Expression of Maternally and Embryonically Derived Hypoxanthine Phosphoribosyl Transferase (Hprt) Activity in Mouse Eggs and Early Embryos

X-chromosome activity in early mouse development has been studied by a gene dosage method that involves measuring the activity level of the X-linked enzyme hypoxanthine phosphoribosyl transferase (HPRT) in single eggs and embryos from XO females and from females heterozygous for In(X)1H, a paracentric inversion of the X chromosome. The HPRT activity in oocytes increased threefold over a 24-hr period beginning after ovulation. Afterward, the activity plateaued in unfertilized eggs but continued to increase for at least 66 hr in presumed OY embryos. Both before and after ovulation, the level of activity in unfertilized eggs from In(X)/X females was twice that from XO females, and the distributions of activity in eggs for both sets of females remained unimodal. Beginning with the two-cell stage, distributions of activity for embryos from In(X)/X females were trimodal, which is evidence for embryonic activity. It is proposed that activation of a maternal mRNA or proenzyme is responsible for the HPRT activity increase in oocytes and early embryos and is supplemented by dosage-dependent activity of the embryonic Hprt gene as early as the two-cell stage.     

The effects of temperature and aging of Drosophila males on the frequencies of XXY and XO progeny

Drosophila males of the constitution y/y⁺Y were aged for 10 days at 25° and 10° and then mated daily for 13 days at 25° to virgin yw (XX) females. The total frequencies of exceptional XXY and XO offspring to which the father contributed either (a) both an X and a Y chromosome, or (b) neither of them, were highly significantly more numbers in the 7th- and 8th-day broods of the 10° than the 25° pre-aged series. In all experiments the frequency of paternal XO exceptions was greatly in excess of that of XXY exceptions. The data on brood patterns suggest that the stages most sensitive to the production of paternal exceptions by pre-aging at 10° are those of the primary spermatocytes. The same stages are also sensitive to low temperature induction of temporarily low fertility.     

Cell lineage restrictions in the genital disc ofDrosophila revealed byMinute gynandromorphs

Summary The genital imaginal disc ofDrosophila differentiates the terminalia, i.e. the genitalia and analia, of both sexes. It represents a composite anlage, containing a female genital primordium, a male genital primordium and an anal primordium. In normal males and females, only one of the two genital primordia differentiates; the other is developmentally repressed. Therefore, cell-lineage relationships between the male and female genital primordia can only be studied in sexual mosaics which differentiate female and male cells. We producedMinute (M)non-Minute(M⁺) gynandromorphs and selected those with sexually mosaic terminalia for a cell-lineage analysis. In these mosaics, either the male (XO) or female (XX) cells wereM ⁺ and thus had a growth advantage. The differential growth rates served as a tool to detect clonal restrictions. In control gynandromorphs (M ⁺M ⁺), the amount of female genitalia differentiated was largely independent of the amount of male genitalia present. In contrast, male and female anal structures, as a rule, added up to one full set. The same was true for the experimentalMM ⁺ gynandromorphs, but the contribution ofXX andXO cells to mosaic terminalia changed drastically due toM ⁺ cells competing successfully against the more slowly growingM cells. Specific subsamples ofMM ⁺ gynandromorphs showed thatM cells in a non-mosaic primordium are shielded from cell competition taking place in the neighbouring mosaic primordium. We conclude that the three primordia of the genital disc represent developmental compartments. In the genital primordia, even developmentally repressedM ⁺ cells compete successfully against developmentally activeM cells.     

Properties of the sex chromosomes of Lucilia cuprina deduced from radiation studies

From a study of radiation-induced X-chromosome deletions the locus of black body (b) has been localized to the proximal portion of C-band defined euchromatin. Radiation produced mostly X-chromosome deletions rather than point mutations, total X or Y chromosome loss through breakage, or increased frequency of non-disjunction. Aberrant sex ratios obtained indicate that the X chromosome carries vital loci that were deleted with b ⁺ in many cases. The X/O karyotype produces fertile adult females with a characteristic phenotype which is also produced by X deletions. Sex chromosome non-disjunction to give X/O females and X/X/Y males is normally rare but is enhanced by the presence of chromosome rearrangements even when the X and Y are not involved.     

Different behaviour of Xbb+ and Xbb chromosomes in D. melanogaster with only one nucleolus organizer.

