A highly polymorphic locus very tightly linked to the Huntington's disease gene

Abstract

The genetic defect in Huntington's disease (HD), an inherited neuropsychiatric disorder of unknown etiology, has not been defined. The discovery of linkage between HD and the DNA marker D4S10(G8) raised the possibility of isolating the disease gene on the basis of its chromosomal location, in addition to providing a limited presymptomatic test for the late onset disorder. But it has been difficult to isolate other DNA markers nearer to the HD gene, and this has hampered attempts to identify the disease locus and limited the applicability and accuracy of predictive testing. Recently, several new DNA markers from the region of the genome near the HD gene have been isolated using a directed cloning strategy. We describe here the characterization of one of these new markers, D4S95, a highly polymorphic locus which displays no recombination with the HD gene in the families tested. The high degree of polymorphism at this locus and its proximity to the HD gene make it extremely useful for predictive testing and as a new starting point for attempts to clone the disease gene.

Clustering of multiallele DNA markers near the Huntington's disease gene.

“…Two ofthese, D4S43 and D4S95 have been shown to be more tightly linked to HD than D4S10 (5,6). In this study, we have concentrated on expanding the previously described D4S43 locus, and on finding RFLPs for D4S11I1 and D4S 1 15, two loci representing NotI-linking clones mapped by physical means distal to D4S10 and D4S43 (9).…”

“…A second probe for this locus, S281, is a 2.3 kb Eco RI fragment excised from the adjacent cosmid S28. The probes YNZ32 representing D4S125 and pBS674 representing D4S95 have been described previously (6,11,12).…”

“…Linkage analysis with DNA markers has localized the site of the genetic defect to the tip of the chromosome 4 short arm, 3-4 cM distal to the anonymous DNA marker D4S10 (2)(3)(4). Two additional polymorphic markers D4S43, and D4S95, have recently been located closer to the telomere than D4S10 and both show very tight linkage with the disease gene (5,6).…”

The potential for misusing “genetic predisposition” in Canadian courts and tribunals: Table 1:

“…Although increased communication of genetic information among scientists, clinicians, patients and family members can increase understanding [1][2][3][4] and possibly mitigate the effects of genetic conditions, this is not the reason for presenting genetic information in courts and tribunals. Rather, genetic information is usually presented to substantiate the claim that an employee's health problem is related to a genetic predisposition instead of an occupational injury.…”

Chromosome jumping from D4S10 (G8) toward the Huntington disease gene.

“…If, on the other hand, it reflects a general tendency for recombination to occur more frequently near the telomere of 4p, then the HD gene may lie less than a million bases away. Intense further efforts to cross this distance by using jumps from D4M81, D4S43, and other probes being generated in this region (32) (33).…”