Chimerism 46,XX/46,XY in a phenotypic female

Summary A female patient is reported with lymphocyte chromosome chimerism (46,XX/46,XY). Her whole-body chimerism was confirmed in the AB0 blood group system by the presence of two different erythrycyte populations, A₁0 and 00. Normal findings were recorded at physical and gynecological examination, except for mammary hypoplasia and sterility of 7 years duration, the latter complaint being the cause for genetic examination of the patient.     

Autoradiographic studies of the human Y chromosome

An autoradiographic analysis (using continuous labeling with tritiated thymidine) was made on 317 cells from four normal males. The labeling pattern of the Y chromosome was compared to the first and the last chromosomes to complete replication as well as to G21–22. The Y chromosome was never found to be the last chromosome in the cell to complete replication. Instead, it completed DNA synthesis relatively early (usually among the first 10 chromosomes) but had a distinctively heavy label during the earliest stages of late-S. In 51% of those cells with one labeled G+Y chromosome, a G21–22 was labeled and the Y was not.—It was concluded, therefore, that the human Y chromosome is not a late-replicating chromosome but terminates replication earlier than most of the autosomes. In addition, the Y chromosome cannot be distinguished from the G chromosomes on the basis of a consistent and differential labeling pattern.Supported by USPHS Grant GM 15361.     

Gonadal agenesis in a 46,XY female with multiple malformations and positive testing for the sex-determining region of the Y chromosome.

A full-term 46,XY female newborn presented with respiratory failure due to a right-sided diaphragmatic hernia. During surgical repair, exploration revealed isolated dextrocardia and hypoplasia of the right lung. Neither gonads nor wolffian or müllerian structures could be palpated. Cardiac catheterization demonstrated defects of the ventricular septum, hypoplasia of the right pulmonary artery, persistence of the left vena cava superior and a patent ductus arteriosus. Anthropometric data were normal at birth, but fell below the 3rd percentile during follow-up. Body proportions displayed a predominance of the upper compared to the lower segment. Endocrine studies indicated no defect of steroid biosynthesis and no functional gonadal tissue. Using genetic analyses of various loci within the testis-determining region of the Y chromosome, a mutation could not be detected. The patient died from pneumonia at the age of 19 months. Postmortem examination confirmed the diagnosis of gonadal agenesis.     

Sexual ambiguity and a non-fluorescent Y chromosome

The personal experience in three patients with ambiguous external genitalia and 45,X/46,XYnf karyotype is reported. The different clinical and cytogenetic aspects of this entity are described and discussed.     

Mutations and sequence variants in the testis-determining region of the Y chromosome in individuals with a 46,XY female phenotype

The testis-determining gene SRY (sex determining region, Y) is located on the short arm of the Y chromosome and consists of a single exon, the central third of which is predicted to encode a conserved motif with DNA binding/bending properties. We describe the screening of 26 patients who presented with 46,XY partial or complete gonadal dysgenesis for mutations in both the SRY open reading frame (ORF) and in 3.8 kb of Y-specific flanking sequences. DNA samples were screened by using the fluorescence-assisted mismatch analysis (FAMA) method. In two patients, de novo mutations causing complete gonadal dysgenesis were detected in the SRY ORF. One was a nonsense mutation 5′ to the HMG box, whereas the other was a missense substitution located at the C terminus of the conserved motif and identical to one previously detected in an unrelated patient. In addition, two Y-specific polymorphisms were found 5′ to the SRY gene, and a sequence variant was identified 3′ to the SRY polyadenylation site. No duplications of the DSS region in 20 of these patients were detected. Received: 18 November 1996 / Revised: 13 December 1996     

The role of the Y chromosome in human evolutionary studies

Analyses of molecular genetic data have added a new dimension to human evolutionary research. Pioneering studies of variation in human populations were based on analyses of blood groups¹ and electromorphs,² both of which represent qualitative multistate phenotypes. With the development of recombinant DNA methods in the 1970s and 1980s, the focus shifted from gene products to a new and plentiful source of human variability, restriction fragment length polymorphisms (RFLPs).^3,4 Finally, the addition of DNA sequencining survey data to the rapidly growing RFLP data base made it feasible for the first time to determine the exact number of nucleotide substitutions between different alleles, as well as to construct gene trees and reconstruct the phylogenetic history of populations.^5–7     

Ring Y chromosome: 45,X/46,X,r(Y) chromosome mosaicism in a phenotypically normal male with azoospermia

Summary Chromosome analysis of lymphocytes in a phenotypically normal male with azoospermia showed a mosaicism 45,X/46,X,r(Y). Seven other cases from the literature are discussed.     

The sole presence of the testis-determining region of the Y chromosome (SRY) in 46,XX patients is associated with phenotypic variability.

