A chromosome Yqs was detected in a normal male. The origin and structure of this chromosome was investigated by means of different techniques: CBG, Ag-NOR, QFQ, THA, DA/DAPI and Distamycin A. The conclusion was reached that the Yqs chromosome was actually a Yq/15p translocation, where the Y chromosome had lost completely the Yq12 band. These findings suggested that the absence of the heterochromatic portion of the Y chromosome does not determine infertility.Close

Probes for unique and repetitive copy deoxyribonucleic acid (DNA) are available to detect and characterize Y DNA. The probe pS4 detects repetitive copy DNA mapped to Yq12. The upper limits of the pS4 sequences are defined by the upper limits of C-banding. The probe 4B-2 is a recombinant phage construct developed from a Y library and contains a unique copy 3.3 kb Eco RI fragment mapped to Yq11. A family was ascertained through a pregnant female who had a history of four consecutive abortions and two normal daughters. Cytogenetic analysis revealed the mother and one of her daughters to have a 46,XX,15p+ karyotype. Amniocytes were karyotyped as 46,XY,15p+. Genomic DNA from controls, mother, daughters, and amniocytes was digested with Mbo I and hybridized to 32P-labeled pS4 probe. DNAs from both 46,XX,15p+ females and 46,XY,15p+ amniocytes demonstrated a clear male-specific 2.3 kb band. Digestion of the same genomic DNAs with Eco RI and blot hybridization to 32P-labeled 4B-2 probe revealed the 3.3 kb male-specific band only in the 46,XY,15p+ amniocyte DNA. The additional sequences located on 15p segregating in the female members of this family correspond to Yq12. The effect of this additional DNA on gametogenesis is unknown.Close

We have used Y-specific and Y-derived DNA probes for in situ hybridization and Southern blotting analysis to characterize a Y;15 translocation showing normal Mendelian inheritance in a family. Cytogenetically there appeared to be an unbalanced translocation of Yqh to 15p; this translocation may be considered as a prototype of those translocations between Yq and the short arm of an acrocentric chromosome which have a population incidence of approximately 1 in 2,000. Our molecular studies showed that, in all probability, the breakpoints were near the border between Yq11.23 and Yq12, and in 15p11, respectively; the translocation is abbreviated t(Y;15)(q12;p11). Using the Y-specific probe pY431 in a quantitative Southern hybridization assay, normal females had no hybridization, female carriers and normal men had the same amount, and male carriers had twice that amount. Cytogenetic analysis and quantitative in situ hybridization using probes pY431 and pY3.4 were consistent with the hypothesis that the portion of Yq translocated to 15p comprised all of Yq12 and none of Yq11. The absence of Southern hybridization with probes specific for Yp and Yq11 confirmed this observation. Even though the family was ascertained through two brothers who both had schizophrenia and were carriers of the translocation, the clinical evaluation of a total of nine individuals with the translocation and five without it did not suggest its association with an abnormal phenotype.Close

Human chromosomes terminate with specialized telomeric structures including the simple tandem repeat (TTAGGG)n and additional complex subtelomeric repeats. Unique sequence DNA for each telomere is located 100-300 kilobases (kb) from the end of most chromosomes. A high concentration of genes and a number of candidate genes for recognizable syndromes are known to be present in telomeric regions. The human telomeric regions represent a major diagnostic challenge in clinical cytogenetics, because most of the terminal bands are G negative, and cryptic deletions and translocations in the telomeric regions are therefore difficult to detect by conventional cytogenetic methods. In fact, several submicroscopic chromosomal abnormalities in patients with undiagnosed mental retardation or multiple congenital anomalies have been identified by other molecular methods such as DNA polymorphism analysis. To improve the sensitivity for deletion detection and to determine whether such cryptic rearrangements represent a significant source of human pathology that has not been previously appreciated, it would be valuable to have specific FISH probes for all human telomeres. We report here the isolation and characterization of a complete set of specific FISH probes representing each human telomere. As most of these clones are at a known distance of within 100-300 kb from the end of the chromosome arm, this provides a 10-fold improvement in deletion detection sensitivity compared with high-resolution cytogenetics (2-3 Mb resolution). While testing these probes, we serendipitously identified a family with multiple members carrying a cryptic 1q;11p rearrangement in the balanced or unbalanced state.Close

