A gene controlling H-Y antigen on the X chromosome

Summary The existence of a strict correlation between presence of testicular tissue and presence of H-Y antigen in mammals and man leads to the conclusion that H-Y antigen is an essential differentiation factor in testicular morphogenesis. Presence of low titers of this differentiation antigen even in fertile females indicates that its morphogenetic effect depends on a threshold. Here, studies on H-Y antigen in female individuals with various deletions of the X-chromosome are reported. It turns out that deletion of Xp results in the synthesis of reduced amounts of H-Y antigen, while deletion of Xq does not. In a fertile female with only Xp223 deleted due to an X/Y translocation, including the distal Yq, presence of a reduced H-Y titer allows for the tentative assignment of a controlling gene repressing the H-Y structural gene. From the cases studied, it follows that the H-Y structural gene is autosomal and under the control of X- and Y-linked genes. The conception emerges that interaction between X- and Y-linked genes or their products results in variation of the H-Y antigen titer. The fate of the indifferent gonadal anlage to differentiate into the male or the female direction will depend on the titer of H-Y antigen reached by the action or interaction of the controlling genes involved.Supported by the Deutsche Forschungsgemeinschaft (SFB 46)     

H-Y transplantation antigen in human XO females

Summary When sensitized with human cultured fibroblasts of the XY and XO, but not XX, sex chromosomal types C57BL/6 female mice reject syngeneic male grafts accelerated (second set graft reaction). These findings demonstrate that the antigenic determinants of H-Y antigen of man and mouse are homologous and that XO females (at least those tested) carry the H-Y transplantation antigen. The results are discussed in the light of the question of differences between the H-Y antigen as defined by grafting and serology and the chromosomal localization of the H-Y structural gene(s).     

The H-Y antigen and its role in natural transplantation

Summary A concise overview of the transplantation biology of the H-Y antigen is presented with particular reference to: its prototypic behavior as a weak transplantation antigen; the facility with which mice of certain inbred strains can be rendered tolerant of H-Y incompatible skin grafts; its capacity to instigate graft-versus-host reactions; its significance in clinical transplantation; and finally, H-2 control of anti-H-Y immune responses.The role of the H-Y antigen in natural transplantation, i.e. pregnancy, is then reviewed. Evidence is presented to support the hypothesis that in certain cases maternal immune responses directed specifically to the H-Y antigen can exert selective pressures on male zygotes, producing deviant sex ratios in certain experimental and clinical situations.     

H-Y antigen: localization of the H-Y gene

Testicular development in a patient with deletion of the distal (fluorescent) segment of the Y chromosome is described. The presence of a normal dose of H-Y antigen was demonstrated by Goldberg's cytotoxicity test. It is concluded that the distal fluorescent segment of the Y chromosome is void of genes regulating H-Y antigen activity.     

X-linked genes of the H-Y antigen system in the wood lemming (Myopus schisticolor)

Summary H-Y antigen was investigated in 18 specimens representing six different sex chromosome constitutions of the wood lemming (Myopus schisticolor). The control range of H-Y antigen was defined by the sex difference between normal XX females (H-Y negativeper definitionem) and normal XY males (H-Y positive, full titer). H-Y antigen titers of the X^*Y and X^*0 females were in the male control range, while in the X^*X and X0 females the titers were intermediary. Data were obtained with two different H-Y antigen assays: the Raji cell cytotoxicity test and the peroxidase-antiperoxidase (PAP) method. Fibroblasts, gonadal cells, and spleen cells were checked. Presence of full titers of H-Y antigen in the absence of testis differentiation is readily explained by the assumption of a deficiency of the gonadspecific receptor of H-Y antigen. Since sex reversal is inherited as an X-linked trait, genes for this receptor are most likely X-linked. The implications of our findings are discussed in connection with earlier findings concerning H-Y antigen in XY gonadal dysgenesis in man and the X0 situation in man and mouse.     

H-Y antigen in the teleost

H-Y antigen, presumably the product of mammalian testis-determining genes, has been detected in three species of teleost fish, Xiphophorus maculatus. Haplochromis burtoni, and Oryzias latipes, and in hybrids of the genus Tilapia. In X. maculatus H-Y was most readily detected in YY males, suggesting that a genetic determinant of H-Y antigen expression may exist on the teleost Y-chromosome. Although H-Y was detected in males and not in feamles in each of the species that we studied, male heterogamety has not been firmly established for H. burtoni. Thus despite the extreme phlyogenetic conservation of H-Y genes and their association with the Y-chromosome, it remains open to question whether H-Y will always be found in the heterogametic sex, and whether serologically defined H-Y antigen plays any part in the differentiation of the teleost gonad.     

On the secretion of H-Y antigen

It has been proposed that H-Y antigen secreted by cells of the Sertoli lineage is bound by receptors on these and other cells of the primordial gonad and thereby initiates formation of the testicular cords, and that H-Y is not an integral transmembrane component but a part of a ternary system with β₂-microglobulin and products of the MHC. It follows that cultured Daudi cells, which lack β₂-microglobulin and HLA, should secrete H-Y. This is consistent with evidence obtained with monoclonal H-Y antibody and an ELISA. By this method, free H-Y was demonstrable in the supernatant fluids of cultured Sertoli cells and Daudi cells. The assay provides a useful alternative to detection of H-Y in the complement-dependent cytotoxicity test.     

