Relative phylogenetic divergence of the members of the Pongidae family has been based on genetic evidence. The recent isolation of subtelomeric probes specific for human (HSA) chromosomes 1q, 11p, 13q, and 16q has prompted us to cross-hybridize these to the chromosomes of the chimpanzee (Pan troglodytes, PTR), gorilla (Gorilla gorilla, GGO), and orangutan (Pongo pygmaeus, PPY) to search for their equivalent locations in the great apes. Hybridization signals to the 1q subtelomeric DNA sequence probe were observed at the termini of human (HSA) 1q, PTR 1q, GGO 1q, PPY 1q, while the fluorescent signals to the 11p subtelomeric DNA sequence probe were observed at the termini of HSA 11p, PTR 9p, GGO 9p, and PPY 8p. Fluorescent signals to the 13q subtelomeric DNA sequence probe were observed at the termini of HSA 13q, PTR 14q, GGO 14q, and PPY 14q, and positive signals to the 16p subtelomeric DNA sequence probe were observed at the termini of HSA 16q, PTR 18q, GGO 17q, and PPY 19q. These findings apparently suggest sequence homology of these DNA families in the ape chromosomes. Obviously, analogous subtelomeric sequences exist in apes' chromosomes that apparently have been conserved through the course of differentiation of the hominoid species.Close

In this study, we assess the evolutionary relationships among different chromosomal copies of a subtelomeric block of sequence. This block contains homology to three olfactory receptor genes and is dispersed on at least 14 different chromosome ends in humans. It is single-copy in non-human primates. We analyzed single nucleotide polymorphisms in two 1 kb subregions and a polymorphic Alu insertion within 181 copies of this block from 12 chromosome ends and found evidence for recent interactions between the subtelomeric regions of non-homologous chromosomes. First, several sequence haplotypes are each present on multiple chromosomes, and several chromosomes each have multiple alleles with divergent haplotypes. Secondly, the observed variation clearly indicates that chromosomes 5q, 8p, 11p and/or 15q have each received the block from at least two different sources by non-homologous exchange. In addition, we observe at least one ectopic gene conversion event. Awareness of such exchange among sequences on non-homologous chromosomes is critical for accurate analysis of these complex and dynamic regions of the genome.Close

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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

Relative phylogenetic divergence of the members of the Pongidae family has been based on genetic evidence. The recent isolation of subtelomeric probes specific for human (HSA) chromosomes 1q, 11p, 13q, and 16q has prompted us to cross-hybridize these to the chromosomes of the chimpanzee (Pan troglodytes, PTR), gorilla (Gorilla gorilla, GGO), and orangutan (Pongo pygmaeus, PPY) to search for their equivalent locations in the great apes. Hybridization signals to the 1q subtelomeric DNA sequence probe were observed at the termini of human (HSA) 1q, PTR 1q, GGO 1q, PPY 1q, while the fluorescent signals to the 11p subtelomeric DNA sequence probe were observed at the termini of HSA 11p, PTR 9p, GGO 9p, and PPY 8p. Fluorescent signals to the 13q subtelomeric DNA sequence probe were observed at the termini of HSA 13q, PTR 14q, GGO 14q, and PPY 14q, and positive signals to the 16p subtelomeric DNA sequence probe were observed at the termini of HSA 16q, PTR 18q, GGO 17q, and PPY 19q. These findings apparently suggest sequence homology of these DNA families in the ape chromosomes. Obviously, analogous subtelomeric sequences exist in apes' chromosomes that apparently have been conserved through the course of differentiation of the hominoid species.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

In this study, we assess the evolutionary relationships among different chromosomal copies of a subtelomeric block of sequence. This block contains homology to three olfactory receptor genes and is dispersed on at least 14 different chromosome ends in humans. It is single-copy in non-human primates. We analyzed single nucleotide polymorphisms in two 1 kb subregions and a polymorphic Alu insertion within 181 copies of this block from 12 chromosome ends and found evidence for recent interactions between the subtelomeric regions of non-homologous chromosomes. First, several sequence haplotypes are each present on multiple chromosomes, and several chromosomes each have multiple alleles with divergent haplotypes. Secondly, the observed variation clearly indicates that chromosomes 5q, 8p, 11p and/or 15q have each received the block from at least two different sources by non-homologous exchange. In addition, we observe at least one ectopic gene conversion event. Awareness of such exchange among sequences on non-homologous chromosomes is critical for accurate analysis of these complex and dynamic regions of the genome.Close

The recent spreading of a subtelomeric region at nine different human chromosome ends was characterized by a combination of segregation analyses, physical mapping, junction cloning, and FISH investigations. The events occurred very recently in human genome evolution as demonstrated by sequence analysis of different alleles and the single location of the ancestral site at chromosome 17qter in chimpanzee and orangutan. The domain successfully colonized most 1p, 5q, and 6q chromosome ends and is also present at a significant frequency of 6p, 7p, 8p, 11p, 15q, and 19p ends. On 6qter, the transposed domain is immediately distal to the highly conserved, single-copy gene PDCD2.Close

