Showing papers on "Chromosome 21 published in 1992"

Cytogenetic analysis by chromosome painting using dop-pcr amplified flow-sorted chromosomes

Abstract: A novel polymerase chain reaction (PCR) technique has been combined with chromosome flow sorting to characterise two lymphoblastoid cell lines and one medullary thyroid carcinoma cell line carrying translocations close to the locus for multiple endocrine neoplasia type 2A (MEN 2A). Five hundred copies of the derivative chromosome(s) were flow sorted from each cell line and amplified by degenerate oligonucleotide-primed-polymerase chain reaction (DOP-PCR). This generated pools of DNA sequences corresponding to the abnormal chromosomes, which were then used as probes in fluorescence in situ hybridisation (FISH) experiments on normal metaphase cells. The resultant chromosome paints revealed the portions of the normal chromosomes related to those involved in the translocations. By this technique, translocation breakpoints in bands p15, q11.2, and q21 of chromosome 10 were defined in the above cell lines, in two cases refining previous cytogenetic data. This study shows that flow sorting of aberrant chromosomes and chromosome painting can be used as a rapid aid to cytogenetic analysis, particularly in cases of difficult karyotypes, such as tumours. Furthermore, the DOP-PCR technique described here will have applications to other areas of genome analysis, such as cloning of new markers; its design will allow a general and representative amplification to occur from any starting DNA in any species.

The human Y chromosome: a 43-interval map based on naturally occurring deletions.

Abstract: A deletion map of the human Y chromosome was constructed by testing 96 individuals with partial Y chromosomes for the presence or absence of many DNA loci. The individuals studied included XX males, XY females, and persons in whom chromosome banding had revealed translocated, deleted, isodicentric, or ring Y chromosomes. Most of the 132 Y chromosomal loci mapped were sequence-tagged sites, detected by means of the polymerase chain reaction. These studies resolved the euchromatic region (short arm, centromere, and proximal long arm) of the Y chromosome into 43 ordered intervals, all defined by naturally occurring chromosomal breakpoints and averaging less than 800 kilobases in length. This deletion map should be useful in identifying Y chromosomal genes, in exploring the origin of chromosomal disorders, and in tracing the evolution of the Y chromosome.

Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14

Abstract: Familial Alzheimer's disease (FAD) has been shown to be genetically heterogeneous, with a very small proportion of early onset pedigrees being associated with mutations in the amyloid precursor protein (APP) gene on chromosome 21, and some late onset pedigrees showing associations with markers on chromosome 19. We now provide evidence for a major early onset FAD locus on the long arm of chromosome 14 near the markers D14S43 and D14S53 (multipoint lod score z = 23.4) and suggest that the inheritance of FAD may be more complex than had initially been suspected.

The human Y chromosome: overlapping DNA clones spanning the euchromatic region

Abstract: The human Y chromosome was physically mapped by assembling 196 recombinant DNA clones, each containing a segment of the chromosome, into a single overlapping array. This array included more than 98 percent of the euchromatic portion of the Y chromosome. First, a library of yeast artificial chromosome (YAC) clones was prepared from the genomic DNA of a human XYYYY male. The library was screened to identify clones containing 160 sequence-tagged sites and the map was then constructed from this information. In all, 207 Y-chromosomal DNA loci were assigned to 127 ordered intervals on the basis of their presence or absence in the YAC's, yielding ordered landmarks at an average spacing of 220 kilobases across the euchromatic region. The map reveals that Y-chromosomal genes are scattered among a patchwork of X-homologous, Y-specific repetitive, and single-copy DNA sequences. This map of overlapping clones and ordered, densely spaced markers should accelerate studies of the chromosome.

Continuum of overlapping clones spanning the entire human chromosome 21q.