Four cases of XX patients with testis development are reported. The aim of this study was to describe their clinical features and to see if there was any relationship between phenotypes and the presence of Y material. Several human Y-derived sequences including the SRY probe were used to analyze the DNA of the patients. Yp material including the pseudo-autosomal region and SRY was detected. The cases reported in this study confirm that XX true hermaphrodites cannot be distinguished from XX males on the basis of their genotypes. There is no relationship between clinical and anatomical phenotypes and the presence of Y material. SRY does not warrant a complete and normal testis differentiation. Although similar in some features with Klinefelter's syndrome patients, XX males exhibit specific clinical manifestations due to the lack of Y-specific genes.     

Regional localization of human gene loci on chromosome 9: studies of somatic cell hybrids containing human translocations.

Somatic cell hybrids were derived from the fusion of (1) Chinese hamster cells deficient in hypoxanthine guanine phosphoribosyltransferase (HPRT) and human cells carrying an X/9 translocation and (2) Chinese hamster cells deficient in thymidine kinase (TK) and human cells carrying a 17/9 translocation. Several independent primary hybrid clones from these two series of cell hybrids were analyzed cytogenitically for human chromosome content and electrophoretically for the expression of human markers known to be on human chromosome 9. The results allow the assignment of the loci for the enzymes galactose-1-phosphate uridyltransferase (GALT), soluble aconitase (ACONs), and adenylate kinase-3 (AK3) to the short arm of chromosome 9 (p11 to pter) and the locus for the enzyme adenylate kinase-1 (AK1) to the distal end of the long arm of human chromosome 9 (hand q34). Earlier family studies have shown that the locus for AK1 is closely linked to the ABO blood group locus and to the locus of the nail-patella (Np) syndrome. Thus the regional localization of AK1 locus permits the localization of the AK1-Np-ABO linkage group.     

The human Y chromosome, in the light of evolution

Most eukaryotic chromosomes, akin to messy toolboxes, store jumbles of genes with diverse biological uses. The linkage of a gene to a particular chromosome therefore rarely hints strongly at that gene's function. One striking exception to this pattern of gene distribution is the human Y chromosome. Far from being random and diverse, known human Y-chromosome genes show just a few distinct expression profiles. Their relative functional conformity reflects evolutionary factors inherent to sex-specific chromosomes.     

Population growth of human Y chromosomes: a study of Y chromosome microsatellites

We use variation at a set of eight human Y chromosome microsatellite loci to investigate the demographic history of the Y chromosome. Instead of assuming a population of constant size, as in most of the previous work on the Y chromosome, we consider a model which permits a period of recent population growth. We show that for most of the populations in our sample this model fits the data far better than a model with no growth. We estimate the demographic parameters of this model for each population and also the time to the most recent common ancestor. Since there is some uncertainty about the details of the microsatellite mutation process, we consider several plausible mutation schemes and estimate the variance in mutation size simultaneously with the demographic parameters of interest. Our finding of a recent common ancestor (probably in the last 120,000 years), coupled with a strong signal of demographic expansion in all populations, suggests either a recent human expansion from a small ancestral population, or natural selection acting on the Y chromosome.     

Characterization and evolution of a single-copy sequence from the human Y chromosome.

To study the evolution and organization of DNA from the human Y chromosome, we constructed a recombinant library of human Y DNA by using a somatic cell hybrid in which the only cytologically detectable human chromosome is the Y. One recombinant (4B2) contained a 3.3-kilobase EcoRI single-copy fragment which was localized to the proximal portion of the Y long arm. Sequences homologous to this human DNA are present in male gorilla, chimpanzee, and orangutan DNAs but not in female ape DNAs. Under stringent hybridization conditions, the homologous sequence is either a single-copy or a low-order repeat in humans and in the apes. With relaxed hybridization conditions, this human Y probe detected several homologous DNA fragments which are all derived from the Y in that they occur in male DNAs from humans and the apes but not in female DNAs. In contrast, this probe hybridized to highly repeated sequences in both male and female DNAs from old world monkeys. Thus, sequences homologous to this probe underwent a change in copy number and chromosomal distribution during primate evolution.     

Dicentric Y chromosome in a male pseudohermaphrodite 45,X/46,X, dic (Y)/47, XYY]

The mosaicism 45,X/46,XY,terrea(Y,Y)(pterpter)/47,XYY was observed in an 8-month-old child with male pseudohermaphroditism. The presence of a 47,XYY population points to a post-zygotic origin of the rearrangement. The loss of Yp material is in favor of localization of masculinization factor(s) to the proximal segment of Yq. Twenty-two relevant observations reported in the literature previously are discussed.