Summary We have examined the rDNA content of male and female adult flies having only one nucleolus organizer (NO), using X chromosomes carrying wild or partially deleted bobbed loci (Xbb ⁺/O, Xbb ⁺/X_NO-and Xbb/O, Xbb/X_NO ^-).The results show that in Xbb ⁺/O and Xbb ⁺/X_NO ^-flies, where only somatic gene compensation is supposed to occur, the rDNA increase, although less pronounced than previously reported, is directly proportional to the number of rRNA genes initially present in the nucleolus organizer. In Xbb/O and in Xbb/X_NO ^-flies the rDNA increase is relatively much higher than that observed in flies carrying bb ⁺ instead of bb. It is suggested that this may be due to rDNA premagnification and somatic gene compensation occurring simultaneously in the former flies.On leave of absence from International Institute of Genetics and Biophysics, Naples, Italy     

Indirect evidence of alteration in the expression of the rDNA genes in interspecific hybrids betweenDrosophila melanogaster andDrosophila simulans

Crosses betweenDrosophila melanogaster females andD. simulans males produce viable hybrid females, while males are lethal. These males are rescued if they carry theD. simulans Lhr gene. This paper reports that females of the wild-typeD. melanogaster population Staket do not produce viable hybrid males when crossed withD. simulans Lhr males, a phenomenon which we designate as the Staket phenotype. The agent responsible for this phenomenon was found to be the StaketX chromosome (X ^mel ,Stk). Analysis of the Staket phenotype showed that it is suppressed by extra copies ofD. melanogaster rDNA genes and that theX ^mel ,Stk chromosome manifests a weak bobbed phenotype inD. melanogaster X ^mel ,Stk/0 males. The numbers of functional rDNA genes inX ^mel ,Stk andX ^mel ,y w (control) chromosomes were found not to differ significantly. Thus a reduction in rDNA gene number cannot account for the weak bobbedX ^mel ,Stk phenotype let alone the Staket phenotype. The rRNA precursor molecules transcribed from theX ^mel ,Stk rDNA genes seem to be correctly processed in both intraspecific (melanogaster) and interspecific (melanogaster-simulans) conditions. It is therefore suggested that theX ^mel ,Stk rDNA genes are inefficiently transcribed in themelanogaster-simulans hybrids.     

Foliar physiology of yellow-poplar ( Liriodendron tulipifera L.) exposed to O3 and elevated CO2 over five seasons.

The chronic effects of ozone (O₃) alone or combined with elevated carbon dioxide (CO₂) on the foliar physiology of unfertilized field-grown yellow-poplar ( Liriodendron tulipifera L.) seedlings were studied from 1992 to 1996. Within open-top chambers, juvenile trees were exposed to the following: charcoal-filtered air (CF); 1× ambient ozone (1XO₃); 1.5× ambient ozone (1.5XO₃); 1.5× ambient ozone plus 700 ppm carbon dioxide (1.5XO₃+CO₂); or chamberless open-air (OA). Seasonal 24-h mean ambient O₃ concentrations ranged from 32 to 46 ppm over the five seasons. Averaged over 5 years, midseason net photosynthesis at saturating light ( A _sat) was reduced by 14% ( P =0.029) and stomatal conductance ( g _s) was reduced, albeit non-significant, by 13% ( P =0.096) in upper canopy foliage exposed to 1.5XO₃-air relative to CF controls. There were no significant differences over the 5 years in A _sat and g _s between trees grown in 1XO₃- and 1.5XO₃-air. Our results support the hypothesis that the magnitude of O₃ effects on A _sat and g _s decreases as saplings age. When averaged over the five seasons of exposure, total chlorophyll concentration ( chl) was not significantly affected by exposure to elevated O₃; however, in 1.5XO₃+CO₂-air, foliar chl was reduced by 33% relative to all others ( P <0.001). In 1.5XO₃+CO₂-air, A _sat was 1.4–1.9 times higher ( P <0.001) and g _s was 0.7 times lower ( P =0.022) than all others. O₃ uptake in juvenile trees exposed to elevated O₃ plus elevated CO₂ (1.5XO₃+CO₂-air) was most comparable to trees exposed to ambient air (1XO₃) throughout the study. These findings suggest that elevated CO₂ may minimize the negative effects of O₃ by reducing O₃ uptake through decreased stomatal conductance.     