Abstract: A continuous array of overlapping clones covering the entire human chromosome 21q was constructed from human yeast artificial chromosome libraries using sequence-tagged sites as landmarks specifically detected by polymerase chain reaction. The yeast artificial chromosome contiguous unit starts with pericentromeric and ends with subtelomeric loci of 21q. The resulting order of sequence-tagged sites is consistent with other physical and genetic mapping data. This set of overlapping clones will promote our knowledge of the structure of this chromosome and the function of its genes.

Mapping of a gene predisposing to early-onset Alzheimer's disease to chromosome 14q24.3

Abstract: Genetic linkage studies with chromosome 21 DNA markers and mutation analysis of the beta-amyloid protein precursor gene located in 21q21.3 have indicated that early-onset Alzheimer's disease (EOAD) is a heterogeneous disorder for which at least one other chromosomal locus exists. We examined two extended histopathologically confirmed EOAD pedigrees, AD/A and AD/B, with highly informative short tandem repeat (STR) polymorphisms and found complete linkage of the disease to a (CA)n dinucleotide repeat polymorphism at locus D14S43 in 14q24.3 (Zmax = 13.25 at theta = 0.0). Using additional chromosome 14 STR polymorphisms we were able to delineate the region containing the EOAD gene to an area of, at most, 8.9 centiMorgans between D14S42 and D14S53, flanking D14S43 on both sides.

A locus for familial early–onset Alzhelmer's disease on the long arm of chromosome 14, proximal to the α1–antichymotrypsin gene

Abstract: Although mutations in the beta-amyloid precursor protein gene (APP) on chromosome 21 cause some cases of early-onset Alzheimer's disease (AD), most cases evidently do not have mutations in APP. We analysed ten early-onset families for linkage to APP and markers elsewhere in the genome. One family (F172) was consistent with linkage to chromosome 21 and was subsequently found to have an APP Val to Ile mutation. Of the others, all but one were consistent with linkage to markers in the middle long arm of chromosome 14. However, no family showed independent evidence of linkage with two point analysis and only one showed independent evidence of linkage on multipoint analysis. Therefore, we cannot rule out heterogeneity at these loci although tests for heterogeneity were not significant.

Peripheral myelin protein–22 gene maps in the duplication in chromosome 17p11.2 associated with Charcot–Marie–Tooth 1A

Abstract: Charcot–Marie–Tooth disease 1A (CMT1A) is a hereditary demyelinating peripheral neuropathy, associated with a DNA duplication on chromosome 17p11.2. A related disorder in the mouse, trembler (Tr), maps to mouse chromosome 11 which has syntenic homology to human chromosome 17p. Recently, the peripheral myelin protein–22 (pmp–22) gene was identified as the likely Tr locus. We have constructed a partial yeast artificial chromosome contig spanning the CMT1A gene region and mapped the PMP–22 gene to the duplicated region. These observations further implicate PMP–22 as a candidate gene for CMT1A, and suggest that over–expression of this gene may be one mechanism that produces the CMT1A phenotype.

Maternal age effect: The enigma of Down syndrome and other trisomic conditions

Abstract: Aneuploidy is the most frequently observed chromosome abnormality in human liveborn, abortuses and oocytes. The only etiological factor that has been established is advanced maternal age for the occurrence of trisomies, particularly trisomy 21 which causes Down syndrome. The maternal age effect remains an enigma. Recent molecular data bearing on this question are reviewed as are the hypotheses that have been proposed linking nondisjunction and maternal age. Rationale is presented for a compromised microcirculation hypothesis that explains the cause of nondisjunction and why its occurrence changes with maternal age from menarche to menopause. It takes into account two facts: (1) 95% of Down syndrome children receive their extra chromosome from their mother, and in 80% or more of these the nondisjunction occurred in the first meiotic division, which is completed in the ovary. (2) The ovarian follicle containing the primary oocyte has no internal circulation. The hypothesis proposes that aneuploid oocytes arise from a concatenation of events. It begins with hormonal imbalance that causes a less-than-optimal microvasculature to develop around the maturing and mature follicles. The resulting decrease in the size of the perifollicular capillary bed reduces the volume of blood flow through the area, leading to an oxygen deficit and a concomitant increase inside the follicle of carbon dioxide and anaerobic products, such as lactic acid. This in turn causes a decrease in the intracellular pH of the oocyte that diminishes the size of the spindle, with consequent displacement and nondisjunction of a chromosome. The compromised microcirculation hypothesis explains the occurrence of aneuploidy in primary and secondary oocytes, sperm precursor cells, tumor and embryonic cells. It also explains why women of all reproductive ages may have a Down syndrome child.

