Identity-by-descent analysis using all genotype solutions.
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Alleles↗
Biomedical subjects
M P Baur
Publications and source records attributed to M P Baur.
Preliminary ordering of multipoint linkage data.
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Chromosome Mapping↗
Family studies in scleroderma (systemic sclerosis) demonstrating an HLA-linked increased chromosomal breakage rate in cultured lymphocytes.
An increased chromosomal breakage rate (ICBR) was found in 27 of 28 patients with scleroderma (systemic sclerosis, SS) - 5 with the syndrome including calcinosis cutis, Raynaud phenomenon, esophagus hypomotility, sclerodactyly and telangiectasia (CREST), 4 incomplete CREST, 1 overlapping syndrome, 18 progressive systemic sclerosis (PSS). Not only the patients, but also about half of their first-degree relatives showed an increased chromosomal breakage rate (more than 5 breaks per 100 metaphases). This character segregated as a dominant marker in nine families of scleroderma patients. In the six informative of the nine families, the ICBR trait showed close linkage with the HLA region on chromosome 6 (total lod score 5.5 at theta = 0). In these families, ICBR was predominantly observed in linkage with HLA haplotype A1, Cw7, B8, C4AQ0B1, DR3 which is frequently observed in autoimmune diseases. The nature of the agent inducing chromosomal breakage in cultured lymphocytes of some, but not all family members of scleroderma patients remains to be clarified.
Cells, Cultured↗
Aberrant MN bloodgroup inheritance in a German family: a 'silent' allele?
By means of extensive serogenetic testing of a family, RFLP analysis and biostatistic evaluation we present evidence for the rare transmittance of a 'silent' information at the MN blood group locus in a Caucasian family.
Adolescent↗
Genetic heterogeneity, modes of inheritance, and risk estimates for a joint study of Caucasians with insulin-dependent diabetes mellitus.
From 11 studies, a total of 1,792 Caucasian probands with insulin-dependent diabetes mellitus (IDDM) are analyzed. Antigen genotype frequencies in patients, transmission from affected parents to affected children, and the relative frequencies of HLA-DR3 and -DR4 homozygous patients all indicate that DR3 predisposes in a "recessive"-like and DR4 in a "dominant"-like or "intermediate" fashion, after allowing for the DR3/DR4 synergistic effect. Removal of DR3 and DR4 reveals an overall protective effect of DR2, predisposing effects of DR1 and DRw8, and a slight protective effect of DR5 and a predisposing effect of DRw6. Analysis of affected-parent-to-affected-child data indicates that a subset of DR2 may predispose. The non-DR3, non-DR4 antigens are not independently associated with DR3 and DR4; the largest effect is a deficiency of DR2, followed by excesses of DR1, DRw8, and DRw6, in DR4 individuals, as compared with DR3 individuals. HLA-B locus distributions on patient haplotypes indicate that only subsets of both DR3 and DR4 are predisposing. The presence or absence of Asp at position 57 of the DQ beta gene, recently implicated in IDDM predisposition, is not by itself sufficient to explain the inheritance of IDDM. At a minimum, the distinguishing features of the DR3-associated and DR4-associated predisposition remain to be identified at the molecular level. Risk estimates for sibs of probands are calculated based on an overall sibling risk of 6%; estimates for those sharing two, one, or zero haplotypes are 12.9%, 4.5%, and 1.8%, respectively. Risk estimates subdivided by the DR type of the proband are also calculated, the highest being 19.2% for sibs sharing two haplotypes with a DR3/DR4 proband.
Adolescent↗
A comprehensive search for segregation distortion in HLA.
Segregation distortion, the non-Mendelian segregation of gametes, has been well documented among diverse groups of organisms. These cases are characterized by extreme segregation ratios found only in males. Previous reports have suggested the existence of segregation distortion operating in the HLA system of humans, a tightly linked complex of genes which regulates the immune system. In mice, some alleles of the T/t complex, which is linked to H-2 (the HLA homologue of mice), cause extreme segregation distortion in wild mice populations. Here we report on the examination of a large body of pedigree data on non-diseased families, scored for the alleles of five HLA region loci. We searched for segregation distortion on the basis of five different models of inheritance: allelic, haplotypic, genotypic, diffuse occurrence in families, and autosomal effects on the sex ratio. There was no clear evidence for segregation distortion. In particular, the possibility of extreme levels of segregation distortion was firmly rejected in the populations examined, thus reducing the likelihood of common distortion-causing HLA associated haplotypes in our species.
Alleles↗
Chromosomal assignment of human cytochrome P-450 (debrisoquine/sparteine type) to chromosome 22.