Autosomal suppression and fitness costs of an old driving X chromosome in Drosophila testacea

Driving X chromosomes (X^Ds) bias their own transmission through males by killing Y‐bearing gametes. These chromosomes can in theory spread rapidly in populations and cause extinction, but many are found as balanced polymorphisms or as “cryptic” X^Ds shut down by drive suppressors. The relative likelihood of these outcomes and the evolutionary pathways through which they come about are not well understood. An X^D was recently discovered in the mycophagous fly, Drosophila testacea, presenting the opportunity to compare this X^D with the well‐studied X^D of its sister species, Drosophila neotestacea. Comparing features of independently evolved X^Ds in young sister species is a promising avenue towards understanding how X^Ds and their counteracting forces change over time. In contrast to the X^D of D. neotestacea, we find that the X^D of D. testacea is old, with its origin predating the radiation of three species: D. testacea, D. neotestacea and their shared sister species, Drosophila orientacea. Motivated by the suggestion that older X^Ds should be more deleterious to carriers, we assessed the effect of the X^D on both male and female fertility. Unlike what is known from D. neotestacea, we found a strong fitness cost in females homozygous for the X^D in D. testacea: a large proportion of homozygous females failed to produce offspring after being housed with males for several days. Our male fertility experiments show that although X^D male fertility is lower under sperm‐depleting conditions, X^D males have comparable fertility to males carrying a standard X chromosome under a free‐mating regime, which may better approximate conditions in wild populations of D. testacea. Lastly, we demonstrate the presence of autosomal suppression of X chromosome drive. Our results provide support for a model of X^D evolution where the dynamics of young X^Ds are governed by fitness consequences in males, whereas in older X^D systems, both suppression and fitness consequences in females likely supersede male fitness costs.     

Cytological identification of two X-chromosome types in the wood lemming (Myopus schisticolor)

In the wood lemming (Myopus schisticolor) three genetic types of sex chromosome constitution in females are postulated: XX, X^*X and X^*Y (X^*=X with a mutation inactivating the male determining effect of the Y chromosome). Males are all XY. It is shown in the present paper that the two types of X chromosomes, X and X^*, exhibit differences in the G-band patterns of their short arms. In addition, it was demonstrated in unbanded chromosomes that the short arm in X^* is shorter than in X. The origin of these differences is still obscure; but they allow to identify and to distinguish the individual types of sex chromosome constitution, as of XX versus X^*X females and of X^*Y females versus XY males, on the basis of G-banded chromosome preparations from somatic cells.     

Sex determination and phenotype in wood lemmings with XXY and related karyotypic anomalies

Summary The wood lemming, Myopus schisticolor, possesses a unique sex determining system comprising both XX and XY females. Normal female development in the presence of XY is guaranteed by a mutation on the X, apparently associated with a structural rearrangement in Xp. This mutation inactivates the testis-inducing and male-determining factor on the Y and distinguishes X^* from X, and X^*Y females from XY males. Normal fertility of X^*Y females is ensured by a mitotic (double) nondisjunction mechanism which, at an early fetal stage, eliminates the Y from the germ line and replaces it by a copy of the X^*.Numerical sex chromosome aberrations are not infrequent and the trisomics XXY and X^*XY are relatively common. XXY individuals are sterile males with severe suppression of spermatogenesis. Among X^*XY animals, both males and females, as well as a true lateral hermaphrodite have been observed. Primary deficiency of germ cells, impairment of spermatogenesis and sterility are characteristic traits of the X^*XY males, whereas X^*XY females have normal oogenesis and are fertile. Both these extremes (except female fertility) coexist in the true hermaphrodite described in the present study. These apparently contradictory observations are explainable under the assumption that X^* and X in X^*XY individuals are inactivated non-randomly or that the cells are distributed unequally. Inactivation of the X or X^* determines whether or not the H-Y antigen will be expressed. When comparing conditions in Myopus and in man, an additional assumption has to be made in relation to the gene(s) involved in sex determination, located in Xp:In Myopus they do not escape inactivation, whereas in man they have been claimed to remain active.     

The chromosomes of Schoutedenia lutea (homoptera,aphidoidea, greenideinae), with an account of meiosis in the male

Somatic chromosomes of both sexes and chromosome behaviour during spermatogenesis were studied in the aphid Schoutedenia lutea (van der Goot). Four long but unequal chromosomes in females were interpreted as X chromosomes (X₁X₁X₂X₂) with one member of an autosome pair attached to one X₁, and the other member to one X₂, so that the four long chromosomes were actually X₁+A, X₁, X₂+A, X₂. Males (normally XO in aphids) received X chromosomes corresponding in relative length to the two longest (X₁+A, X₂+A) in females. During spermatogenesis parallel pairing occurred in prophase 1 and the X₁ and X₂ chromosomes became associated via their autosomal segments. In anaphase I, the autosomal segment became detached from one of the X chromosomes and entered the non-viable (non-X-bearing) spermatocyte, while the viable spermatocyte received both X₁ and X₂ (either one of which still carried an autosome) and the haploid set of free autosomes. The consequences for sex determination and zygote formation of this unusual system are discussed; a stable chromosomal constitution for the zygote can be achieved only at the expense of considerable gamete wastage.     

rDNA magnification in D. melanogaster: state of rDNA copies following the first step.

