Localization of the huntington's disease gene to a small segment of chromosome 4 flanked by D4S10 and the telomere

Gilliam, T. Conrad; Tanzi, Rudolph E.; Haines, Jonathan L.; Bonner, Tom I.; Faryniarz, Ann; Hobbs, Wendy; MacDonald, Marcy E.; Cheng, Shirley V.; Folstein, Susan E.; Conneally, P. Michael; Wexler, Nancy S.; Gusella, James F.

doi:10.1016/0092-8674(87)90029-8

Cited by 107 publications

(39 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…DNA markers were radiolabeled and hybridized to Southern blots as described previously (6). DNA samples were restriction digested with either HindIII or EcoRI, separated electrophoretically, and transferred to nylon membranes for hybridization.…”

Section: Figmentioning

confidence: 99%

Deletion mapping of DNA markers to a region of chromosome 5 that cosegregates with schizophrenia

et al. 1989

Self Cite

View full text Add to dashboard Cite

Two independent lines of evidence support the localization of a schizophrenia susceptibility locus to the proximal long arm of chromosome 5. A partial trisomy of chromosome 5 (5q11.2-q13.3) cosegregates with the disorder in a Canadian family of Chinese descent, and DNA markers from proximal 5q cosegregate with schizophrenia (plus related disorders) in families of British and Icelandic descent. We constructed a human:hamster hybrid cell line (HHW 1064) whose only human complement is a chromosome 5 that is missing the trisomic region associated with schizophrenia. In combination with a "matched" cell hybrid (HHW 105) containing an intact chromosome 5, we physically mapped DNA markers relative to the trisomy. "Schizophrenialinked" DNA markers p105-153Ra (D5S39) and p105-599Ha (D5S76) map within the trisomy and proximal to the 5q11.2 breakpoint, respectively. The hybrid cell lines HHW 105 and HHW 1064 together provide a means to identify and generate syntenic DNA markers to further investigate the location of a schizophrenia locus.A report by Bassett et al. (1988) describes the coin-heritance of a chromosomal triplication, 5q11.2-5q13.3, with schizophrenia in a well-characterized Canadian family of Chinese descent. The two affected members of this family, a 20-year-old man and his 53-year-old uncle, share a phenotype of neuroleptic responsive schizophrenia with typical psychotic and deficit symptoms. The affected individuals also suffer mild physical anomalies which prompted clinicians to investigate and subsequently discover a chromosomal abnormality associated with the occurrence of schizophrenia in this family. High-resolution karyotyping revealed a balanced direct insertion (46, XX, inv ins) (1;5) (q32.3; q13.3-q11.2) in an unaffected relative (the mother and sister, respectively) of the two affected probands. Both affected individuals were trisomic for the translocated 5q segment, whereas other unaffected relatives had normal genomic karyotypes. This finding encouraged several laboratories to test DNA markers from the long arm of chromosome 5 for linkage to the disease phenotype in large schizophrenia pedigrees. Recently, one group has reported linkage with markers from the proximal portion of 5q to seven British and Icelandic families (Sherrington et al., 1988), while several groups report the absence of linkage in other kindreds (Kennedy et al.,

show abstract

Section: Figmentioning

confidence: 99%

Deletion mapping of DNA markers to a region of chromosome 5 that cosegregates with schizophrenia

et al. 1989

Self Cite

View full text Add to dashboard Cite

show abstract

“…Sau3AI-digested pTYAC1 (1.5 ,ug/ml) was included in prehybridization and hybridization solutions that employed this probe and calf thymus DNA was omitted. Hybridization was carried out at 68°C for [14][15][16][17][18][19][20][21][22][23][24] hr in the same buffer that was described above.…”

Section: Methodsmentioning

confidence: 99%

“…Unique, physically defined genetic markers associated with individual telomeres would provide the boundaries for genetic maps. Cloned sequences specific for individual telomeres may also be in close proximity to some diseaseassociated genes that appear to map near the ends of particular human chromosomes (19). We describe here a cloning system that can be used to isolate large telomeric fragments of human chromosomes in yeast.…”

mentioning

confidence: 99%

Cloning human telomeric DNA fragments into Saccharomyces cerevisiae using a yeast-artificial-chromosome vector.