A Third Wilms' Tumor Locus on Chromosome 16q

Abstract: Loss of heterozygosity studies have been used to identify chromosomal regions which are frequently deleted and thus indicate areas which may harbor tumor suppressor genes. As a result, both the WT1 gene located in chromosome 11p13 and an unidentified gene(s) within chromosome 11p15 have been implicated in Wilms' tumorigenesis. Cytogenetic and linkage studies suggest that additional non-chromosome 11 sites are involved in Wilms' tumor. Because these sites may also involve loss of heterozygosity, loci on 33 autosomal arms were screened for allele loss in a series of Wilms' tumors. We found that in addition to loss on chromosome 11p (11 of 25 informative tumors) there was significant loss on chromosome 16q (9 of 45 informative tumors), while the total frequency of allele loss excluding these loci was low (9 of 426 total informative loci). These data indicate that losses of both chromosome 11p and 16q alleles are nonrandom events and suggest that 16q is the location of a third tumor suppressor gene underlying Wilms' tumorigenesis. The parental origin of the lost chromosome 16q allele was determined in eight sporadic tumors. Alleles of paternal and of maternal origin were each lost in four sporadic tumors indicating that, unlike chromosome 11p, alleles of either parental origin are lost on 16q.

Reverse chromosome painting: a method for the rapid analysis of aberrant chromosomes in clinical cytogenetics.

Abstract: We describe a method, termed reverse chromosome painting, which allows the rapid analysis of the content and breakpoints of aberrant chromosomes. The method involves the sorting of small numbers of the aberrant chromosome from short term blood culture preparations or cell lines by using bivariate flow karyotype analysis. The sorted chromosomes are amplified and biotin labelled enzymatically using a degenerate oligonucleotide-primed polymerase chain reaction (DOP-PCR), the product annealed to metaphase spreads from normal subjects, and hybridisation detected using fluorescence in situ hybridisation (FISH). We show the usefulness of this method for routine clinical cytogenetics by the analysis of cases involving an insertion, a deletion, a translocation, and two cases of a chromosome with additional material of unknown origin. The method has particular application for the rapid resolution of the origin of de novo unbalanced chromosome duplications.

Homologies in human and Macaca fuscata chromosomes revealed by in situ suppression hybridization with human chromosome specific DNA libraries.

Abstract: We established chromosomal homologies between all chromosomes of the human karyotype and that of an old world monkey (Macaca fuscata) by chromosomal in situ suppression (CISS) hybridization with human chromosome specific DNA libraries. Except for the human chromosome 2 library and limited cross-hybridization of X and Y chromosome libraries all human DNA libraries hybridized to single GTG-banded macaque chromosomes. Only three macaque chromosomes (2, 7, 13) were each hybridized by two separate human libraries (7 and 21, 14 and 15, 20 and 22 respectively). Thus, an unequivocally high degree of synteny between human and macaque chromosomes has been maintained for more than 20 million years. As previously suggested, both Papionini (macaques, baboons, mandrills and cercocebus monkeys, all of which have nearly identical karyotypes) and humans are chromosomally conservative. The results suggest, that CISS hybridization can be expected to become an indispensable tool in comparative chromosome and gene mapping and will help clarify chromosomal phylogenies with speed and accuracy.

Down syndrome: molecular mapping of the congenital heart disease and duodenal stenosis.

