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Linkage analysis in adenomatous polyposis coli families in the United Kingdom, and a search for highly polymorphic markers

Cachon-Gonzalez, Maria Begona; (1991) Linkage analysis in adenomatous polyposis coli families in the United Kingdom, and a search for highly polymorphic markers. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Familial adenomatous polyposis (FAP), also known as adenomatous polyposis coli (APC), is a relatively common autosomal dominant disorder characterized by the development of hundreds to thousands of pre-malignant adenomatous polyps in the colon and rectum by the third decade of life in most affected individuals. Colonic polyposis with the addition of extracolonic lesions was formerly considered to constitute a distinct syndrome first described by Gardner. The gene for APC has been mapped to chromosome 5, region q21-22, by linkage to the DNA marker, C11p11 (D5S71). Linkage to the more informative markers, n227 (D5S37), ECB27 (D5S98) and YN5.48 (D5S81) was subsequently reported. The evidence now available suggests that Gardner's syndrome maps to the same region of chromosome 5 as APC and the prevailing opinion is that the two cannot be clinically distinguished. This study comprised 26 families, 206 individuals, segregating for FAP. The DNA markers used for the linkage analysis were C11p11, n227, ECB27 and YN5.48. The purpose was to estimate the genetic distance between these markers and the disease locus in order to be able to assess the reliability of these markers for prenatal and presymtomatic diagnosis of FAP. Not a single gene order could be established from our data, although either of the orders 227-Cllpll-ECB27-APC-YN5.48 or 227-C11p11-ECB27-YN5.48-APC were possible. The genetic distances were estimated as 17 cM between n227 and AFC, 4 cM between n227 and ECB27. YN5.48 was found to be extremely close to AFC, with the highest lod score obtained at a recombination fraction of nought. Although the DNA markers were quite informative, there were instances where none or only one was informative in a given family. The recent discovery of frequent length variation in dinucleotide (C-A) repeats which are uniformly spaced throughout the genome, provides the basis for the isolation of potentially informative markers. The construction of a cosmid library was undertaken and it was subsequently screened with all the DNA probes. Two different clones were isolated using ECB27, both of which contain the same (C-A) repeat. One of them was sequenced and found to be repeated nine times. When tested for its polymorphic value it gave two alleles, one corresponding to (C-A)9 the other to (C-A) 10. This polymorphic marker showed complete linkage disequilibrium with ECB27.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Linkage analysis in adenomatous polyposis coli families in the United Kingdom, and a search for highly polymorphic markers
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Autosomal dominant disorders
URI: https://discovery.ucl.ac.uk/id/eprint/10111301
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