A search of a 35-kilobase region of the human Y chromosome necessary for male sex determination has resulted in the identification of a new gene. This gene is conserved and Y-specific among a wide range of mammals, and encodes a testis-specific transcript. It shares homology with the mating-type protein, Mc, from the fission yeast Schizosaccharomyces pombe and a conserved DNA-binding motif present in the nuclear high-mobility-group proteins HMG1 and HMG2. This gene has been termed SRY (for sex-determining region Y) and proposed to be a candidate for the elusive testis-determining gene, TDF.

A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif

https://www.cell.com/cell/pdf/0092-8674(87)90595-2.pdf

The sex-determining region of the human Y chromosome encodes a finger protein

Chromosomally derived sterility has long been recognized. A review of the literature of somatic chromosome investigations in infertile males has shown that 13.7% of azoospermic males and 4.6% of oligozoospermic males have an abnormal karyotype. In the first group, sex chromosome abnormalities predominate (mainly 47,XXY), whereas in the latter, autosome anomalies (i.e. Robertsonian and reciprocal translocations) are the most frequent. A similar review on meiotic studies revealed that meiotic chromosome anomalies can explain male infertility in 4.3-40.4% of patients. Recently, fluorescent in-situ hybridization studies on spermatozoa from infertile men were published; it was suggested that both X-Y pairing and pairing of the autosomes were impaired, resulting in spermatogenic disruption. We investigated cytogenetically 694 infertile men with abnormal sperm parameters. More patients are needed for this research to investigate the relationship, if any, between the type of chromosome abnormality and its influence on the number, morphology and motility of spermatozoa. To be able to provide proper counselling for those couples whose male infertility can now be treated by intracytoplasmic sperm injection, it is suggested that clinical investigations should include mitotic and meiotic studies, an analysis of the chromosome content of individual spermatozoa and a DNA analysis of blood and spermatozoa to detect partially deleted Y chromosome material.

Cytogenetics of infertile men

Over 600 cases with a Y aneuploidy (other than non-mosaic 47,XYY) were reviewed for phenotype/karyotype correlations. Except for 93 prenatally diagnosed cases of mosaicism 45,X/46,XY (79 cases), 45,X/47,XYY (8 cases), and 45,X/46,XY/47,XYY (6 cases), all other cases were ascertained postnatally. Special emphasis was placed on structural abnormalities. This review includes 11 cases of 46,XYp-; 90 cases of 46,XYq- (52 cases non-mosaic; 38 cases 45,X mosaic); 34 cases of 46,X,r(Y) (9 cases non-mosaic and 25 cases 45,X mosaic); 8 cases of 46,X,i(Yp) (4 non-mosaic and 4 mosaic with 45,X); 12 cases of 46,X,i(Yq) (7 non-mosaic and 5 mosaic); 44 cases of 46,X,idic(Yq); 80 cases of 46,X, idic(Yp) (74 cases had breakpoints at Yq11 and 6 cases had breakpoints at Yq12); 130 cases of Y/autosome translocations (50 cases with a Y/A reciprocal translocation, 20 cases of Y/A translocation in 45,X males, 60 cases of Y/DP or Y/Gp translocations); 52 cases of Y/X translocations [47 cases with der(X); 4 cases with der(Y), and 1 case with 45,X with a der(X)], 7 cases of Y/Y translocations; 151 postnatally diagnosed cases of 45,X/46,XY; 14 postnatally diagnosed cases of 45,X/47,XYY; 18 cases of 45,X/46,XY/47,XYY; and 93 aforementioned prenatally diagnosed cases with a 45,X cell line. It is clear that in the absence of a 45,X cell line, the presence of an entire Yp or a region of it including SRY would lead to a male phenotype in an individual with a Y aneuploidy, whereas the lack of Yp invariably leads to a female phenotype with typical or atypical Ullrich-Turner syndrome (UTS). Once there is a 45,X cell line, regardless of whether there is Yp, Yq, or both Yp and Yq, or even a free Y chromosome in other cell line, there is an increased chance for that individual to be a phenotypic female with UTS manifestations or to have ambiguous external genitalia. This review once again shows a major difference in reported phenotypes between postnatally and prenatally diagnosed cases of 45,X/46,XY, 45,X/47,XYY, and 45,X/46,XY/47,XYY mosaicism. It appears that ascertainment bias can explain the fact that all known patients with postnatal diagnosis are phenotypically abnormal, while over 90% of prenatally diagnosed cases are reported to have a normal male phenotype. Further elucidation of major Y genes and their clinical significance can be expected in the rapidly expanding gene mapping projects. More, consequently better, phenotype/karyotype correlations can be anticipated at both the cytogenetic and the molecular level.

Phenotype/Karyotype correlations of Y chromosome aneuploidy with emphasis on structural aberrations in postnatally diagnosed cases

IN mammals, the testis determining gene (TDF), present on the Y chromosome, induces the undifferentiated gonads to form testes1. The position of TDF on the human Y chromosome has been defined by analysing the genomes of XX males and XY females2, generated by abnormal genetic exchange between the X and Y chromosomes in male meiosis3. In this way TDF has been localized close to the pseudoautosomal region shared by the sex chromosomes, in the distal Y-specific region. A recently cloned human gene, ZFY, has many features indicating that it is TDF4–6. For example, ZFY encodes a protein with many features of a transcription factor including a domain with multiple 'zinc-finger' motifs4–6. Less consistent with ZFY being TDF, however, is the presence of a very similar gene, ZFX, on the X chromosome4,7, and the presence of a sequence related to ZFY on autosomes in marsupials8. We now report on analysis of XX males lacking ZFY. In these individuals, the male phenotype could be explained by a mutation in a gene 'downstream' of ZFY in the sex-determining hierarchy; but in that case there should be no exchange of material between the X and Y chromosomes. We find on the contrary that in 4 XX males lacking ZFY, there is exchange of Y-specific sequences next to the pseudoautosomal boundary, redefining the region in which TDF must lie.

Sylvia Copaja Castillo

Papers

An abnormal terminal X-Y interchange accounts for most but not all cases of human XX maleness.