We have used radiation hybrid (RH) mapping and pulsedfield gel electrophoresis (PFGE) to determine the order and positions of 28 DNA markers from the distal region of the long arm of human chromosome 21. The maps generated by these two methods are in good agreement. This study, combined with that of D. R. Cox et al. (1990, Science 250:245–250), results in an RH map that covers the long arm of chromosome 21 (21q). We have used a subtelomeric probe to show that our map includes the telomere and have identified single-copy genes and markers within 200 kbp of the telomere. Comparison of the physical and RH maps with genetic linkage maps shows “hot spots” of meiotic recombination in the distal region, one of which is close to the telomere, in agreement with previous cytogenetic observations of increased recombination frequency near telomeres.
"Originally, the pS2 gene was mapped to 21q22.3 by pulsed-field gel electrophoresis (Moisan et al. 1985) and later placed at a distance of about 4 Mb from the telomere (Burmeister et al. 1991). Consecutively, the second trefoil peptide gene (SML1/hSP) was assigned to the same region (Theisinger et al. 1992; Tomasetto et al. 1992). "
[Show abstract][Hide abstract] ABSTRACT: A group of small peptides with a typical cysteine-rich domain (termed trefoil motif or P-domain) is abundantly expressed at mucosal surfaces of specific normal and neoplastic tissues. Their association with the maintenance of surface integrity was suggested. The first known human trefoil peptide (pS2) was isolated from breast cancer cells (MCF7). Its oestrogen-inducible gene, and the human homologue to the porcine spasmolytic peptide gene (hSP/SML1) appear synchronously expressed in healthy stomach mucosa and several carcinomas of the gastrointestinal tract. Both genes were shown to be localised at 21q22.3. A new trefoil peptide from human intestinal mucosa (hITF/hP1.B) and its gene were described recently. By using suitable oligonucleotide primers and PCR and isolating large (110-250 kb) genomic recombinants cloned in the bacterial artificial chromosome (BAC) system, we present a genomic region from chromosome band 21q22.3 cloned in contiguous sequences and encoding all three members of human P-domain/trefoil peptides proving a physical linkage of all three trefoil peptide genes. Such genomic sequences will provide useful experimental material for analysis of gene regulation, for gene modification experiments and for establishing transgenic cells or animals.
Human Genetics 09/1996; 98(2):233-5. DOI:10.1007/s004390050198 · 4.82 Impact Factor
"This precedent notwithstanding, our data are consistent with a single mutation identical by descent. Lack of homozygosity may be attributed to high recombination rates associated with telomeric regions of most chromosomes , including chromosome 21 (Tanzi et al. 1988; Burmeister et al. 1991; Petersen et al. 1991). Excessive recombination may have led to the occurrence of the large number of haplotypes observed in a single inbred family (table 2). "
[Show abstract][Hide abstract] ABSTRACT: Deafness is a heterogeneous trait affecting approximately 1/1,000 newborns. Genetic linkage studies have already implicated more than a dozen distinct loci causing deafness. We conducted a genome search for linkage in a large Palestinian family segregating an autosomal recessive form of nonsyndromic deafness. Our results indicate that in this family the defective gene, DFNB10, is located in a 12-cM region near the telomere of chromosome 21. This genetic distance corresponds to <2.4 Mbp. Five marker loci typed from this region gave maximum LOD scores > or = to 3. Homozygosity of marker alleles was evident for only the most telomeric marker, D21S1259, suggesting that DFNB10 is closest to this locus. To our knowledge, this is the first evidence, at this location, for a gene that is involved in the development or maintenance of hearing. As candidate genes at these and other deafness loci are isolated and characterized, their roles in hearing will be revealed and may lead to development of mechanisms to prevent deafness.
The American Journal of Human Genetics 06/1996; 58(6):1254-9. · 10.93 Impact Factor
"For example, when the Haldane Analysis of Disease Gene Loci mapping function is used, the error is amplified by factors of 1.2, 2.8, 6.3, and 25.0 for u Å 0.1, 0.2, 0.3, and The method has been tested on clusters of closely linked markers that bracket loci known to be involved 0.4, respectively. For the RH mapping function, the / m4275$3717 10-05-95 07:48:16 gnmas AP-Genomics FIG. 4. Map constructed from the combined radiation hybrid data sets of Cox et al. (1990) and Burmeister et al. (1991) for human chromosome 21. The scale is in units of R 8000 , and the marker width obtained from 1 cR 8000 É 0.05 Mb (Cox et al., 1990). "
[Show abstract][Hide abstract] ABSTRACT: The techniques of distance geometry, which generate coordinates from observed interpoint distances, have been applied to the problem of determining the relative positions of linked genetic loci from observed interlocus distances. Only the most precise data needed to join the loci are used, with missing distances substituted by sums of precise intermediate distances. Good initial positions (and therefore the order) of loci on a linear map are obtained in an operation of complexity O(N3). The method can therefore be used to generate good initial framework maps for the large numbers of markers encountered in current mapping projects. The locus positions can be subsequently refined to maximize the agreement with the originally observed distances, taking account of the weights of individual interlocus distances. By choosing only small distances from which to construct the map, the method reduces any error due to an incorrect choice of mapping function. It also prevents undue expansion of the map due to error-prone markers, since such markers are accommodated in higher dimensions. The method estimates the error in the positions of individual markers on the final map and identifies well- and ill-defined regions of the map.
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