Gonadal development and birth weight in X*X and X*Y females of the wood lemming, Myopus schisticolor

A quantitative histological analysis of ovaries from 8- to 10-day-old wood lemmings revealed significant differences between females with X*Y and X*X sex chromosome constitutions. The ovarian volume of X*Y females was on average 57% of X*X, and the number of oocytes was less than half in X*Y compared to X*X. However, the frequency of growing oocytes in relation to the total number was 6.5% for X*Y compared to 3.0% for X*X. Oogenesis in X*Y wood lemmings resembles in many respects that of mice heterozygous for certain translocations and with tertiary trisomy (Ts31H), and those with X0 monosomy. The fertility in X*Y wood lemmings is not reduced. On the contrary, X*Y females have a higher reproductive fitness than X*X and XX. This is discussed in relation to the present findings. The body weight at birth was 8% higher in X*Y than in X*X.     

Studies on the H-Y antigen in rats

The H-Y antigen has been studied under a variety of experimental conditions in BN and Lewis rats. The results indicate that 1. graft size is crucially important in determining the fate of male skin isografts on females; 2. H-Y incompatible ear skin grafts survive significantly better than those of trunk origin; 3. prior exposure of females to male lymphoid cells greatly increases their capacity to reject male skin isografts; 4. neonatal castration has no influence on the expression of H-Y; 5. multiparity can induce unresponsiveness to H-Y; and 6. although BN females respond better than do Lewis females to H-Y, the antigen is stronger in Lewis males. These findings are compared with the results of similar experiments conducted with mice.Submitted in memory of Dr. Joy Palm, member of the Wistar Institute, who pioneered the genetic analysis of histocompatibility in rats.     

XY gonadal dysgenesis and the H-Y antigen

Summary H-Y antigen was determined in 12 patients affected by XY gonadal dysgenesis. Of these, three proved to be H-Y negative, and nine, including two sisters, were H-Y positive; two of the unrelated positive cases exhibited a reduced antigen titer. Therefore, this clinical condition must be genetically heterogeneous. It is assumed that in the negative cases and possibly in those with reduced antigen titer, the H-Y generating system is affected by mutation, while in the regular positive cases the target cells are unable to respond due to a defect of the gonad-specific H-Y antigen receptor.I dedicate this article to the memory of Ilse Aschmoneit     

Does H-Y antigen induce the heterogametic ovary?

To determine whether phylogenetically conservative H-Y antigen plays any part in gonadal differentiation among the nonmammalian vertebrates, we studied expression and binding of H-Y in the frog, Xenopus laevis. Soluble H-Y obtained from mouse testis and soluble H-W from chicken ovary bound specifically to cells of the ZZ testis from normal Xenopus males. In addition, H-Y (H-W) appeared selectively in the ovaries of ZZ genetic males that had been induced to become functional females by exposure to estradiol. Our observations suggest that H-Y (H-W) antigen may be involved in differentiation of the ZW ovary, and also that synthesis of H-Y may be regulated by sex steroids in the primitive $\text{ZW}\text{ZZ}$ species.     

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.     

EM studies of female meiosis in wood lemmings with different sex chromosome constitutions

The chromosomes were studied throughout meiotic prophase by electron microscopy of surface-spread oocytes from one XX, four X*X, and three X*Y female wood lemmings, Myopus schisticolor. The X* chromosome had originated from X by a deletion and an inversion in the short arm. The deletion was confirmed in pachytene cells from X*X females; a D-loop was present in the sex bivalent in 16.8% of the cells, and asynapsis of unequal ends was seen in 9.1% of other cells. At late pachytene the D-loop underwent synaptic adjustment. The breakpoints of the deletion are in G-light bands. No inversion loop was seen, which also is in agreement with Ashley's ('88) hypothesis; at least one of the presumed breakpoints of the inversion is in G-dark chromatin. Various types of synaptic abnormalities, such as nonhomologous pairing (triple pairing, interchange, self-synapsis), univalents, foldbacks, and broken lateral elements, were encountered in all types of female. X*Y females showed a high frequency of abnormal oocytes (70.7%), which significantly exceeded that of X*X (23.1%) and XX (8.1%). Univalents were particularly common in the X*Y females. J. Exp. Zool. 290:504-516, 2001.     

Familial XX true hermaphroditism and the H-Y antigen

Summary Two 46,XX sibs, one of female, one of male gender, and both with ambiguous external genitalia and ovotestis, were H-Y positive. The mother was H-Y negative. It is assumed that the underlying mutation was transmitted by the father, resulting in an autosomal dominant mode of inheritance. The common origin and the nature of the mutation leading to XX sex reversal are discussed.     

Absence of H-Y antigen in an XY female with campomelic dysplasia

Summary We have studied a stillborn infant who had the clinical and radiographic characteristics of campomelic dysplasia. External and internal genitalia were those of a normal female, except for slight enlargement of the clitoris. Microscopic examination of the ovaries revealed some areas resembling immature dysgenetic testicular tissue. Karyotypes from lymphocyte and fibroblast cultures were 46,XY with a structurally normal Y chromosome and no evidence of mosaicism. H-Y antigen was not detected on the fibroblasts in repeated assays using Raji cells as target cells after absorption. The sexreversal (chromosomal malephenotypic female) previously noted in patients with autosomal recessive campomelic dysplasia thus may be mediated through lack of detectable H-Y antigen on the cell surface. It appears that the mutation leading to campomelic dysplasia interferes with normal H-Y antigen expression.