Chromosomal fragile site, FRA16A: Implications for fragile site genesis
- Women`s and Children`s Hospital, North Adelaide (Australia); and others
Fragile sites are chemically induced non-staining gaps in chromosomes. Different fragile sites vary in frequency in the population and in the chemistry of their induction. The fragile sites sequenced to date (FRAXA and FRAXE) are rare, folate sensitive sites located on the X chromosomes. They have similar DNA sequence composition of a p(CCG)n repeat adjacent to a methylatable CpG island. Individuals expressing the fragile site have an unstable expanded repeat and methylation of the adjacent CpG island. FRAXA is associated with the most common form of familial mental retardation, Fragile X Syndrome. In order to further understand the relationship between the DNA sequence composition, position in the genome, and the chemistry of induction of fragile sites, we have characterized the rare, folate sensitive fragile site on human chromosome 16 referred to as FRA16A. The molecular basis of FRA16A was found to be expansion of a normally polymorphic p(CCG)n repeat. This repeat was adjacent to a CpG island that was methylated in fragile-site-expressing individuals. The FRA16A locus in individuals who do not express the fragile site is not a site of DNA methylation (imprinting) which suggests that the methylation associated with fragile sites may be a consequence and not a cause of their genesis. We have analyzed the normal repeat copy numbers for the fragile site p(CCG)n repeats in European, Japanese and Indian populations. While the FRAXA and FRAXE repeats show similar distributions of copy numbers, the FRA16A p(CCG)n repeat in Europeans has a greater range and number of alleles (23.7% have n>25) than its Japanese and Indian counterparts. In conjunction with our previous data demonstrating linkage disequilibrium (founder chromosomes) at the FRAXA locus, these data suggest that certain p(CCG)n repeats are inherently unstable.
- OSTI ID:
- 133304
- Report Number(s):
- CONF-941009--
- Journal Information:
- American Journal of Human Genetics, Journal Name: American Journal of Human Genetics Journal Issue: Suppl.3 Vol. 55; ISSN AJHGAG; ISSN 0002-9297
- Country of Publication:
- United States
- Language:
- English
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