The telomeres of Xq and Yq have been observed to associate during meiosis, and in rare cases a short synaptonemal complex is present. Molecular cloning of loci from Xqter and Yqter has revealed that their sequence homology extends over 400 kilobases, which suggests the possibility of genetic exchange. This hypothesis was tested by the development of two highly informative microsatellite markers from yeast artificial chromosome clones that carried Xqter sequences and the following of their inheritance in a set of reference pedigrees from the Centre d'Etude du Polymorphisme Humain in Paris, France. From a total of 195 informative male meioses, four recombination events between these loci were observed. In three cases, paternal X alleles were inherited by male offspring, and in one case a female offspring inherited her father's Y allele. These data support the existence of genetic exchange at Xq-Yq, which defines a second pseudoautosomal region between the sex chromosomes.Close

First described in 1971, partial trisomy 6p is uncommon and generally secondary to a familial reciprocal translocation. The proximal breakpoint of the reported cases varies from p11 to p25. We here report on a patient with moderate mental retardation, craniofacial and pigmentary anomalies, proteinuria, and hyperglycemia who was found to have a mosaic karyotype 46,X,add(Y)(q12)/45,X. Fluorescence in situ hybridization (FISH) enabled us to identify that the additional material on Yqh derived from 6p and to define the rearrangement as der(Y)t(Y;6)(q12;p22). To the best of our knowledge, this is the first case of trisomy 6p22-pter without an associated deleted segment; the second breakpoint of the rearrangement is in Yqh. Precise mapping of the centromeric breakpoint of the trisomic 6p segment allowed a more convincing correlation between partial 6p trisomy and clinical phenotype to be addressed. In particular, the proteinuria often observed in 6p trisomic patients could be assigned to the 6p22-6pter region.Close

Cosmids containing the human IL-9 receptor (R) gene (IL9R) have been isolated from a genomic library using the IL9R cDNA as a probe. We have shown that the human IL9R cDNA as a probe. We have shown that hte human IL9R gene is composed of 11 exons and 10 introns, stretching over approximately 17 kb, and is located within the pseudoautosomal region of the Xq and Yq chromosome, in the vicinity of the telomere. Analysis f the 5' flanking region revealed multiple transcription initiation sites as well as potential binding motifs for AP1, AP2, AP3, Sp1, and NF-kB, although this region lacks a TATA box. Using the human IL9R cosmid as a probe to perform fluorescence in situ hybridization, additional signals were identified in the subtelomeric regions of chromosomes 9q, 10p, 16p, and 18p. IL9R homologs located on chromosomes 16 and 10 were completely sequenced. Although they are similar to the IL9R gene (approximately 90% identity), none of these copies encodes a functional receptor: none of them contains sequences homologous to the 5' flanking region or exon 1 of the IL9R gene, and the remaining ORFs have been inactivated by various point mutations and deletions. Taken together, our results indicate that the IL9R gene is located at Xq28 and Yq12, in the long arm pseudoautosomal region, and that four IL9R pseudogenes are located on 9q34, 10p15, 16p13.3, and 18p11.3, probably dispersed as the result of translocations during evolution.Close

Cosmids containing the human IL-9 receptor (R) gene (IL9R) have been isolated from a genomic library using the IL9R cDNA as a probe. We have shown that the human IL9R cDNA as a probe. We have shown that hte human IL9R gene is composed of 11 exons and 10 introns, stretching over approximately 17 kb, and is located within the pseudoautosomal region of the Xq and Yq chromosome, in the vicinity of the telomere. Analysis f the 5' flanking region revealed multiple transcription initiation sites as well as potential binding motifs for AP1, AP2, AP3, Sp1, and NF-kB, although this region lacks a TATA box. Using the human IL9R cosmid as a probe to perform fluorescence in situ hybridization, additional signals were identified in the subtelomeric regions of chromosomes 9q, 10p, 16p, and 18p. IL9R homologs located on chromosomes 16 and 10 were completely sequenced. Although they are similar to the IL9R gene (approximately 90% identity), none of these copies encodes a functional receptor: none of them contains sequences homologous to the 5' flanking region or exon 1 of the IL9R gene, and the remaining ORFs have been inactivated by various point mutations and deletions. Taken together, our results indicate that the IL9R gene is located at Xq28 and Yq12, in the long arm pseudoautosomal region, and that four IL9R pseudogenes are located on 9q34, 10p15, 16p13.3, and 18p11.3, probably dispersed as the result of translocations during evolution.Close