In order to determine on which chromosome the gene controlling human cytochrome P-450 (debrisoquine/sparteine type) is located a linkage study of polymorphic sparteine oxidation (PSO) to various polymorphic markers was carried out. Positive information for linkage between PSO and the P1 blood group was obtained with a maximal LOD-score of LOD = 3.35 for both male and female recombination fraction estimates of theta m = theta f = 0.0. The P1 blood group has been recently mapped to the long arm of chromosome 22. Thus it can be concluded that the gene controlling human cytochrome P-450 (debrisoquine/sparteine) is situated on the long arm of chromosome 22 in close vicinity to P1.
Alleles↗
Genetic analysis workshop IV: insulin dependent diabetes mellitus--summary.
The Insulin Dependent Diabetes Mellitus (IDDM) study was one of the topics of Genetic Analysis Workshop IV (GAW IV) discussed October 7 - 8 at a pre-workshop meeting and presented October 9, 1985 at the American Society of Human Genetics meeting in Salt Lake City. The aim of the study was to have different groups analyze an identical body of real data in order to compare their analytical methods and the results based on their different approaches. This summary describes the available datasets and presents the main results of the nine participating groups. The detailed descriptions of analytical methods and results are presented in the individual papers following this overview. Although differing analytical methods were used there were no discrepancies regarding the interpretation of the data. Whereas the presented gametic associations were well established before, the real gain of this workshop was the unanimous result that the recessive 2-allele-model with incomplete penetrance had to be rejected and at least a 3-allele-model with differing susceptibility alleles and differing penetrances for heterozygotes and homozygotes had to be postulated for the transmission of IDDM.
Alleles↗
HLA-DR effects in a large German IDDM dataset.
DR4 and DR3 are in strongest linkage disequilibrium with IDDM susceptibility genes, and DR1 demonstrates a lesser degree of positive disequilibrium. DR3/DR4 heterozygotes have the highest risk. The DR1 increase occurs almost exclusively in DR4/DR1 heterozygotes, suggesting that DR1 may be in disequilibrium with the same susceptibility gene as DR3. Homozygotes for DR4 and especially DR3 have a higher risk than heterozygotes of either with DRX. GLO-2 is increased in diabetic haplotypes carrying DR4, DR3 or DR1.
Alleles↗
Family analysis for IDDM--HLA. Comparison of the two-allele model versus the three-allele model.
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Alleles↗
Extended polymorphism of the human esterase D isozyme system: description of a "new" allele EsD*11.
Using "new" techniques (malic acid thin layer agarose gel electrophoresis and/or isoelectric focusing), the polymorphism of the human red cell isozyme system esterase D (ESD) was shown to be extended. We report the gene frequencies observed among 312 unrelated Caucasian individuals living in the Düsseldorf area. The finding of a "new" allele at the ESD locus is also described.
Alleles↗
Homogeneity of HLA-DQ,DR phenotypes in lymphocyte subsets of normal individuals.
The study was performed to evaluate the association of HLA-DQ and DR antigens with the composition of peripheral blood lymphocytes. B cells, T cells, and T subsets were enumerated in 200 normal individuals by indirect immunofluorescence microscopy using the monoclonal antibodies OKT3, OKT4, OKT8, and OKIa1. Results were related to the HLA-DQ,DR phenotypes of the investigated population. No significant correlation between any of the lymphocyte subsets and of the HLA-DQ,DR antigens was found.
Antibodies, Monoclonal↗
Human C81 (alpha-gamma) polymorphism: detection in the alpha-gamma subunit on SDS-PAGE, formal genetics and linkage relationship.
The molecular basis of human C81 (alpha-gamma) polymorphism could be elucidated by immunoprecipitation of human C81 allotypes and separation of the alpha-gamma and beta subunits on sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) under nonreducing conditions. If the C8 molecules were completely reduced, C81 polymorphism was no longer detectable on SDS-PAGE. It is concluded that C81 variation depends on charge rather than molecular weight differences. Four C81 allotypes, the common A and B and two rare allotypes provisionally named A2 and B1, could be distinguished. The rare allotype A1 as detected by isoelectric focusing with subsequent C8 (alpha-gamma)-dependent functional overlay could no longer be visualized on SDS-PAGE. This allotype may therefore be elicited only in the intact C8 molecule. The beta-chain polymorphism named C82, probably also reflecting charge variation of the C8 molecule, could not be detected yet on SDS-PAGE. The distributions of C81 phenotypes and their respective allele frequencies were in good agreement with previously reported data. In the study of 30 families with 100 offspring, no deviation from the rule of at least four codominant alleles at one genetic locus was found. Linkage between C81 gene(s) and PGM1a encoded on chromosome 1 could be confirmed. The following estimates were obtained: (formula; see text) with S theta being the standard error of the maximum likelihood estimate theta. The new technique for allotyping human C81 at the subunit may provide a new tool for the differentiation of qualitative and quantitative variation of the eighth component of human complement.
