Correlated fragile site expression allows the identification of candidate fragile genes involved in immunity and associated with carcinogenesis
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Common fragile sites (cfs) are specific regions in the human genome that are particularly prone to genomic instability under conditions of replicative stress. Several investigations support the view that common fragile sites play a role in carcinogenesis. We discuss a genome-wide approach based on graph theory and Gene Ontology vocabulary for the functional characterization of common fragile sites and for the identification of genes that contribute to tumour cell biology. CFS were assembled in a network based on a simple measure of correlation among common fragile site patterns of expression. By applying robust measurements to capture in quantitative terms the non triviality of the network, we identified several topological features clearly indicating departure from the Erdos-Renyi random graph model. The most important outcome was the presence of an unexpected large connected component far below the percolation threshold. Most of the best characterized common fragile sites belonged to this connected component. By filtering this connected component with Gene Ontology, statistically significant shared functional features were detected. Common fragile sites were found to be enriched for genes associated to the immune response and to mechanisms involved in tumour progression such as extracellular space remodeling and angiogenesis. Our results support the hypothesis that fragile sites serve a function; we propose that fragility is linked to a coordinated regulation of fragile genes expression.Keywords:
Chromosomal fragile site
Identification
Candidate gene
Fragile X syndrome is the most common form of heritable mental retardation affecting approximately 1 in 4000 males and 1 in 8000 females. Martin and Bell first documented X-linked mental retardation in 1943. Subsequent identification of a fragile site on the long arm of the X chromosome (Lubs, 1969), discovery of cell culture medium-dependent fragile site, and recognition of a unique constellation of physical features served to distinguish fragile X syndrome from other X-linked mental retardation syndromes.
Chromosomal fragile site
Fragile X Syndrome
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Chromosomal fragile site
Fragile X Syndrome
Mentally retarded
Heterozygote advantage
Replication
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The common fragile site on the end of the long arm of the human X chromosome has been shown to be at a different location from the rare fragile site which produces the fragile X syndrome of intellectual handicap. The different locations can be clearly seen in chromosomes at about the 550 band level of resolution. This finding should help resolve difficulties in fragile X cytogenetics where expression of the common fragile site can lead to false positive diagnoses.
Chromosomal fragile site
Fragile X Syndrome
Long arm
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Chromosomal fragile site
Fragile X Syndrome
Mentally retarded
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Chromosomal fragile site
Fragile X Syndrome
Long arm
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In their commentary, "Fragile Sites on Chromosomes," (Pediatrics 69:121, 1982) Hecht, Glover, and Kaiser-Hecht stress the possibility of therapy in cases of fragile-X linked mental retardation. I have had the opportunity to treat three members of a family with the fragile-X chromosome. A 21-year-old man with mental retardation and psychotic symptoms, had macroorchidism and fragile-X site in 13% of his cells in 199 medium. A first therapeutic trial with folic acid, 10 mg, orally, per day and vitamin B12, 1 mg, orally, per day resulted in a great improvement of his comportment without change in the percentage of the fragile-X site.
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Fragile X Syndrome
Mentally retarded
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Chromosomal fragile site
Fragile X Syndrome
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Chromosomal fragile site
Fragile X Syndrome
Long arm
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Chromosomal fragile site
Fragile X Syndrome
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To assist in cell sample size selection and detect the fragile X chromosome, statistical tables have been presented. A comparable approach had been suggested earlier for the diagnosis of chromosome mosaicism. The cytologic detection of the fragile X or any fragile site is simply a special case in the detection of mosaicism. Minimum numbers of metaphases are recommended for fragile X analysis to have 95% confidence that the fragile X is not manifest in a given proportion of cells and similar recommendations apply to all other fragile sites.
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