (A2B3), which is characterized by the apparent inheritance of both A and B genes on one chromosome. The nature of the bases present at nucleotide positions (nps) 261, 526, 703, 796 and 803 is important for the specificity of the alleles at the ABO locus and the DNA from the cis AB donors was analysed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to determine which nucleotides are present at these positions. The results indicated that the cisAB allele had the AAAB-structure, which was a chimera of normal A and B alleles, when the expression 'AAAA' and 'BBBB' indicated the nucleotides of normal A (C, G, C and G) and B (G, A, A and C) genes at nps 526, 703, 796 and 803, respectively. The AAAB allele was found in all 27 individuals (17 families) with the cisAB including three phenotypes A2B3, A1B3 and A2B and no other chimeric gene was found. The causative gene of cisAB was the AAAB allele, and the A and B alleles were not on one chromosome. The cisAB allele appeared to be a product of the normal A allele due to a point mutation at nucleotide position 803, from G to C. The AAAB allele is thought to be normally transcribed and translated to produce an unusual transferase polypeptide, which has weak A- and weaker B-specific activity. PCR-RFLP is a rapid and useful means of detecting the cisAB allele (the AAAB allele) without a family study, even when they have A1B3 and A2B phenotypes, because trans-type A1B3 and A2B samples have obviously different PCR-RFLP profiles.

ABO Blood-Group System↗
PubMed2026

Polysomal Profiling Coupled to Allele-Specific Proteomics Reveals an EIF4H TranSNP Allele Possessing Higher mRNA Translation Potential.

To search for genetic sources of allele-specific mRNA translation, we leveraged heterozygous polymorphisms and variants present in the exome of HCT116 colorectal adenocarcinoma-derived cells, computing allelic fractions from both total and polysome-associated RNA from RNA-Seq data. Allelic imbalance in polysomal RNA led us to nominate 52 coding variants associated with allele-specific mRNA translation, of which 16 are nonsynonymous. To validate instances of allele-specific translation, a proteomics workflow was developed that combines label-free shotgun analysis, high-pH reversed-phase peptide fractionation, and targeted parallel reaction monitoring using isotope-labeled peptide standards. Using this approach, we provide proof-of-concept validation of the heterozygous G>A, R183H missense single-nucleotide variant rs1554710467 in the eukaryotic initiation factor 4H (EIF4H) gene. The variant is present in two EIF4H alternatively spliced variants, which showed equivalent translation efficiency in HCT116 cells but differ in abundance. The alternative peptide containing H183 was significantly more abundant than the corresponding reference peptide containing R183, consistent with the over-representation of the alternative allele in polysomal RNA in HCT116 cells. A dual-fluorescence ribosome-stalling assay confirmed the enhanced translation potential of the variant allele. The two EIF4H allelic proteins exhibited similar stability and subpolysomal localization. This study demonstrates the feasibility of using allele-specific proteomics at the endogenous protein levels by exploiting heterozygous coding variants. Overall, our approach extends the toolbox available to investigate allele-specific differences in mRNA translation potential, a relatively underexplored layer of gene expression regulation that could reveal interindividual differences in disease-relevant phenotypes.

Humans↗
PubMed2004

RUNX2 alleles associated with BMD in Scottish women; interaction of RUNX2 alleles with menopausal status and body mass index.

Bone mineral density (BMD) is influenced by both environmental and genetic factors. We previously reported the association of the RUNX2 A allele with increased bone mineral density (BMD) and protection against a common form of osteoporotic fracture within a Geelong population. We genotyped 991 women from a Scottish cohort to decipher the role of RUNX2 alleles in regulating BMD. The alleles of RUNX2 within the glutamine-alanine repeat were determined by MspA1I restriction digest. Allele frequencies estimated from Scottish cohort were G allele, 0.87 +/- 0.01; A allele, 0.08 +/- 0.01; and 11Ala alanine deletion allele, 0.05 +/- 0.01. Analysis of covariance (ANCOVA) was used to adjust for the covariates weight and age for BMD at the femoral neck (FN). The A allele was associated with higher FN BMD (P = 0.035) within a postmenopausal subgroup of the population (n = 312). The effect of RUNX2 A alleles increased with increasing weight; A alleles were associated with FN BMD in those above the median BMI (BMI > 25), while no association was observed in thin/normal (BMI </= 25) postmenopausal women. Glutamine variants and an alanine insertion were identified within the group. These data suggest that the RUNX2 alleles are associated with BMD in a menopause- and weight-dependent manner.