Summary D. melanogaster males of bb/O genetic constitution undergoing rDNA magnification were mated singly to XXbb ⁺/O females, yielding bb/O male progeny, and to X_NO-w sn bb ⁺ fameles, yielding bb/X_NO- females. The male and female offspring were scored for the bb ⁺ phenotype.Results show that there is a higher percentage of bb ⁺ flies in the bb/O male progeny than in bb/X_NO- females progeny, in single crosses as well as in the combined data. rRNA/DNA hybridization experiments agree with this observation, by showing that the rDNA content in the progeny of premagnified flies was higher in the sons than in the daughters.These data indicate that the increase of ribosomal RNA genes is not due to a stable event such as an unequal mitotic sister exchange, whereas they do not contrast with the extracopy model.     

Difference in the expression pattern of dystrophin on the surface membrane between the skeletal and cardiac muscles of mdx carrier mice

Summary We examined the expression of dystrophin by immunohistochemical and immunoblot analyses in the skeletal and cardiac muscles of X^mdx/X⁺ heterozygous mice, which were obtained by mating male mdx mice (X^mdx/Y) with female wild type mice (X⁺/X⁺). Dystrophin was expressed on the surface membrane in both muscles, but the mode of expression was different between the two muscles. In cardiac muscle, dystrophin positive and negative cells were present in roughly equal numbers intermingled in a mosaic pattern; this was considered to reflect the random inactivation of X-chromosomes in early development. In skeletal muscle, most of the surface membrane was dystrophin positive. There were little signs of fiber necrosis or regeneration, and serum creatine kinase levels were normal. We are at present of opinion that the predominance of dystrophin-positive area in skeletal muscle is due to intracellular diffusion of dystrophin. On leave from The Department of Pediatrics, Tokyo Women's Medical College     

Non mendelian female sterility in Drosophila melanogaster, further data on chromosomal contamination

Summary In relation to non Mendelian female sterility, Drosophila melanogaster strains can be divided into two main classes, inducer and reactive. The genetic element responsible for the inducer condition (I factor) is chromosomal and may be linked to any chromosome of inducer strains. Each chromosome carrying the I factor (i ⁺ chromosome) can produce females (denoted SF ) showing more or less reduced fertility when introduced by paternal gametes into reactive oocytes. The amount of fertility reduction of SF females depends chiefly on the level of reactivity of their reactive mother i.e. on the particular state of the cytoplasm in the oocytes from which they are issued. As long as i ⁺ chromosomes are transmitted through heterozygous males with reactive originating chromosomes (r chromosomes), the I factor strictly follows Mendelian segregations. In contrast, in heterozygous i ⁺/r females, a varying proportion of r chromosomes may acquire irreversibly I factor, independently of classical genetic recombination, by a process denoted chromosomal contamination. The contaminated r chromosomes behave like i ⁺ chromosomes.The experiments reported in this paper show that chromosomal contamination is a chance event which arises independently in individual r chromosomes. r chromosomes may differ in their ability to be contaminated and there is a systematic difference between chromosomes X and 2. In addition, it is demonstrated that the efficiency of contamination increases with the level of reactivity of the mothers of SF females and therefore is closely correlated with the amount of fertility reduction of SF females.     

