Evidence for HL-A-linked genes in "juvenile" diabetes mellitus.

HL-A typing of 150 patients who had developed diabetes mellitus by the age of 30 years showed a significant association with HL-A 8 and W 15. The HL-A genotypes were determined in 17 families in which two or more siblings had this type of diabetes. The zygotic assortment of HL-A haplotypes was found to be significantly disturbed from the expected random pattern, with a reduction in the number of siblings showing no identical haplotypes and an appreciable increase in the number with both haplotypes identical. This appears to be most consistent with the presence of a gene or genes pre-disposing to this type of diabetes at a locus closely linked to the HL-A chromosomal loci. This locus appears to have a fundamental role in the susceptibility to juvenile diabetes.     

Possible linkage of HL-A and GLO

Summary In 21 informative families with 60 children, a possible linkage between HL-A and GLO was found (recombination fraction approximatively 0.15). The sequence of the loci on chromosome 6 might be GLO, HL-A, PGM₃, MNSs.

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Zusammenfassung Koppelungsuntersuchungen bei 21 informativen Familien mit 60 Kindern zeigten, daß die Loci HL-A und GLO möglicherweise gekoppelt sind (Rekombinationsfrequenz ca. 15%). Die Reihenfolge der Loci am Chromosom 6 kann wie folgt angenommen werden: GLO, HL-A, PGM₃, MNSs.

     

Analysis for possible linkage between the loci for the Waardenburg syndrome and various blood groups and serological traits

Summary Linkage was sought between the Waardenburg syndrome locus and the loci for various genetic markers segregating in a single family. Close linkage was shown to be unlikely with the loci for Rh, MN, Ag, ADA, HL-A, and Gm. Evidence obtained is consistent with the possibility of linkage with the locus for the AB0 blood group, but study of additional families will be required to provide a definite answer.

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Zusammenfassung In einer Familie wurde nach Genkopplung zwischen dem locus für das Waardenburg-Syndrom und verschiedenen genetischen Markern gefahndet. Für die loci für Rh, MN, Ag, ADA, HL-A und Gm wurde enge Kopplung als unwahrscheinlich erwiesen. Dagegen lassen die Daten die Annahme einer Kopplung mit dem AB0-locus zu. Für eine endgültige Entscheidung müßten zusätzliche Familien untersucht werden.

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Research supported by grants No. HD 04134, HL 09011, and HL 08630 from the National Institutes of Health.     

The zygosity in the human HL-A transplantation system

Summary If by serological methods of tissue typing one antigen only is detected in one or both of the loci LA and 4 of the histocompatibility system HL-A, the question arises whether it is homozygous or heterozygous. The probability thereof is calculated. It depends on the frequency of the known and unknown genes in the HL-A-system. If e.g. the HL-A type of an examinee is 1,3,8 this subject could be homozygous 1,3,8,8 or heterozygous (with an unknown antigen X) 1,3,8,X. The frequencies of homozygous and heterozygous individuals are calculated in all possible combinations of the LA and 4 loci. The results justify always for both the LA-and 4 locus the assumption of heterozygosity, with the one exception that the gene HL-A 2 is under consideration. There the calculations result in a value of 49% for homozygosity (2,2) and 51% for heterozygosity (2,X). Neither alternative is in this case essentially more probable.For transplantations generally heterozygosity can be assumed — with the exception of HL-A 2 — and therefore the minor grade of histocompatibility.National Blood Group Reference Laboratory — WHO (Director: Prof. Dr. P. Speiser)     

Characterization of a serum inhibitor of MLC reactions. III. Specificity: HL-A-related antibodies.

A mixed leukocyte culture (MLC)-inhibitory serum from a healthy multipara, JH, has been characterized with regard to the specificity of its inhibitory antibody. When added directly to MLC, JH serum will inhibit most combinations. However, when lymphocytes intended as responder or stimulator cells in MLC were preincubated with this serum, the specificity narrowed considerably. Four groups of lymphocyte donors were recognized, depending upon whether their lymphocytes were inhibited as responders, as stimulators, as both, or as neither. Absorptions of inhibitory activity, followed by assay of the absorbed sera in pretested MLC combinations, yielded reliable data for determining which donors' cells shared pertinent antigens. An association of MLC inhibition by JH serum with the HL-A types of the involved lymphocytes was observed and these relationships are summarized in Table 4. The three HL-A specificities identified, W19, W29, and 12, correspond with the HL-A typing of the husband of the serum donor. Various cell types absorbed relevant inhibitory activity (against responder and stimulator functions) in the following order of efficiency: LCL cells, B lymphocytes, T lymphocytes, fibroblasts, and erythrocytes. When the above three HL-A specificities were removed by absorption, the serum was no longer inhibitory in any combinations. Whether the inhibitory activity of JH serum is directly related to anti-HL-A antibodies or to antibodies against closely related MLR determinants will depend to a large extent upon the degree of linkage disequilibria found between W19, W29, and 12 antigens and the MLR locus.     