Analysis of Variance↗
PubMed2003

Mono-allelic amplification of exons 2-4 using allele group-specific primers for sequence-based typing (SBT) of the HLA-A, -B and -C genes: preparation and validation of ready-to-use pre-SBT mini-kits.

Class I allelic typing based on sequencing is reliable, immutable and easy to analyse when only one allele is amplified using a specific mono-allelic technique. A strategy has been developed to selectively amplify exons 2, 3 and 4 of each allele of the three class I loci, previously identified by generic typing, in order to sequence these alleles from their intronic parts in only one direction. This procedure is based mainly on the polymorphism of exon 1 and intron 1 of the HLA-A, -B and -C genes with allele group-specific forward primers and locus-specific reverse primers so as to perform mono-allelic amplification in a 'One Step' pre-sequence-based typing (pre-SBT) PCR. The 5' polymorphism found at each locus is nevertheless not sufficient to discriminate all allelic combinations. Hence exon 2 and exon 3 polymorphism had to be used in a 'Two Step' pre-SBT PCR method to selectively amplify the two alleles in the 1.8%, 7.6% and 0.9% of unresolved combinations found in our laboratory for, respectively, the HLA-A, -B and -C loci. Preparation and validation of 'ready-to-use' aliquots of primer-mixes, pre-SBT buffer and sets of Dye terminator reaction mixtures containing locus-specific intronic primers makes the procedure easy and efficient. The SBT method is the only allelic typing technique used in our laboratory (to date, 742 HLA-A*, 802 HLA-B* and 615 HLA-Cw* alleles have been sequenced) and our successful participation in the national and international quality controls of 4 years ago testifies to the accuracy of the results.

DNA Primers↗
PubMed1999

Characterization of Mhc-DRB allelic diversity in white-tailed deer (Odocoileus virginianus) provides insight into Mhc-DRB allelic evolution within Cervidae.

Although white-tailed deer (Odocoileus virginianus) are one of North America's best studied mammals, no information is available concerning allelic diversity at any locus of the major histocompatibility complex in this taxon. Using the polymerase chain reaction, single-stranded conformation polymorphism analysis, and DNA sequencing techniques, 15 DRB exon 2 alleles were identified among 150 white-tailed deer from a single population in southeastern Oklahoma. These alleles represent a single locus and exhibit a high degree of nucleotide and amino acid polymorphism, with most amino acid variation occurring at positions forming the peptide binding sites. Furthermore, twenty-seven amino acid residues unique to white-tailed deer DRB alleles were detected, with 19 of these occurring at residues forming contact points of the peptide binding region. Significantly higher rates of nonsynonymous than synonymous substitutions were detected among these DRB alleles. In contrast to other studies of Artiodactyla DRB sequences, interallelic recombination does not appear to be playing a significant role in the generation of allelic diversity at this locus in white-tailed deer. To examine evolution of white-tailed deer (Odvi-DRB) alleles within Cervidae, we performed a phylogenetic analysis of all published red deer (Ceel-DRB), roe deer (Caca-DRB), and moose (Alal-DRB) DRB alleles. The phylogenetic tree clearly shows a trans-species persistence of DRB lineages among these taxa. Moreover, this phylogenetic tree provides insight into evolution of DRB allelic lineages within Cervidae and may aid in assignment of red deer DRB alleles to specific loci.

Alleles↗
PubMed1997

Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele. The IMDIAB Group.