The chromosomes of mantids (Orthoptera; Manteidae) in relation to taxonomy

Summary The distinguishing cytological characters, including chromosome number and sex chromosome mechanism, have been tabulated for all mantids thus far studied cytologically—including 16 species (starred in Table 1) not hitherto examined. Data on 46 species in 17 subfamilies are reviewed.The XO—XX sex chromosome mechanism represents the ancestral condition for the family and has been retained in 14 of the subfamilies sampled.The distribution of the X¹X²Y—X¹X¹X²X² mechanism, previously known in the subfamilies Manteinae and Choeradodinae, is extended to include Mellierinae, Acromantinae and Vatinae.Cytological evidence indicates a monophyletic origin of the compound sex chromosomes and necessitates a reconsideration of the taxonomic association of XO and X¹X²Y forms in the same subfamily, specifically of Miomantis and Callimantis with the other Manteinae, and Aethalocroa with Vates and Phyllovates in the Vatinae.The pre-metaphase stretch is established as a regular stage in male meiosis in 14—and is absent in 3—of the species checked for this character. It should prove of taxonomic value when a wider sampling of the lower categories is available.The prolongation of parallel pairing of homologous chromosomes in male meiosis appears to be characteristic of the Manteidae as a whole. No correlation is apparent between the degree of its expression and taxonomic category. Since it provides a mechanism, additional or alternative to chiasmata, for the post-pachytene association of homologues, its establishment permits the evolution of non-chiasmate meiosis in the group.Two structural types of bivalents—one with, one without chiasmata—are found. Present evidence favors the multiple origin of the non-chiasmate type within the family, and since both types may coexist in the karyotype of the same sex of a single species, presence or absence of chiasmata cannot be considered a valid taxonomic criterion.     

Bestimmung des Heterochromatisierungsstadiums beim white-Positionseffekt mittels r?ntgeninduzierter mitotischer Rekombination in der Augenanlage von Drosophila melanogaster

Summary Position-effect variegation of eye pigmentation in the examined Dp(1;3)N ^264-58 females is due to an insertion of a X-chromosome section including the white-locus into the proximal heterochromatic region of the third chromosome. The light and dark pigmented areas have a cell lineage basis (Fig. 2). Flies bearing the w ⁺-duplication had two X-chromosomes marked with w ^a lz ⁵⁰ e and w ^a rb rux ² respectively (Fig. 3). X-ray induced mitotic recombination in presumptive eye cells of larvae resulted in w ^a lz ^50e /w ^a rb rux ² twin mosaic spots in the adult eyes. After young larvae were treated twin spots appeared, which had one partner light colored and one dark. Such combinations were rarely found after older larvae were treated. Treatment of young larvae in addition produced twin spots with one or both partners variegated (Figs. 5 and 6). Sometime after the stage at which younger larvae were treated and before the stage at which older larvae were treated the translocated w ⁺-gene in each cell was determined for function or no function. As a result the progeny of each of these cells synthesized pigment or not during the pupal stage. At a temperature of 25.5° C the developmental phase during which determination, i.e. heterochromatization of the white gene, takes place, begins not earlier than 39 hours after egg laying and ends about 8 hours later (Fig. 7). In females heterozygous for the short arm of the heterochromatic Y-chromosome linked distally to the X-chromosome (Y ^S X/X) one twin spot partners is homozygous for this arm (Y ^SX/Y^S X), the other lacks it (X/X; Fig.4a). The Y ^SX/Y^S X-partner were more frequently dark pigmented than the X/X-partners (Tables 3 and 4). This shows that heterochromatization of the translocated w ⁺-genes is markedly influenced by the genotype of the single cell. When two genotypes with varied amounts of heterochromatin were compared (Fig. 4) no difference in the phases of heterochromatization could be observed (Table 5). Therefore, when position-effect variegation is modified by varying the amount of heterochromatin in the genome the modification is probably not due to a shift in the phase of heterochromatization.

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Vorgelegt von E. Hadorn     

An Autosomal Gene That Affects X Chromosome Expression and Sex Determination in CAENORHABDITIS ELEGANS

Recessive mutant alleles at the autosomal dpy-21 locus of C. elegans cause a dumpy phenotype in XX animals but not in XO animals. This dumpy phenotype is characteristic of X chromosome aneuploids with higher than normal X to autosome ratios and is proposed to result from overexpression of X-linked genes. We have isolated a new dpy-21 allele that also causes partial hermaphroditization of XO males, without causing the dumpy phenotype. All dpy-21 alleles show hermaphroditization effects in XO males that carry a duplication of part of the X chromosome and also partially suppress a transformer (tra-1) mutation that converts XX animals into males. Experiments with a set of X chromosome duplications show that the defects of dpy-21 mutants can result from interaction with several different regions of the X chromosome. We propose that dpy-21 regulates X chromosome expression and may be involved in interpreting X chromosome dose for the developmental decisions of both sex determination and dosage compensation.     