Abstract: Down syndrome (DS) is a major cause of congenital heart and gut disease and mental retardation. DS individuals also have characteristic facies, hands, and dermatoglyphics, in addition to abnormalities of the immune system, an increased risk of leukemia, and an Alzheimer-like dementia. Although their molecular basis is unknown, recent work on patients with DS and partial duplications of chromosome 21 has suggested small chromosomal regions located in band q22 that are likely to contain the genes for some of these features. We now extend these analyses to define molecular markers for the congenital heart disease, the duodenal stenosis, and an "overlap" region for the facial and some of the skeletal features. We report the clinical, cytogenetic, and molecular analysis of two patients. The first is DUP21JS, who carries both a partial duplication of chromosome 21, including the region 21q21.1-q22.13, or proximal q22.2, and DS features including duodenal stenosis. Using quantitative Southern blot dosage analysis and 15 DNA sequences unique to chromosome 21, we have defined the molecular extent of the duplication. This includes the region defined by DNA sequences for APP (amyloid precursor protein), SOD1 (CuZn superoxide dismutase), D21S47, SF57, D21S17, D21S55, D21S3, and D21S15 and excludes the regions defined by DNA sequences for D21S16, D21S46, D21S1, D21S19, BCE I (breast cancer estrogen-inducible gene), D21S39, and D21S44. Using similar techniques, we have also defined the region duplicated in the second case occurring in a family carrying a translocation associated with DS and congenital heart disease. This region includes DNA sequences for D21S55 and D21S3 and excludes DNA sequences for D21S47 and D21S17.(ABSTRACT TRUNCATED AT 250 WORDS)

The chromosome complement of human gametes.

Abstract: The comparisons of observed and predicted rates of chromosomally abnormal gametes for two major classes of abnormality and for three specific trisomies are summarized in Table 2.10. As can be seen there is not very good agreement between the two sets of data. For sperm the observed abnormality rates are, with the exception of polyploidy, all in excess of those predicted. For structural abnormalities the excess is absurd and suggests that most structural abnormalities seen in sperm chromosomes may be preparation artefacts. On the other hand, it could be argued that the excess of hyperhaploidy among sperm is real and represents those trisomic conceptuses lost in the early stages of pregnancy. However, both chromosome 21 and the sex chromosomes are represented more often than any other chromosomes. Recent observations among all clinically recognized pregnancies do not suggest an excess of trisomy 21 conceptions arising from non-disjunction in spermatogenesis. As can be seen from Table 2.10, the observed frequencies of trisomy 21 is 10 times greater than that predicted, a difference that seems too great to be accounted for by early pregnancy wastage. While the X chromosome does appear to undergo non-disjunction much more frequently than the autosomes during spermatogenesis, the increase is restricted to non-disjunction of the XY bivalent at the first male meiotic division. In this class the observed and predicted frequencies are rather similar and it is even possible that the observed excess in sperm is accounted for by early post-zygotic loss. However, with the exception of the 24, XY class, the distribution of individual chromosomes among the hyperhaploid sperm bears little relation to that predicted. The most likely explanation for this is that banding of sperm chromosomes is of such poor quality that there are many errors in the identification of individual chromosomes. Most authors use some form of Q banding and this technique should give unequivocal identification of the highly-fluorescent Y chromosome even when other chromosomes are not clearly distinguishable. An increased accuracy of Y-chromosome identification may account for the relative concordance between observed and predicted rates of 24, XY sperm. By the same argument, 24, YY sperm might be expected to be accurately enumerated.(ABSTRACT TRUNCATED AT 400 WORDS)

SOD2: a new type of tumor-suppressor gene?

