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

Abstract

Previous studies have shown that specific short-tandem-repeat (STR) and single-nucleotide-polymorphism (SNP)-based haplotypes within and among unaffected and fragile X white populations are found to be associated with specific CGG-repeat patterns. It has been hypothesized that these associations result from different mutational mechanisms, possibly influenced by the CGG structure and/or cis-acting factors. Alternatively, haplotype associations may result from the long mutational history of increasing instability. To understand the basis of the mutational process, we examined the CGG-repeat size, 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 differences were found between the two ethnic groups. First, in contrast to that seen in the white population, no associations were observed among the African American intermediate or "predisposed" alleles (41-60 repeats). Second, two previously undescribed haplotypes accounted for the majority of the African American fragile X population. Third, a putative "protective" haplotype 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 equilibrium among African Americans, and it did not add new information to the 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.

Figure 1

Location and nomenclature of FRAXA interspersion patterns and STR- and SNP-based haplotypes. This figure was adapted from Eichler et al. (1996). We show here the position of the STR and SNP markers relative to the FRAXA CGG repeat. We also included the FRAXE GCC repeat, the STR marker DXS1691, and the recently described polymorphism within DXS548 (DXS548-P). The numbers above the marker represent the allele assignment and the numbers in parentheses represent the base-pair size, according to our protocol. The numbering systems and interspersion-pattern nomenclature are from Eichler et al. (1996) and Murray et al. (1996). We have extended the numbering system for DXS548 and FRAXAC2 to include the alleles not previously described in a white population. All STR-based haplotypes are constructed as follows: 5′-DXS548-P (if there is an insertion or deletion event)-DXS548-FRAXAC1-FRAXAC2-3′. Interspersion patterns are described as the number of consecutive CGGs followed by a plus sign (+) to designate the presence of an AGG interruption.

Figure 2

A, DXS548; B, DXS548-P; C, FRAXAC1; and D, FRAXAC2 allele distributions in whites (n=721; unshaded bars) and African Americans (n=637; shaded bars). Absolute numbers are reported above each bar for each allele of each locus in both populations.