The IDDM2 type 1 diabetes susceptibility locus was mapped to and identified as allelic variation at the insulin gene (INS) VNTR regulatory polymorphism. In Caucasians, INS VNTR alleles divide into two discrete size classes. Class I alleles (26 to 63 repeats) predispose in a recessive way to type 1 diabetes, while class III alleles (140 to more than 200 repeats) are dominantly protective. The protective effect may be explained by higher levels of class III VNTR-associated INS mRNA in thymus such that elevated levels of preproinsulin protein enhance immune tolerance to preproinsulin, a key autoantigen in type 1 diabetes pathogenesis. The mode of action of IDDM2 is complicated, however, by parent-of-origin effects and possible allelic heterogeneity within the two defined allele classes. We have now analysed transmission of specific VNTR alleles in 1,316 families and demonstrate that a particular class I allele does not predispose to disease when paternally inherited, suggestive of polymorphic imprinting. But this paternal effect is observed only when the father's untransmitted allele is a class III. This allelic interaction is reminiscent of epigenetic phenomena observed in plants (for example, paramutation; ref. 17) and in yeast (for example, trans-inactivation; ref. 18). If untransmitted chromosomes can have functional effects on the biological properties of transmitted chromosomes, the implications for human genetics and disease are potentially considerable.

Alleles↗
PubMed2002

Genotyping for HLA-A, B and C alleles in Japanese patients with pemphigus: prevalence of Asian alleles of the HLA-B15 family.

BACKGROUND: There have been only limited reports on major histocompatibility complex class I antigens in pemphigus. OBJECTIVES: To characterize HLA-A, B and C class I alleles by genotyping in Japanese patients with pemphigus, and to analyse the possible association of class I alleles with disease susceptibility within a relatively homogeneous ethnic population. METHODS: Alleles of HLA-A, B and C, and DRB1 and DQB1 loci were fully determined in 51 Japanese patients with pemphigus. RESULTS: Asian alleles of the HLA-B15 family, including the allele B*1507, which was significantly increased in comparison with normal controls, were prevalent in patients with pemphigus vulgaris (PV). The prevalence of B*15 alleles in patients with PV was not due to linkage disequilibrium with HLA-DR4 or DR14 alleles, which have been shown to confer strong susceptibility to PV across racial barriers. In contrast to the unique distribution of the HLA-B alleles, HLA-A and C alleles were unremarkable in patients with PV when compared with normal control subjects. CONCLUSIONS: These results suggest that there may be differences in the ethnic concentrations of different HLA-B alleles in patients with PV.

Alleles↗
PubMed2000

Evidence for a role of HLA DRB1 alleles in the control of IgE levels, strengthened by interacting TCR A/D marker alleles.

BACKGROUND: MHC class II alleles at human chromosome 6p21.1 and alleles in the TCR A/D locus at human chromosome 14q11.2 have been implicated in susceptibility to specific allergies and the modulation of total serum IgE. It has also been hypothesized that HLA and TCR allelic interactions may have a strong influence on predisposition to allergic disease. OBJECTIVE: This study was performed to investigate the influence of HLA-DRB and DQB1 alleles and D14S50 alleles (adjacent to TCR A/D locus on 14q11.2), individually and in-combination, on total serum IgE levels, and on the development of specific allergies. METHODS: We performed an association study between HLA-DRB, HLA-DQB1 polymorphisms, D14S50 alleles, total serum IgE expression and specific allergies to house dust mite, grass pollens and cat fur. A sample of 181 individuals was drawn from a larger set of 2415 adults, sampled at random from a district in Nottingham. RESULTS: Strong association was observed between HLA-DRB1*0701 allele and high total serum IgE expression (P < 0.001). D14S50 alleles alone showed no evidence for independent association. However, there was a significant interaction between DRB1*0701 and D14S50 allele 170 such that, when both were present, there was a further increase in total serum IgE levels. CONCLUSION: This study suggests that DRB1*0701 allele is involved in the modulation of total serum IgE, and that there is an interaction between DRB1*0701 and a marker adjacent to TCR A/D in the control of IgE expression.