六盘山南坡华北落叶松人工林冠层LAI的坡面尺度效应

叶面积指数(LAI)是评价森林的生长、结构及众多服务功能的重要参数,受坡面上环境条件变化影响而有坡面变化与尺度效应,对此需要深入理解和精细刻画。在六盘山半湿润区香水河小流域选择了33年生华北落叶松人工林的一个斜坡长480.6m、水平长398.2m的东南坡向的典型坡面,在整个坡面上建立了宽30 m的调查样带,均匀分为空间连续的16个样地,在2014年生长季中期测定了林冠层LAI,并分析其坡面变化规律。结果表明:林冠层LAI存在明显的坡面差异,其坡面平均值为3.11,变化在2.66—3.49,变幅为0.83,变异系数为0.09;LAI总体上随着从坡顶向下的坡长增加呈波动性增大趋势,在坡面中部(水平坡长188.45 m时)达到最大,之后稍微减小。森林冠层LAI存在着坡面空间尺度效应,即冠层LAI的顺坡滑动平均值(Y_1)随水平坡长(X,m)增加而逐渐增大,平均每100 m升高0.12,其回归关系式为:Y_1=-2×10~(-8)X~3+8×10~(-6)X~2+5×10~(-4)X+2.6523,(R~2=0.99);各样地LAI与整个坡面平均值的比值(Y_2,小数)随水平坡长(X_1,m)增加呈现为波动性的非线性变化,其回归关系式为:Y_2=-9×10~(-9)X_1~3+2×10~(-6)X_1~2+1×10~(-3)X1+0.829,(R~2=0.78),可基于此式将特定坡位样地的实测LAI推算整个坡面的估计值。造成研究坡面上LAI坡位变化的主要原因是不同坡位(海拔)样地的气温与土壤含水量的差异。     

An X‐linked Myh11‐CreERT2 mouse line resulting from Y to X chromosome‐translocation of the Cre allele

The Myh11‐CreER^T2 mouse line (Cre⁺) has gained increasing application because of its high lineage specificity relative to other Cre drivers targeting smooth muscle cells (SMCs). This Cre allele, however, was initially inserted into the Y chromosome (X/Y^Cre+), which excluded its application in female mice. Our group established a Cre⁺ colony from male ancestors. Surprisingly, genotype screening identified female carriers that stably transmitted the Cre allele to the following generations. Crossbreeding experiments revealed a pattern of X‐linked inheritance for the transgene (k > 1000), indicating that these female carries acquired the Cre allele through a mechanism of Y to X chromosome translocation. Further characterization demonstrated that in hemizygous X/X^Cre+ mice Cre activity was restricted to a subset arterial SMCs, with Cre expression in arteries decreased by 50% compared to X/Y^Cre+ mice. This mosaicism, however, diminished in homozygous X^Cre+/X^Cre+ mice. In a model of aortic aneurysm induced by a SMC‐specific Tgfbr1 deletion, the homozygous X^Cre+/X^Cre+ Cre driver unmasked the aortic phenotype that is otherwise subclinical when driven by the hemizygous X/X^Cre+ Cre line. In conclusion, the Cre allele carried by this female mouse line is located on the X chromosome and subjected to X‐inactivation. The homozygous X^Cre+/X^Cre+ mice produce uniform Cre activity in arterial SMCs.     

Different HLA DR-DQ associations in subgroups of idiopathic myasthenia gravis

We have investigated theHLA-DRB and -DQB gene polymorphism in 131 myasthenia gravis (MG) patients. TheHLA genotypes in these patients were assigned by means of restriction fragment length polymorphism (RFLP)-definedDR-DQ haplotypes, correlating to serologic HLA class II typing. Using this technique we could, among randomly selected non-thymomatous (NT)-MG patients, confirm the strong association to DR3, and 70% of the patients were found to carry a specific DR3-positiveDR-DQ haplotype,T-3.1. Furthermore, an analysis of T-3.1^– NT-MG patients revealed that 59 % were T-4.1^÷ (DR4, DQw8). Thymic hyperplasia was found in approximately 85 % of the T-3.1⁺ , as well as of the T-4.1⁺ /3.1^– patients. As previously observed, we found a clear dominance of females among the T-3.1⁺ NT-MG patients. However, among T-4.1⁺/3.1- patients, males were as common as females. Furthermore, the T-4.1⁺ patients were significantly older at the onset of disease than those who were T-3.1⁺. In female MG patients, the DRwl5-Dw2-positive haplotypeT-2.1 was strongly correlated with the presence of thymoma (T-MG). These data indicate that the HLA associations in early vs late onset of NT-MG are different, and that female patients with and without thymoma differ from each other with regard to HLA markers. Thus, at least three different HLA DR-DQ associations are found in subgroups of idiopathic MG.