Immunogenetic aspects of a canine breeding colony

A colony of dogs was expanded by selective breeding to study the immunogenetic determinants coded for by the major histocompatibility complex (DLA). Polymorphic determinants were identified by alloantisera specific for DLA-A and B loci antigens and by the mixed lymphocyte culture (MLC) which defined alleles at the D locus. Thirteen families totaling 58 offspring were produced and typed for allelic determinants coded for by each of the three gene loci. Allelic segregation in a codominant manner occurred as expected and a recombinant between the A and B loci was detected. A number of animals were homozygous at one or more loci, thus providing genetically standardized animals as a source of typing cells, antigens, and sera to further study the immunogenetic details of DLA and for in vivo studies in transplantation biology.     

Human MHC class III genes, Bf and C4. Polymorphism, complotypes and association with MHC class I genes in the Finnish population

Electrophoretically detected genetic polymorphism of human MHC class III genes, factor B (Bf) and complement C4A and C4B, was studied in the Finnish population. Bf alleles were determined in a panel of sera from 70 unrelated individuals. The common Bf alleles, Bf*S and Bf*F, had frequencies of 73% and 26%, respectively. Only in 1 individual was another allele, Bf*F1, detected. The frequencies of the C4A and C4B alleles were based on studies of 254 unrelated individuals. In this panel, five different alleles were detected at the C4A locus and four at the C4B locus. At both loci an allele without a gene product, i.e. a 'null' allele, was observed with high frequency, 11% for C4A 'null' and 17% for C4B 'null'. The association of complotypes to HLA haplotypes was analyzed in 70 chromosomes. The most common combination, defined by class I and class III alleles, was HLA-B7-S31 (13%), followed by HLA-B35-F20 (8.4%) and HLA-B8-S03 (7.1%). Some HLA-B specificities, for example B15, B27 and B40, were associated with a variety of complotypes. The importance of complotyping in HLA genetics is discussed.     

Alpha 1 antitrypsin deficiency: a study of the relationship between the Pi system and genetic markers.

Twenty-four members (4 generations) of a family with alpha 1 antitrypsin deficiency were studied in an attempt to determine the chromosomal location of the Pi system locus. Three alpha 1 antitrypsin alleles (PiM, PiI, and PiZ) and five phenotypes (MM, MZ, MI, IZ, and ZZ) were detected in family members. The quinacrine fluorescent banding technique was successfully utilized to reveal eight polymorphic chromosomal markers in family members. Eight red cell antigens and HL-A antigens were identified for each family member. No linkage between the Pi system and chromosomal markers, four polymorphic red cell antigens, and HL-A antigens was detected. On the basis of this family study, the Pi locus as defined by alpha 1 antitrypsin deficiency does not appear to be on chromosomes 2, 3, 13, 14, 21, or 22 within measurable distance of the markers used.     

Genetic analyses of a putative Mutator-induced deletion involving the blue fluorescent1 (bf1) and brown midrib4 (bm4) loci in maize.

A putative Mutator-induced alteration (isolate) involving the blue fluorescent1 (Bf1) and the brown midrib4 (bm4) loci is described. This isolate (Bf1-Mu-044-4) was one of the blue fluorescent1 mutants in a large experiment designed to produce Mutator-induced mutations involving this locus. Evidence is presented supporting the conclusion that this alteration deletes all or part of both the bf1 and bm4 loci. The isolate is infrequently transmitted through the pollen, but is more readily transmitted through the egg, although at less than the expected frequency of 50% for a simple mutation. Heterozygotes of this isolate with the bm4-R allele have brown midribs. These brown midrib plants are shorter than homozygous bm4-R plants and approximately 50% of these Bf1-Mu-044-4/bm4-R heterozygotes do not reach maturity. One putative Mutator-induced bm4 mutation, which occurred in the course of the analysis of the Bf1-Mu-044 isolate, is described. Key words : Mutator, deletion, bf1-bm4 loci.     