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth disorder with a varying spectrum of clinical manifestations including macroglossia, omphalocele, hemihypertrophy, and a predisposition to a subset of embryonal tumors, most frequently Wilms' tumor (WT). A variety of cytogenetic, genetic linkage, and molecular mapping data implicate a gene or genes on chromosome band 11p15.5 in BWS and its related tumors. However, some families with BWS do not show linkage to 11p15, and other alterations have been found in Wilms' tumors as well. One such alteration is loss of heterozygosity (LOH) for chromosome arm 16q. Here we have analyzed a balanced t(11;16)(p15;q13) chromosomal translocation associated with the BWS phenotype and mapped the breakpoint positions for both chromosomes 11 and 16 by using somatic cell hybrids and polymorphic markers. The chromosome 11 breakpoint was found to lie distal to the D11S12 locus, but proximal to TH on 11p15.5, a region shown previously to contain other BWS-related chromosomal events. The chromosome 16 breakpoint was distal to D16S290 in 16q13, but proximal to loci D16S265, D16S267, and D16S164 in band 16q21. This area encompasses the region of LOH occurring through mitotic recombination in sporadic WT. This raises interesting possibilities for the genetic and epigenetic involvement of both chromosomal regions (11p15 and 16q13) in the pathogenesis of BWS and Wilms' tumor.Close

A female infant with severe growth-weight retardation and with a ring chromosome 11, associated with trisomy X in 15% of metaphases, has been reported. A literature review of cases of r(11) shows that the clinical features of these patients, although showing different frequencies, are similar to those of the del(11q) syndrome. It has been suggested that the variability of the mental retardation in r(11) patients is attributable to the unstability of the ring and to the different break points in these two chromosomal rearrangements. The origin of the r(11) was also addressed by studying fragile sites of the parents at 11p15 and 11q25.Close

We describe three unrelated cases of Wiedemann-Beckwith syndrome (WBS). Two of them were diagnosed postnatally while the third was detected during pregnancy that resulted in elective termination. Amniotic karyotypes were normal in all. PCR amplification of polymorphic loci mapping to 11p15.5 region documented partial trisomy of 11p15.5 due to paternal translocation in one, and segmental and mosaic segmental unipaternal disomy (UPD) in the second and third cases, respectively. Based on findings documented in these cases and the literature, we tabulated the anomalies that might be detected prenatally by ultrasound and that may suggest the syndrome. Constant findings included fetal overgrowth, polyhydramios, enlarged placenta, and specifically a distended abdomen. As most described signs developed after 22 weeks of gestation, a careful follow-up should be carried on until late stages of pregnancy. An amniotic karyotype might not detect subtle chromosomal rearrangements. We therefore recommend utilizing PCR of polymorphic loci on 11p15.5, in addition to conventional cytogenetic analysis of the fetus and both parents to detect possible maternal deletions or inversions, paternal duplications, and UPD that may account for the largest subset of sporadic WBS reaching 25% of cases. An early diagnosis of WBS is important for counseling the parents concerning potential risk for developing embryonic tumors, selection of the mode of delivery due to potential adrenal cysts that might bleed during labor, and prevention of neonatal hypoglycemia.Close

A contiguous physical map was constructed from the Harvey ras-1 (HRAS1) gene to the 11p telomere. The contig spans approximately 500 kb and is minimally composed of a telomere-containing YAC and P1 and cosmid clones. Included in the contig are 11 sequence-tagged sites derived from P1 and cosmid ends. Three genes were placed on the contig in the following order: telomere-ribonuclease/angiogenin inhibitor (RNH)-Harvey ras-1 (HRAS1)-HRAS1-related complex (HRC). Two novel tetranucleotide repeats (heterozygosity of 66 and 68%) and a complex CA repeat (heterozygosity of 78%) were isolated and characterized.Close

To define the region of 11p15 involved in Beckwith-Wiedemann syndrome (BWS), we have carried out a molecular genetic analysis of six patients with features of BWS and constitutional cytogenetic abnormalities involving chromosome band 11p15. Molecular analysis confirmed the 11p origin of the duplicated material and defined the smallest region of overlap for such duplications, within which a gene involved in BWS must be located. This region encompasses the beta-globin gene complex (HBB) to 11pter. In both of our informative cases, the 11p duplication was found to be of paternal origin. Two BWS associated balanced translocations of 11p15 were studied to localize the breakpoints on 11p15. Somatic cell hybrids, Southern blotting and fluorescent in situ hybridization (FISH) showed that both breakpoints were between D11S12 and the insulin-like growth factor 2 (IGF2) gene. A non-BWS translocation breakpoint was more proximal, between HBB and calcitonin-A (CALCA). Pedigree analysis showed that both BWS associated 11p15 translocations were transmitted by phenotypically normal mothers. The data are compatible with the hypothesis that the BWS gene is imprinted and that the maternally inherited BWS gene is normally suppressed whereas the paternally inherited allele is active. Thus, duplications of paternal origin would lead to increased dosage of the BWS gene. Similarly increased dosage of the BWS gene could account for the findings in maternally inherited 11p15 translocations by altering normal imprinting, so that the translocated maternal allele remains active. This study defines one or more gene loci for BWS on 11p15.5 in the genomic region from D11S12 to IGF2.Close