Abstract: The activity of superoxide dismutases (SOD) 1 and 2 was analysed in correlation with mRNA and chromosome content in 6 SV40-transformed (TF) and in non-transformed (NF) human fibroblast cell lines. Total SOD activity was fairly constant, whereas the ratio SOD2/SOD1 was much lower in TF than in NF. The decrease in SOD2 activity was correlated with a low mRNA content, and with the presence of various chromosomal rearrangements leading to deletions of the long arm of chromosome 6 where the gene is mapped. In contrast, chromosome 21, carrying the gene for SOD1, was not found to be deficient and the SOD1 activity was high. This shows that in TF, the activity of SOD2 is largely determined by gene dosage. It has been proposed that SOD activity could be inversely correlated with cell proliferation, and that SOD2 activity, in particular, was related to cell differentiation. Thus, there is a cascade of events occurring in cell transformation, involving gene deregulation, chromosome (gene) deletion, low mRNA and protein content, low enzyme activity, and acquisition of growth advantage which makes the SOD2 gene a possible new type of tumor-suppressor gene.

Prader-Willi syndrome and Angelman syndrome in cousins from a family with a translocation between chromosomes 6 and 15.

Abstract: PRADER—WILLI syndrome represents the most common form of genetic obesity and is associated with mental retardation, short stature, sexual infantilism, and hypotonia1 2 3 4 5 6 (Table 1). In about 60 percent of affected persons a microscopically visible interstitial deletion in chromosome 15 (band ql2) is observed,2 , 3 , 7 8 9 10 and in up to 75 percent deletions can be found at the molecular level.11 122 13 14 DNA studies with polymorphic markers have indicated that in Prader-Willi syndrome the aberrant chromosome 15 is always of paternal origin,11 , 12 suggesting that the two parental chromosomes are differently imprinte1515 and that the presence of a gene or genes on the paternally . . .

The presence of interstitial telomeric sequences in constitutional chromosome abnormalities.

Abstract: We describe a novel chromosome structure in which telomeric sequences are present interstitially, at the apparent breakpoint junctions of structurally abnormal chromosomes. In the linear chromosomes with interstitial telomeric sequences, there were three sites of hybridization of the telomere consensus sequence within each derived chromosome: one at each terminus and one at the breakpoint junction. Telomeric sequences also were observed within a ring chromosome. The rearrangements examined were constitutional chromosome abnormalities with a breakpoint assigned to a terminal band. In each case (with the exception of the ring chromosome), an acentric segment of one chromosome was joined to the terminus of an apparently intact recipient chromosome. One case exhibited apparent instability of the chromosome rearrangement, resulting in somatic mosaicism. The rearrangements described here differ from the telomeric associations observed in certain tumors, which appear to represent end-to-end fusion of two or more intact chromosomes. The observed interstitial telomeric sequences appear to represent nonfunctional chromosomal elements, analogous to the inactivated centromeres observed in dicentric chromosomes.

Organization and nucleotide sequence of the human KIT (mast/stem cell growth factor receptor) proto-oncogene.

Abstract: We have cloned and sequenced the human KIT proto-oncogene, which contains 21 exons and spans more than 34 kb of DNA on chromosome segment 4q12. We also establish physical linkage between the KIT gene and the related PDGFRA gene. The organization of the KIT gene is virtually identical to that of the homologous FMS gene, located on chromosome 5. Together, these data suggest that the KIT and PDGFRA genes on chromosome 4 and the FMS and PDGFRB genes on chromosome 5 arose by duplication of a common ancestral gene, followed by duplication of a chromosome.

Automated DNA sequencing and analysis of 106 kilobases from human chromosome 19q13.3

Abstract: A total of 116,118 basepairs (bp) derived from three cosmids spanning the ERCC1 locus of human chromosome 19q13.3 have been sequenced with automated fluorescence-based sequencers and analysed by polymerase chain reaction amplification and computer methods. The assembled sequence forms two contigs totalling 105,831 bp, which contain a human fosB proto-oncogene, a gene encoding a protein phosphatase, two genes of unknown function and the previously-characterized ERCC1 DNA repair gene. This light band region has a high average density of 1.4 Alu repeats per kilobase. Human chromosome light bands could therefore contain up to 75,000 genes and 1.5 million Alu repeats.