Adolescent↗
PubMed2000

CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: evidence for an allelic variant with altered catalytic activity.

OBJECTIVE: To determine the existence of mutant and variant CgammaP3A4 alleles in three racial groups and to assess functions of the variant alleles by complementary deoxyribonucleic acid (cDNA) expression. METHODS: A bacterial artificial chromosome that contains the complete CgammaP3A4 gene was isolated and the exons and surrounding introns were directly sequenced to develop primers to polymerase chain reaction (PCR) amplify and sequence the gene from lymphocyte DNA. DNA samples from Chinese, black, and white subjects were screened. Mutating the affected amino acid in the wild-type cDNA and expressing the variant enzyme with use of the baculovirus system was used to functionally evaluate the variant allele having a missense mutation. RESULTS: To investigate the existence of mutant and variant CgammaP3A4 alleles in humans, all 13 exons and the 5'-flanking region of the human CgammaP3A4 gene in three racial groups were sequenced and four alleles were identified. An A-->G point mutation in the 5'-flanking region of the human CgammaP3A4 gene, designated CgammaP3A4*1B, was found in the three different racial groups. The frequency of this allele in a white population was 4.2%, whereas it was 66.7% in black subjects. The CgammaP3A4*1B allele was not found in Chinese subjects. A second variant allele, designated CgammaP3A4*2, having a Ser222Pro change, was found at a frequency of 2.7% in the white population and was absent in the black subjects and Chinese subjects analyzed. Baculovirus-directed cDNA expression revealed that the CYP3A4*2 P450 had a lower intrinsic clearance for the CYP3A4 substrate nifedipine compared with the wild-type enzyme but was not significantly different from the wild-type enzyme for testosterone 6beta-hydroxylation. Another rare allele, designated CgammaP3A4*3, was found in a single Chinese subject who had a Met445Thr change in the conserved heme-binding region of the P450. CONCLUSIONS: These are the first examples of potential function polymorphisms resulting from missense mutations in the CgammaP3A4 gene. The CgammaP3A4*2 allele was found to encode a P450 with substrate-dependent altered kinetics compared with the wild-type P450.

Alleles↗
PubMed1991

Implication of specific DQB1 alleles in genetic susceptibility and resistance by identification of IDDM siblings with novel HLA-DQB1 allele and unusual DR2 and DR1 haplotypes.

Genetic susceptibility to insulin-dependent diabetes mellitus (IDDM) is associated with the HLA-DR3 and DR4 haplotypes. The HLA-DR2 haplotype is negatively associated with IDDM, an association that has been interpreted as dominant protection. Here, we describe the molecular analysis of the HLA class II genes in an unusual family with three HLA-DR1/2 siblings, all of whom have IDDM. With polymerase chain reaction amplification and sequence analysis to characterize the class II alleles, we identified a novel DQB1 allele on the DR1 haplotype and an unusual DQB1 allele on the DR2 haplotype. However, the DRB1 alleles on these DR1 and DR2 haplotypes are the conventional alleles (*0101 and *1501, respectively). These results suggest that it is the conventional DQB1 allele (*0602) not the DRB1 allele (*1501) on the protective DR2 haplotype that confers protection in the general population and, furthermore, that these unusual DQB1 alleles may confer susceptibility to IDDM in this family. The unusual DQB1 allele on this DR2 haplotype encodes Asp at position 57, indicating that it is the allele DQB1*0602 and not simply the presence of this residue that is responsible for the protective effect.

Adolescent↗
PubMed2002

Premutation and intermediate-size FMR1 alleles in 10572 males from the general population: loss of an AGG interruption is a late event in the generation of fragile X syndrome alleles.