Microsatellite isolation, linkage group identification and determination of recombination frequency in the peach-potato aphid, Myzus persicae (Sulzer) (Hemiptera: Aphididae)

Fifteen polymorphic microsatellite markers were used to establish linkage groups and relative rates of recombination in male and female Myzus persicae (Sulzer) (Hemiptera: Aphididae) (peach-potato aphid). We cloned nine markers from M. persicae and for these we report primer sequences and levels of allelic diversity and heterozygosity in four Australian M. persicae populations. Of the remaining six loci, four loci, also cloned from M. persicae, were obtained from G. Malarky (Natural History Museum, London) and two loci from Sitobion miscanthi were used. Additionally, the primer sequences of locus M77, a locus monomorphic in M. persicae but polymorphic in the closely related Myzus antirrhinii, are presented. Eleven of the 15 polymorphic markers were autosomal and four were X-linked. A linkage analysis was performed on a European pedigree of aphids containing five families with between seven and 11 offspring each. There was no linkage between any loci in females. In males, several pairwise comparisons yielded no recombinant offspring. With the exception of locus M40, these observations were supported in a linkage analysis performed on larger families produced from Australian M. persicae crosses. Locus M40 showed segregation consistent with involvement in a translocation between autosomes 1 and 3 in European samples but not in the Australian samples. From the Australian crosses we report an absence of recombination in males but high recombination rates in females. One X chromosome and four autosomal linkage groups were identified and tentatively assigned to chromosomes. The relevance of achiasmate meiosis to the evolution of sex is discussed.     

Structural polymorphism of murine factor B controlled by a locus closely linked to the H-2 complex and demonstration of multiple alleles

New alleles of murine factor B (Bf) protein were demonstrated. When ethylenediaminetetraacetic acid (EDTA)-plasmas from inbred and wild mice were analyzed by isoelectro-focusing (IEF) and immunofixation, murine Bf proteins were visualized as distinct protein bands in all mice tested. Four variants of murine Bf could be demonstrated in a large number of tested mice: Bf 1 (isoelectro-focusing point (P.I.) range of 5.8–6.1) exemplified by B10 and B10.BR, Bf 2 (P.I. range of 5.8–6.0) exemplified by B10.MOL (OHM), Bf 3 (P.I. range of 5.6–5.9) exemplified by B10.MOL (TEN2) and Mus musculus (Mus m.) subspecies Chc, Bf4 (P.I. range of 6.0–6.3) exemplified by Mus m. subspecies Shh. The genetic linkage between S locus and Bf locus was studied with two backcross progenies — [B 10.BR × (B10.BR × Mus m. subspecies Chc)F₁] and [B 10.BR × (B10.BR × Mus m. subspecies Shh)F₁]. Totally, 256 backcross progenies were typed for Bf type and for Ss type (plasma level of the fourth complement protein regulated by S locus). The results indicated that murine Bf was controlled by a single codominant locus located close to the H-2 complex because no mouse showing recombination between Bf locus and S locus was found.     

Mapping of the linkage group GLO-Bf-HLA-B,C, A-PGM3

Summary This study confirms close linkage for the GLO-Bf-HLA-B,C,A complex, and proves linkage between the MHC loci and PGM₃. For GLO-PGM₃ and Bf-PGM₃, respectively, loose linkage seems to be likely, and close linkage can be excluded. Our mapping data on chromosomle 6 favor the hypothesis that the PGM₃ locus is situated on the HLA-A side of the MHC complex. Yet fine-structure mapping should be confirmed only by segregation analyses in crossover families by testing simultaneously all of the relevant marker loci within uniform family material.     

PGM<Subscript>3</Subscript>: HL-A is Another Linkage in Man

EARLIER work has suggested the existence of a linkage between the histocompatibility region, HL-A and the phosphogluco-mutase locus, PGM₃. We have now produced more convincing evidence after investigating a further set of families.     

Multipoint linkage analysis of loci in the proximal long arm of the human X chromosome: application to mapping the choroideremia locus.

Choroideremia (McK30310), an X-linked retinal dystrophy, causes progressive night blindness, visual field constriction, and eventual central blindness in affected males by the third to fourth decade of life. The biochemical basis of the disease is unknown, and prenatal diagnosis is not available. Subregional localization of the choroideremia locus to Xq13-22 was accomplished initially by linkage to two restriction-fragment-length polymorphisms (RFLPs), DXYS1 (Xq13-q21.1) and DXS3 (Xq21.3-22). We have now extended our linkage analysis to 12 families using nine RFLP markers between Xp11.3 and Xq26. Recombination frequencies of 0%-4% were found between choroideremia and five markers (PGK, DXS3, DXYS12, DXS72, and DXYS1) located in Xq13-22. The families were also used to measure recombination frequencies between RFLP loci to provide parameters for the program LINKMAP. Multipoint analysis with LINKMAP provided overwhelming evidence for placing the choroideremia locus within the region bounded by DXS1 (Xq11-13) and DXS17 (Xq21.3-q22). At a finer level of resolution, multipoint analysis suggested that the choroideremia locus was proximal to DXS3 (384:1 odds) rather than distal to it. Data were insufficient, however, to distinguish between a gene order that puts choroideremia between DXS3 and DXYS1 and one that places choroideremia proximal to both RFLP loci. These results provide linkage mapping of choroideremia and RFLP loci in this region that will be of use for further genetic studies as well as for clinical applications in this and other human diseases.     