Mechanisms of ring chromosome formation in 11 cases of human ring chromosome 21.

Abstract: We studied the mechanism of ring chromosome 21 (r(21)) formation in 13 patients (11 unique r(21)s), consisting of 7 from five families with familial r(21) and 6 with de novo r(21). The copy number of chromosome 21 sequences in the rings of these patients was determined by quantitative dosage analyses for 13 loci on 21q. Nine of 11 r(21)s, including the 5 familial r(21)s, showed no evidence for duplication of 21q sequences but did show molecular evidence of partial deletion of 21q. These data were consistent with the breakage and reunion of short- and long-arm regions to form the r(21), resulting in deletion of varying amounts of 21q22.1 to 21qter. The data from one individual who had a Down syndrome phenotype were consistent with asymmetric breakage and reunion of 21q sequences from an intermediate isochromosome or Robertsonian translocation chromosome as reported by Wong et al. Another patient, who also exhibited Down syndrome, showed evidence of a third mechanism of ring formation. The likely initial event was breakage and reunion of the short and long arms, resulting in a small r(21), followed by a sister-chromatid exchange resulting in a double-sized and symmetrically dicentric r(21). The phenotype of patients correlated well with the extent of deletion or duplication of chromosome 21 sequences. These data demonstrate three mechanisms of r(21) formation and show that the phenotype of r(21) patients varies with the extent of chromosome 21 monosomy or trisomy.

Isolation of chromosome 21-specific yeast artificial chromosomes from a total human genome library.

Abstract: A new approach for the isolation of chromosome–specific subsets from a human genomic yeast artificial chromosome (YAC) library is described. It is based on the hybridization with an Alu polymerase chain reaction (PCR) probe. We screened a 1.5 genome equivalent YAC library of megabase insert size with Alu PCR products amplified from hybrid cell lines containing human chromosome 21, and identified a subset of 63 clones representative of this chromosome. The majority of clones were assigned to chromosome 21 by the presence of specific STSs and in situ hybridization. Twenty–nine of 36 STSs that we tested were detected in the subset, and a contig spanning 20 centimorgans in the genetic map and containing 8 STSs in 4 YACs was identified. The proposed approach can greatly speed efforts to construct physical maps of the human genome.

A non-isotopic in situ hybridisation study of the chromosomal origin of 15 supernumerary marker chromosomes in man.

Abstract: Fifteen patients presenting with mosaic or non-mosaic karyotypes containing a distamycin-DAPI negative de novo or familial supernumerary marker chromosome were studied with non-isotopic in situ hybridisation using a library of alphoid centromere specific and satellite II/III probes. The in situ hybridisation studies showed that seven markers were derived from satellited autosomes (three chromosome 13/21, two chromosome 14, two chromosome 22), six from non-satellited autosomes (two chromosome 4, one chromosome 12, one chromosome 16, two chromosome 19), and one from the Y chromosome. One non-mosaic marker was negative for all the alphoid and satellite II/III probes used.

Distribution of telomeric repeats and their role in the healing of broken chromosome ends in wheat

Abstract: The distribution of the telomeric repeats in common wheat and their role in the healing of broken ends of deleted chromosomes was studied. In situ hybridization to mitotic chromosomes was carried out using a synthetic probe that was derived from the sequence of the telomeric repeats of Arabidopsis thaliana. Sites of hybridization were visualized as double dots at both ends of each wheat chromosome. Variation in the strength of the signal that was detected among chromosome arms might be due to the variable number of telomeric repeats of each chromosome end. While signals were absent on normal chromosomes at the pericentric and intercalary regions, hybridization sites were detected at the broken chromosome ends of all deleted chromosomes included in the study. All telocentric chromosomes of multitelocentric lines of 'Chinese Spring' showed a strong signal at the centromeric region. The results suggest that a de novo chromosome healing mechanism exists in wheat involving the addition of the telomeric sequenc...