We previously reported a 1:259 prevalence of female carriers of FMR1 premutation-size alleles (greater than 54 triplet repeats) in the general population. We now have screened 10 572 independent males from the same population for similar alleles using high-throughput Southern blotting. We identified 13 male carriers of an allele with more than 54 repeats. This corresponds to a prevalence of 1:813 males (95% confidence interval 1:527 to 1:1781). Haplotype analysis of four markers flanking the triplet array revealed that the prevalence of the major fragile X mutation-associated haplotype was increased among FMR1 alleles of 40-54 repeats. Although sequencing of highly unstable premutation alleles from fragile X families revealed only pure CGG tracts, this was not the case for alleles of similar size that were identified in males from the general population. Forty-eight out of forty-nine alleles of 40 or more triplets had one or two AGG interruptions. This observation, combined with the observation of the enrichment of major fragile X syndrome haplotypes in all alleles of this size, is evidence that the loss of an AGG interruption in the triplet repeat array is not necessary for expansion of normal alleles of 29-30 triplets to intermediate size. The loss of AGG interruptions thus appears to be a late event that leads to greatly increased instability and may be related to the haplotype background of specific FMR1 alleles.

Fragile X Messenger Ribonucleoprotein 1↗
PubMed2000

Haplotype and AGG-interspersion analysis of FMR1 (CGG)(n) alleles in the Danish population: implications for multiple mutational pathways towards fragile X alleles.

The AGG interspersion pattern and flanking microsatellite markers and their association with instability of the FMR1 (CGG)(n) repeat, involved in the fragile X syndrome, were analyzed in DNA from filter-paper blood spots randomly collected from the Danish newborn population. Comparison of DXS548-FRAXAC1 haplotype frequencies in the normal population and among fragile X patients suggested strong linkage disequilibrium between normal alleles and haplotype 7-3 and between fragile X alleles and haplotype 2-1 and 6-4. Comparison of the AGG interspersion pattern in 143 alleles, ranging in size from 34-62 CGG, and their associated haplotypes indicates the existence of at least three mutational pathways from normal alleles toward fragile X alleles in the Danish population. Two subgroups of normal alleles, with internal sequences of (CGG)(10)AGG(CGG)(19) and (CGG)(9)AGG(CGG)(12) AGG(CGG)(9), possibly predisposed for expansion, were identified in the data set. When alleles larger than 34 CGG were investigated, comparing the length of 3' uninterrupted CGG triplets (uCGG), we found that alleles associated with haplotype 2-1 and 6-4 contain significantly longer stretches of uCGG than alleles associated with haplotype 7-3. Thus, the data support that (CGG)(n) instability is correlated to the length of uCGG.

Alleles↗
PubMed1992

Molecular analysis of HLA-DRB1*08/12 alleles: identification of two additional alleles.

A nonradioactive oligotyping method that takes advantage of selective amplification using the polymerase chain reaction (PCR) and oligonucleotide probe hybridization was developed to distinguish all reported HLA-DRB1*08/12 alleles. Selective amplification was achieved using a primer complementary to the sequence encoding YSTGECY at positions 10-16 in the first hyperpolymorphic region (HPMR). This selective amplification of the HLA-DRB1*08/12 subset of alleles provides a refinement in HLA oligotyping that permits unambiguous oligotyping of many heterozygotes that cannot be resolved using less selective amplification alternatives. The amplified DNA was hybridized with a panel of then digoxigenin-labeled probes to resolve oligotypes that correspond to all reported HLA-DRB1*08/12 alleles. Oligotyping of HLA-DRB1*08/12 samples revealed two previously unknown HLA-DRB alleles. One allele, DRB1*0805, differs from DRB1*0801 by a leucine to alanine substitution at position 74. This allele is of particular interest because it is very similar to HLA-DRB1*08 alleles (YSTGECY and lack of an associated HLA-DRB3 gene), but it lacks leucine at position 74, which is characteristic of all previously reported DRB1*08 alleles. The second HLA-DRB1*08 allele, DRB1*0804, differs from DRB1*0802 by a glycine to valine substitution at position 86.

Alleles↗