Confirmation of the linkage HL-A/PGM3.

In a series of 42 families with 101 children the linkage between HL-A and PGM3 could be confirmed (most likely recombination fraction for male equals 0.15).     

Haplotype analysis of the linkage group HLA-A: HLA-B: Bf in Japanese

Summary Three hundred four HLA-A: HLA-B: Bf haplotypes of the Japanese population as deduced by family analysis are described. Several linkage disequilibriums were observed in the following two-factor haplotypes: HLA-A and HLA-B, HLA-A and Bf, and HLA-B and Bf. Positive linkage disequilibriums between HLA-A and HLA-B noted in the present study seem to be Japanese specific when compared with the results obtained from other ethnic groups reported so far.The striking finding is that three HLA-B: Bf haplotypes, namely B12-Bf ^F , B15-Bf ^F ,and B7-Bf ^S ,are common and show linkage disequilibrium in both Japanese and European Caucasians (German). This finding not only confirms the proximity of the HLA-B and Bf loci but also suggests that the interaction of the two genes plays an important role in the maintenance of stable linkage disequilibrium.This study was partially supported by a Scientific Research Grant (No. 337023) from the Ministry of Education, Science, and Culture of JapanAddress until August, 1981: Dept. Immunohaematology, Bldg. 23, University Hospital, Leiden, The Netherlands     

Die Genetik des HL-A-Systems

Zusammenfassung Die Analyse der Gewebstypen von 300 nichtverwandten Personen der österreichischen Bevölkerung und von 110 Familien mit 381 Kindern, die erstmals in diesem Umfang vorgenommen wurde, bestätigt die formalgenetische Hypothese der Vererbung des HL-A-Systems. Dieses System wird über 2 eng gekoppelte Loci eines Autosoms, den LA- und den 4-Locus, gesteuert, wobei an beiden Loci multiple Allelie vorliegt und die einzelnen Merkmale einen dominanten Erbgang aufweisen. Die Genfrequenzen der HL-A-Gene und die Haplotypenfrequenzen wurden errechnet. Die Häufigkeit der Rekombinationen innerhalb des HL-A-Systems wurde mit 0.38% ermittelt. Es wurde kein Anhaltspunkt für eine Selektion bei der Vererbung der HL-A-Merkmale gefunden. Basierend auf den formalgenetischen Untersuchungen wurde die Brauchbarkeit (Vaterschaftsausschlußchance) und die Wertigkeit (Beweiswert) des HL-A-Systems diskutiert. Zur Berechnung der Vaterschaftsausschlußchance wurde eine Formel, die das Koppelungsungleichgewicht der 2 Loci des HL-A-Systems berücksichtigt, entwickelt.

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The genetics of the HL-A-System A study of population and families and its application in paternity cases

Summary 300 unrelated individuals of the Austrian population and 110 families with 381 children have been typed by means of the microlymphocytotoxic test. The analysis of the results of this study shows that the HL-A-antigens are governed by 2 closely linked loci of an autosomal chromosome, the LA-locus with the genesHL-A1, HL-A2, HL-A3, HL-A9, HL-A10, HL-A11, Ba ^*,Li and the 4-locus with the genesHL-A5, HL-A7, HL-A8, HL-A12, HL-A13, R ^*,BB, FJH, MaKi, AA, MaPi, LND andET. Further, it was found that there must exist more antigens, which are not yet serologically detectable, within both loci. The genes of the HL-A-system are inherited as codominant characters. The gene frequencies of the individual determinants and the haplotype frequencies are calculated. The recombination frequency within the HL-A-system was found to be 0.38%. No evidence with regard to a selection could be recognized analysing the inheritence of the HL-A-genes. Basing on the genetical analysis, the efficiency of the HL-A-system in paternity cases is discussed. The chance of exclusion in false accusations of paternity was calculated by means of a formula developed for this purpose, which takes into account the linkage disequilibrium between the LA- and the 4-locus, and was found to be approximatively 76%.