Loss of chromosome 3 alleles and multiplication of chromosome 8 alleles in uveal melanoma

Abstract: Uveal melanoma is the most frequent primary intraocular tumor. The etiology is unknown. Using neutral DNA polymorphisms on chromosomes 2, 3, and 8, we have detected loss of chromosome 3 alleles in 8 of 13 tumors and multiplication of chromosome 8 alleles in 6 of 11 tumors. No anomalies at a locus on chromosome 2 were found in 10 of 10 tumors. These results confirm and extend previous cytogenetic findings and suggest that a tumor suppressor gene on chromosome 3 and an oncogene on chromosome 8 may be involved in the formation or progression of this tumor.

Consistent Disruption of the AML1 Gene Occurs within a Single Intron in the t(8;21) Chromosomal Translocation

Abstract: The AML1 gene on chromosome 21 was rearranged by the t(8;21) chromosomal translocation in acute myeloid leukemia (AML). Southern blot analysis of 21 AML patients with t(8;21), including three with complex translocations, t(8;V;21), demonstrated that all the breakpoints occurred at random within a single intron between two coding exons of AML1. Clustering of the breakpoints in the restricted intron suggests the formation of a unique fusion gene between the AML1 gene and a presumable counterpart gene on chromosome 8. Nucleotide sequencing of the breakpoint region revealed that the translocation event was accompanied by deletion of a short stretch of nucleotides.

A genetic linkage map of human chromosome 21: analysis of recombination as a function of sex and age.

Abstract: A genetic linkage map of human chromosome 21 has been constructed using 22 anonymous DNA markers and five complementary DNAs (cDNAs) encoding the amyloid beta protein precursor (APP), superoxide dismutase 1 (SOD1), the ets-2 proto-oncogene (ETS2), the estrogen inducible breast cancer locus (BCEI), and the leukocyte antigen, CD18 (CD18). Segregation of RFLPs detected by these DNA markers was traced in the Venezuelan Reference Pedigree (VRP). A comprehensive genetic linkage map consisting of the 27 DNA markers spans 102 cM on the long arm of chromosome 21. We have confirmed our initial findings of a dramatically increased rate of recombination at the telomere in both females and males and of significantly higher recombination in females in the pericentromeric region. By comparing patterns of recombination in specific regions of chromosome 21 with regard to both parental sex and age, we have now identified a statistically significant downward trend in the frequency of crossovers in the most telomeric portion of chromosome 21 with increasing maternal age. A less significant decrease in recombination with increasing maternal age was observed in the pericentromeric region of the chromosome. These results may help in ultimately understanding the physical relationship between recombination and nondisjunction in the occurrence of trisomy 21.

Comparative study of microsatellite and cytogenetic markers for detecting the origin of the nondisjoined chromosome 21 in Down syndrome.

Abstract: Nondisjunction in trisomy 21 has traditionally been studied by cytogenetic heteromorphisms. Those studies assumed no crossing-over on the short arm of chromosome 21. Recently, increased accuracy of detection of the origin of nondisjunction has been demonstrated by DNA polymorphism analysis. We describe a comparative study of cytogenetic heteromorphisms and seven PCR-based DNA polymorphisms for detecting the origin of the additional chromosome 21 in 68 cases of Down syndrome. The polymorphisms studied were the highly informative microsatellites at loci D21S215, D21S120, D21S192, IFNAR, D21S156, HMG14, and D21S171. The meiotic stage of nondisjunction was assigned on the basis of the pericentromeric markers D21S215, D21S120, and D21S192. Only unequivocal cytogenetic results were compared with the results of the DNA analysis. The parental and meiotic division origin could be determined in 51% of the cases by using the cytogenetic markers and in 88% of the cases by using the DNA markers. Although there were no discrepancies between the two scoring systems regarding parental origin, there were eight discrepancies regarding meiotic stage of nondisjunction. Our results raise the possibility of recombination between the two marker systems, particularly on the short arm.