Mini ReviewCommon fragile sites, extremely large genes, neural development and cancer
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FRA3B and FHIT
The common fragile sites (CFSs) are distinct from the rare fragile sites (RFSs) because they are found in all individuals and not in some small proportion of people who have altered DNA sequences [1]. The RFSs are expressed only after sufficient expansion of unstable repeat sequences [2]. In contrast, the CFSs are presumably unstable because of something inherent within their DNA sequence. Over 90 CFSs have been described throughout the human genome and these vary in their frequency of
FRA16D and WWOX
The second most active CFS is FRA16D (16q23.2). This chromosomal region is frequently deleted in a variety of different cancers and approximately 25% of multiple myelomas have a translocation between sequences in this region and those on chromosome 14. We localized the FRA16D CFS using a FISH-based approach with large insert YAC and BAC clones from the chromosome 16q23 region as probes. We then completely characterized the FRA16D CFS to identify the ends of this CFS region as well as the
FRA6E and Parkin
A number of different methods have been used to localize and characterize CFS regions. Both FRA3B and FRA16D were localized by using large insert clones as FISH probes to triangulate and eventually uncover each CFS region. This strategy was also utilized to localize a number of other CFS regions including FRA7G [27], FRAXB [28], and FRA2G [29]. An alternative strategy to localize many other CFS regions was based upon the observation that human papillomaviruses, HPV16 and HPV18, were
GRID2 and FRA4?? (4q22)
GRID2 is another extremely large gene (1.46 Mbs) and Michelle Debatisse and co-workers demonstrated that this gene is localized within a CFS region in both humans and mice [38]. In addition, the mouse gene is a hot-spot for spontaneous deletions resulting in the mouse neurological mutant Lurcher. There is also considerable homology between the mouse and human GRID2 genes even within the introns. Recurrent deletions of subregions of band 4q22 has been described in human hepatocellular carcinomas
Not all CFS regions are associated with extremely large genes
Our observations with several of the most active of the CFS regions and their association with large genes are not applicable to all CFS regions. Indeed more of the characterized CFS regions are not associated with extremely large genes. This includes FRA7G [27], FRAXB [28], FRA7H [40], FRA2G [29] and FRA6F [41]. Some of the CFS regions contain several smaller genes, such as FRA7G, FRAXB, FRA2G and FRA6F, while the 300 kb region spanned by FRA7H is not associated with any genes [40].
The largest human genes
In spite of the fact that not all CFS regions are associated with genes that span vast genomic stretches, we were interested in whether there were other very large genes that could also be derived from CFS regions. We were also curious how large FHIT, Parkin and WWOX were relative to the largest human genes. We obtained lists of the largest known human genes from Dr Robert Kuhn (UCSC Database) and after carefully curating those lists to remove redundant genes discovered that there were 40 human
Many of the largest human genes are localized to chromosomal regions that contain CFSs
An examination of the Table 1 reveals that many of the largest known human genes do indeed map to chromosomal bands that contain a CFS. Although only a few of the CFS regions have been completely characterized we do know the approximate location of 20 additional CFS regions. These were delineated either by the identification of a viral integration site in a cervical tumor or because gene(s) within those regions frequently lost expression in primary ovarian tumors. Although we do not know where
Examining very large genes as possible CFS genes
We used several criteria to determine which large genes to test as potential CFS genes. Since we were particularly interested in genes that could play an important role in the development of cancer, we chose the 1.2 Mb deleted in colorectal cancer (DCC) gene, as well as the 677 kb RAD51L1 gene, which is the human homolog of the bacterial recA gene. The DCC gene is derived from 18q21.1 and the Rad51L1 gene is derived from 14q24.1. We treated lymphocytes with 0.4 uM aphidicolin for 24 h and prepared
Large genes and neurological development
The first large CFS gene that was identified to be involved in neurological development was Parkin, which is mutated in some patients with autosomal recessive juvenile Parkinsonism. In mice there is a spontaneous deletion of Parkin and the immediately distal PARCG gene that results in the Quaker (viable) phenotype [42].
A second large CFS gene is the delta2 glutamate receptor gene (GRID2) which is localized within a chromosomal region in the mouse where there are frequent spontaneous
Role of the CFSs and the large genes contained within them in normal cells
Since the genes within the CFS regions are highly susceptible to genomic instability especially within developing cancer cells, most of the studies on the CFS genes have been in the context of what role they could play in cancer development. A number of these studies have revealed that many of the large CFS genes do play important roles in cancer development and several of the large CFS genes appear to function as tumor suppressors, even if they are not traditional mutational targets in cancer.
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