Genetic diversity of the fragile X syndrome gene (FMR1) in a large Sub-Saharan West African population

Abstract

Fragile X syndrome (OMIM #300624) is caused by the expansion of a CGG trinucleotide repeat found in the 5' untranslated region of the X-linked FMR1 gene. Although examinations of characteristics associated with repeat instability and expansion of the CGG repeat upon transmission from parent to offspring has occurred in various world populations, none has been conducted in large Sub-Saharan African populations. We have examined the FMR1 CGG repeat structure in a sample of 350 males drawn from the general population of Ghana. We found that Ghanaians and African Americans have similar allele frequency distributions of CGG repeat and its flanking STR markers, DXS548 and FRAXAC1. However, the distribution of the more complex marker, FRAXAC2, is significantly different. The haplotype structure of the FMR1 locus indicated that Ghanaians share several haplotypes with African Americans and Caucasians that are associated with the expanded full mutation. In Ghanaians, the majority of repeat structures contained two AGG interruptions, however, the majority of intermediate alleles (35-49) lacked AGG interruptions. Overall, we demonstrate that allelic diversity of the FMR1 locus among Ghanaians is comparable to African Americans, but includes a minority of CGG array structures not found in other populations.

Figure 1

Location of the short tandem repeats (STRs) of the fragile X locus and the FRAXA interspersion patterns adopted from (Crawford et al., 2000a, Zhou et al., 2006). All DNA elements are arranged from centromere (CEN) to telomere (TEL) with filled arrows represent microsatellites and FMR1 exons represented by filled boxes. For each STR the structure is represented below the STR name designation with allele designation and base pairs in parentheses above. DXS548 insertion/deletion polymorphism (DXS548-P) designated (+) for insertion and (-) for deletion, with base pair indicated by number. Exon 1 contains the polymorphic CGG repeat allele (represented by the white insert) with the AGG interspersions represented by (+) and total number of pure CGG arrays for each segment represented by numbers.

Figure 2

A, DXS548 (n = 234); B, DXS548-P in/del (n = 156); C, FRAXAC1 (n = 234); D, FRAXAC2 (n = 234); allele distributions for Ghanaians (black bars), Caucasians (n = 721; white bars) (Crawford et al., 2000a) and African Americans (n = 637; gray bars) (Crawford et al., 2000a).

Figure 2

A, DXS548 (n = 234); B, DXS548-P in/del (n = 156); C, FRAXAC1 (n = 234); D, FRAXAC2 (n = 234); allele distributions for Ghanaians (black bars), Caucasians (n = 721; white bars) (Crawford et al., 2000a) and African Americans (n = 637; gray bars) (Crawford et al., 2000a).

Figure 2

A, DXS548 (n = 234); B, DXS548-P in/del (n = 156); C, FRAXAC1 (n = 234); D, FRAXAC2 (n = 234); allele distributions for Ghanaians (black bars), Caucasians (n = 721; white bars) (Crawford et al., 2000a) and African Americans (n = 637; gray bars) (Crawford et al., 2000a).

Figure 2

A, DXS548 (n = 234); B, DXS548-P in/del (n = 156); C, FRAXAC1 (n = 234); D, FRAXAC2 (n = 234); allele distributions for Ghanaians (black bars), Caucasians (n = 721; white bars) (Crawford et al., 2000a) and African Americans (n = 637; gray bars) (Crawford et al., 2000a).

Figure 3

A, Distribution of FMR1 CGG repeat alleles in Ghanaians (n = 300; black bars), Caucasians (n = 721; white bars) (Crawford et al., 2000a) and African Americans (n = 637; Gray bars) (Crawford et al., 2000a). Distributions of FRAXA CGG repeat alleles in West African populations (3B), Ghanaians (n = 300; black bars), Mandinka (n = 80; light gray bars) (Kunst et al., 1996), Wolof (n = 50; white bars) (Kunst et al., 1996) and Bamileke (n = 82; dark gray bars) (Chiurazzi et al., 1996a).

Figure 3

A, Distribution of FMR1 CGG repeat alleles in Ghanaians (n = 300; black bars), Caucasians (n = 721; white bars) (Crawford et al., 2000a) and African Americans (n = 637; Gray bars) (Crawford et al., 2000a). Distributions of FRAXA CGG repeat alleles in West African populations (3B), Ghanaians (n = 300; black bars), Mandinka (n = 80; light gray bars) (Kunst et al., 1996), Wolof (n = 50; white bars) (Kunst et al., 1996) and Bamileke (n = 82; dark gray bars) (Chiurazzi et al., 1996a).

Figure 4

CGG repeat interspersion patterns among Ghanaian alleles with open circles Representing CGG arrays and filled in circles representing AGG interruptions. Haplotypes associated with fragile X chromosomes found in African Americans and Caucasians (5A) are represented with the AGG interruptions found in Ghanaians arrange in ascending order with respect to FraxA CGG repeat size. Interspersion patterns found associated with the FXS haplotypes in Ghanaians (5B).