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National Blood Group Reference Laboratory (WHO), National Tissue Typing Reference Laboratory (Council of Europe).     

Probable genetic linkage between a locus for human urinary pepsinogen and the HL-A loci.

The genetic basis of familial variation in the relative intensities of human urinary pepsinogen isozymes is not completely clear from family studies. An investigation of the linkage relationships of pepsinogen isozyme 5, considering only segregation for the presence or absence of Pg 5, yields a peak lod score of 4.1 at theta = .1 for linkage with HL-A1 or HL-A2. Added to data from segregation interpreted according to a scheme proposed for the inheritance of intensity differences in Pg 5, the peak lod score becomes 3.0 at theta = .2. Data derived from the segregation of pepsinogen isozyme 4, possibly determined by an allele to that controlling the presence or absence of Pg 5, further reduces the total lod score at theta = .2 to 2.9. The results indicate probable linkage between a locus for urinary pepsinogen and the HL-A loci, but are insufficient to permit any conclusion concerning possible heterogeneity in the linkage relationships of Pg 4 and Pg 5 to HL-A.     

Genetics of the Tubulin Gene Families of Physarum

The organization of the alpha- and beta-tubulin gene families in Physarum was investigated by Mendelian analysis. Restriction endonuclease-generated DNA fragments homologous to alpha- and beta-tubulin show length polymorphisms that can be used as markers for genetic mapping. Analysis of meiotic assortment among progeny of heterozygotes allowed alpha- and beta-tubulin sequence loci to be defined. There are four unlinked alpha-tubulin sequence loci (altA, altB, altC and altD) and at least three unlinked beta-tubulin sequence loci (betA, betB and betC). The alpha-tubulin loci are not linked to the beta-tubulin loci. --Segregation of tubulin sequence loci with respect to ben mutations that confer resistance to antitubulin benzimidazole drugs was used to investigate whether any members of the alpha- or beta-tubulin gene families are allelic to ben loci. The beta-tubulin sequence locus betB is allelic to the resistance locus benD, the betA locus is probably allelic to benA and the alpha-tubulin sequence locus altC may be allelic to benC. The molecular implications of benzimidazole resistance phenotypes when only one of the expressed beta-tubulin gene family members mutates to drug resistance are discussed in relation to tubulin function.     

A combined segregation and linkage analysis of insulin-dependent diabetes mellitus.

In an effort to clarify the mode of inheritance of insulin-dependent diabetes mellitus (IDDM), a total of 230 nuclear families with pointers were analyzed using the computer program COMBIN. Each family was ascertained without deliberate selection for multiplex families, and most families were completely typed for HLA-B, HLA-DR, and properdin factor B (Bf). There were 186 families with normal parents, 44 families with one affected parent, and no families with two affected parents. The computer program COMBIN evaluates evidence for a major locus of disease susceptibility, linkage of the major locus to a known genetic marker locus, linkage disequilibrium between the marker haplotypes and disease susceptibility, pleiotropic effects, and presence of an unlinked modifier. The parameters of COMBIN are T, Q, and D, representing the displacement, gene frequency of the IDDM allele, and dominance, respectively, of the major locus--and TM, QM, and DM being the analogous parameters of the modifier. In addition, the recombination fraction, theta, between the IDDM locus and HLA as well as the coupling frequencies are estimated. Finally, COMBIN simultaneously performs segregation and linkage analysis, with the optimal model being adjusted by the fit to the haplotype sharing distribution of IDDM. The results of these analyses indicated that the best-fitting genetic model of diabetic susceptibility appears to be a single major locus with near recessivity on a scale of standardized genetic liability, with gene frequency of the IDDM susceptibility allele of approximately 14%. In addition, the recombination fraction between the major locus and HLA is zero in all models; that is, for the B-BF-DR haplotype, the IDDM locus is tightly linked, probably (according to data from previous studies) to HLA-DR. Information determined by magnitude of coupling frequencies indicated that there is significant positive linkage disequilibrium with the haplotypes B8-BfS-DR4 and B15-BfS-DR4, significant negative linkage disequilibrium with B7-BfS-DR2, and intermediate disequilibrium for B8-BfS-DR3, B18-BfF1-DR3, and B40-BfS-DR4. Significant evidence in favor of an unlinked (to HLA) modifier (either single major locus or polygenes) could not be demonstrated. In conclusion, genetic susceptibility to IDDM appears to be most consistent with a single major locus with near recessivity that is tightly linked to HLA.