Riethman

Moyzis

Meyne

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

121

View full text Add to dashboard Cite

Telomeric fragments of human DNA ranging in size from 50 to 250 kilobases were cloned into Saccharomyces cerevisiae using a yeast-artificial-chromosome (YAC) vector. Six human-telomeric YAC (HTY) strains were selected by virtue of the specific hybridization of their DNA with the human telomeric terminal-repeat sequence (TTAGGG),, and the telomeric localization of this sequence within each YAC was demonstrated by its sensitivity to nuclease BAL-31. In situ hybridization of DNA from three of these HTY strains with human metaphase chromosomes yielded discrete patterns of hybridization signals at the telomeres of a limited number of human chromosomes, different for each clone. DNA from selected cosmid subclones of one of the HTY strains was used to localize the origin of the cloned telomeric DNA by in situ hybridization to the tip of the long arm of chromosome 7.Specialized telomeric DNA sequences are required for the replication and stability of linear chromosomes (for review, see ref. 1). In many organisms, telomeric DNA is also associated with recombinational events that result in frequent rearrangements of telomere-proximal DNA (for examples, see refs. 2-4). Two classes of repeated DNA elements have been implicated in these functional attributes of telomeres. The first is a simple repeat sequence with a consensus motif containing a G-rich strand (1); this sequence motif has been found at the termini of linear chromosomes of representative plants, animals, protists, and fungi (1,5,6). Particularly striking is the recent demonstration that the terminal-repeat sequence in the human, (TJAGGG)n, is identical to that in trypanosomes and similar to that in yeast, (TG1_3)", and Tetrahymena, (TTGGGG)n (6).The terminal-repeat sequence is apparently maintained in Tetrahymena macronuclei and in Oxytricha by the templateindependent addition of repeat nucleotides through the enzymatic activity of a ribonucleoprotein termed telomerase (7-9). The Tetrahymena telomerase can recognize oligonucleotides corresponding to the G-rich strand of DNA from terminal-repeat sequences of many organisms, suggesting similar mechanisms of telomere maintenance among these organisms and a strong evolutionary conservation of this process (7,8). Recombination may also be involved in the maintenance of the terminal-repeat sequences in Saccharomyces cerevisiae (10).The second class of repeated telomeric DNA element is localized just proximal to the terminal repeat and is speciesspecific. These subtelomeric repeats are not required for telomere replication and maintenance but are involved in the enhanced recombination often associated with telomeres. In S. cerevisiae, two subtelomeric repeat elements have been characterized, X and Y'. X is present at most ofthe telomeres in a single copy. Y' is present on about half of the telomeres, is sometimes present in multiple copies on a single telomere, and is always distal to X (refs. 11 (15)(16)(17), but their proximity to the chromosomal termini has not been determined at the molecular level. Stu...

show abstract

“…Although such optimism is justified by the success that has been achieved in identifying the genetic basis of monogenic diseases and disorders, such as cystic fibrosis 3,4 and Huntington disease 5,6 , unravelling how genes "talk to each other" is likely to be an intimidating effort for more complex traits and processes. This is also true when analysing the genetic actions/interactions that occur in experimental systems: even organisms that have 10 3 -10 4 genes, such as the budding yeast Saccharomyces cerevisiae, can produce more than 10 4 -10 5 gene products, which can easily account for more than 10 5 -10 7 interactions.…”

Section: Perturbing Biological Systemsmentioning

confidence: 99%

Studying complex biological systems using multifactorial perturbation

2003

View full text Add to dashboard Cite

Localization of the huntington's disease gene to a small segment of chromosome 4 flanked by D4S10 and the telomere

Cited by 107 publications

References 22 publications

Deletion mapping of DNA markers to a region of chromosome 5 that cosegregates with schizophrenia

Deletion mapping of DNA markers to a region of chromosome 5 that cosegregates with schizophrenia

Cloning human telomeric DNA fragments into Saccharomyces cerevisiae using a yeast-artificial-chromosome vector.

Studying complex biological systems using multifactorial perturbation

Contact Info

Product

Resources

About