Alleles↗
Contrasting evolutionary histories among tightly linked HLA loci.
Genes comprising the major histocompatibility complex (MHC) play a central role in governing the immune response of vertebrates. A great deal of information has been revealed on the molecular biology and physiology of these loci, but three features-the high polymorphism, tight linkage among the loci, and the nonrandom association of alleles-make the system of particular interest from the perspective of population genetics. Information on the dynamic evolutionary forces that have acted on a locus can be inferred from the number and distribution of alleles that it carries. Ten loci from the HLA region of the human MHC, each sampled from several different populations, have been examined for departures from the expected value of homozygosity under the condition of selective neutrality. The homozygosities of five class I and II loci that code for membrane glycoproteins, HLA-A, -B, -C, -DR, and -DQ, and of glyoxylase I (GLO) were significantly less than the neutrality expectations. This suggests the presence of some form of balancing selection. In spite of being closely linked, in fact, located between the class I and class II histocompatibility loci, the homozygosities of the four class III or complement loci C2, Bf, C4A, and C4B, which are detected by electrophoresis, were indistinguishable from, or exceeded, that expected under neutrality. Although this conforms to the suggestion that, in general, electrophoretic variants are neutral, because of the tight linkage to loci demonstrating a history of selection, it is possible that the mechanism for generating variation in the class III loci may be different from that of the class I and class II loci.
Alleles↗
No fallacies in the formulation of the paternity index.
In a recent publication, Li and Chakravarti claim to have shown that the paternity index is not a likelihood ratio. They present a method of estimating the prior probability of paternity from a sample of previous court cases on the basis of exclusions and nonexclusions. They propose calculating the posterior probability on the basis of this estimated prior and the test result expressed as exclusion/nonexclusion. Their claim is wrong--the paternity index is a likelihood-ratio, that is, the ratio of the likelihood of the observation conditional on the two mutually exclusive hypotheses. Their proposed method of estimating the prior has been long known, has been applied to several samples, and is inferior (in terms of variance of the estimate) to maximum likelihood estimation based on all the phenotypic information available. Their proposed "new method" of calculating a posterior probability is based on the use of a less informative likelihood ratio 1/(1-PE) instead of Gürtler's fully informative paternity index X/Y (Acta Med Leg Soc Liege 9:83-93, 1956), but is otherwise identical to the Bayesian approach originally introduced by Essen-Möller in 1938.
Humans↗
No interaction between HLA and immunoglobulin IgG heavy chain allotypes in early onset type 1 diabetes.
Immunoglobulin heavy and light chain genes are often discussed as susceptibility genes for insulin dependent (type 1) diabetes mellitus (IDDM) in addition to HLA-DR3 and DR4. Accordingly we analysed 175 unrelated patients for an interaction between immunoglobulin allotype antigens (Gm) and HLA. While DR3 and DR4 antigens and DR3/DR4 heterozygotes occur significantly more often among diabetics than among normal controls, their Gm allotype frequencies are very similar. An interaction between special Gm allotypes and phenotypes, on the one side, and DR3, DR4 or DR3, 4 on the other side could not be demonstrated.
Diabetes Mellitus, Type 1↗
Gene and haplotype frequencies of the fourth component of complement (C4) in type 1 diabetics and normal controls.
C4 gene and haplotype frequencies were calculated from phenotype data of 380 unrelated Caucasian patients with insulin dependent (type 1) diabetes mellitus and were compared with analogous frequencies of 382 unrelated healthy Caucasian individuals. In diabetics, a significantly increased frequency of the rare allele C4B 3 (p less than 10(-7] and of the silent alleles C4A Q0 (p less than 10(-7] and B Q0 (p less than 0.002) was observed. Accordingly, insulin dependent diabetes is associated with partial C4 deficiency, which may contribute to the pathogenesis of the disease.
Alleles↗
Third order linkage disequilibrium.
For third order linkage disequilibrium there is a constraint on the maximum value the disequilibrium can take, given pairwise disequilibria values and allele frequencies. As distinct from second order disequilibrium (considered in the context of a two locus model) there is also in some cases a constraint on the minimum value. The appropriate procedures to determine these maximum and minimum values are given, as well as numerical values utilizing HLA data.
Alleles↗