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Telomere-specific clones are a valuable resource for the characterization of chromosomal rearrangements. We previously reported a first-generation set of human telomere probes consisting of 34 genomic clones, which were a known distance from the end of the chromosome ( approximately 300 kb), and 7 clones corresponding to the most distal markers on the integrated genetic/physical map (1p, 5p, 6p, 9p, 12p, 15q, and 20q). Subsequently, this resource has been optimized and completed: the size of the genomic clones has been expanded to a target size of 100-200 kb, which is optimal for use in genome-scanning methodologies, and additional probes for the remaining seven telomeres have been identified. For each clone we give an associated mapped sequence-tagged site and provide distances from the telomere estimated using a combination of fiberFISH, interphase FISH, sequence analysis, and radiation-hybrid mapping. This updated set of telomeric clones is an invaluable resource for clinical diagnosis and represents an important contribution to genetic and physical mapping efforts aimed at telomeric regions.Close

We have analysed the sequence organization of the pseudoautosomal region at the telomeres of the long arms of the human sex chromosomes and shown that it is 320 kb long. A LINE sequence is present on both the X and Y chromosomes immediately adjacent to the breakpoint in homology suggesting that the homology arose as a result of an ectopic recombination event mediated by LINE sequences originally present in non-homologous stretches of X and Y chromosomal DNA. This led to the translocation of sequences from the X chromosome telomere onto the Y chromosome and created a new pseudoautosomal region.Close

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A 45,X karyotype was found in a boy with dysmorphic features, hypoglycaemia and pancytopenia. DNA analysis showed the presence of the Y-chromosomal DNA sequences SRY, ZFY, DYZ4, DYZ3 and DYS1. Using fluorescent in situ hybridization, we located DYZ4 and DYZ3 on chromosome 11qter and concluded that a de novo translocation (Y;11) (q11.2;q24) with a deletion of 11q24—-qter and a deletion of Yq11.2—-Yqter were present; Jacobsen syndrome and azoospermia are associated with these deletions. Signs of Jacobsen syndrome were observed in the patient.Close

A fetus was prenatally diagnosed as having a Y(nfqs) chromosome which was inherited from the father. With the QFQ technique, the Yqh was observed to be nonfluorescent and contained cytological satellites which were attached to the terminal long arm. The satellites were positively stained by the Ag-NOR technique suggesting that the NORs were active. A battery of DNA probes was used to characterise the Y(nfqs). Hybridisation experiments using a chromosome 15 specific classical satellite DNA probe (D15Z1) and a Yq telomere DNA probe showed that the additional satellited material on Yq originated from 15p, and that the Yq terminal region had been lost. This is the first reported case in which the origin of cytological satellites on Yq has been determined by FISH, but this does not imply that all satellited Y chromosomes are derived from 15p. However, the clinical significance of this Y(nfqs) chromosome remains obscure.Close

All human X-linked genes known so far, except for the Xp/Yp pseudoautosomal genes, are conserved as a single linkage group on the murine X chromosome. We show that the interleukin-9 (IL-9) receptor gene (IL9R), which is located within the human Xq/Yq homology region, maps to the murine chromosome 11. The Xq/Yq pseudoautosomal region (Xq PAR) thus represents a second region on the human X chromosome which is not X linked in mice. Furthermore, we show that IL9R is absent on the Y of great apes. IL9R is thus exceptional among X/Y genes in that it is X linked in some mammals, but autosomal or pseudoautosomal in others. Genes located on the X and the Y generally escape X inactivation. An exception to this rule is SYBL1, a gene located in Xq PAR. SYBL1 is X inactivated and is inactive on the Y chromosome. In contrast, we show that IL9R expression does occur from the Y, the active and the inactive X chromosomes. This finding raises the question of how the transcriptional regulation of genes within Xq PAR occurs and how the X inactivation status of IL9R has evolved following the autosome to X and the X to X/Y translocation. The evolutionary analysis of the IL9R gene, which is located at 10 kb from the telomere, and its pseudogenes at several telomeres, also provides insight into the evolution of these loci and of subtelomeric regions in general.Close