Survey of the fragile X syndrome CGG repeat and the short-tendem-repeat and single-nucleotide-polymorphism haplotypes in an African American population

Previous studies have shown that specific short-tandem-repeat (STR) and sin gle-nucleotide-polymorphism (SNP)-based haplotypes within and among unaffec ted and fragile X white populations are found to be associated with specifi c CGG-repeat patterns. It has been hypothesized that these associations res ult from different mutational mechanisms, possibly influenced by the CGG st ructure and/or cis-acting factors. Alternatively, haplotype associations ma y result from the long mutational history of increasing instability. To und erstand the basis of the mutational process, we examined the CGG-repeat siz e, three flanking STR markers (DXS548-FRAXAC1-FRAXAC2), and one SNP (ATL1) spanning 150 kb around the CGG repeat in unaffected (n = 637) and fragile X (n = 63) African American populations and compared them with unaffected (n = 721) and fragile X (n = 102) white populations. Several important differ ences were found between the two ethnic groups. First, in contrast to that seen in the white population, no associations were observed among the Afric an American intermediate or "predisposed" alleles (41-60 repeats). Second, two previously undescribed haplotypes accounted for the majority of the Afr ican American fragile X population. Third, a putative "protective" haplotyp e was not found among African Americans, whereas it was found among whites. Fourth, in contrast to that seen in whites, the SNP ATL1 was in linkage eq uilibrium among African Americans, and it did not add new information to th e STR haplotypes. These data indicate that the STR- and SNP-based haplotype associations identified in whites probably reflect the mutational history of the expansion, rather than a mutational mechanism or pathway.