Data on the CGG repeat at the fragile X site in the non-retarded Japanese population and family suggest the presence of a subgroup of normal alleles predisposing to mutate

Abstract

The fragile X mutation is the result of amplification in the repeat number of p(CGG)n in FMR-1; alleles with more than 52 repeats have been shown to be so unstable as to mutate in the repeat number in almost every transmission. To improve our understanding of mutations in normal alleles of FMR-1, the following studies were carried out in the Japanese population: a study on length variation in the repeat to determine the allele distribution of the repeat length in a non-retarded population, family studies to observe new mutations in normal allele, and haplotype analyses with microsatellite markers flanking the repeat to confirm estimated mutation rates and founder chromosomes in the fragile X syndrome. Analysis of the p(CGG)n in 370 unrelated males detected 24 distinct alleles with repeats of 18-44. A comparison with previously reported data suggests the presence of racial/ethnic differences in the allele distribution. No premutation allele was found in 824 unrelated X chromosomes examined by the polymerase chain reaction and Southern blot analysis. Family studies detected one new mutation in a total of 303 meioses. However, the mutation rate was not in accordance with the expected or observed heterozygosities in the population or with linkage disequilibrium observed between the repeat numbers and the haplotypes of the markers flanking the CGG. The haplotype in the chromosome in which the new mutation was found was the same as that frequently found in the Japanese fragile X chromosomes, and the variance in the CGG repeat number was wider in chromosomes with the haplotypes frequently found in the fragile X chromosome than in those with the other haplotypes. These observations suggest that a subgroup is present in normal alleles and that this subgroup is more liable to mutate than others.

Why do fragile X carrier frequencies differ between Asian and non-Asian populations?

“…Our calculations thus confirm and extend several earlier reports that the frequency of premutation carriers differs for Asian as compared to non-Asian populations (see, e.g., Arinami et al, 1993;Hofstee et al, 1994;Nanba et al, 1995;Otsuka et al, 2010). Our analysis also yielded evidence that there is heterogeneity among non-Asian populations worldwide (adjusted p-value of 0.0014; Table 5), though at a lesser degree than that observed for Asian as compared to non-Asian populations, suggesting the possibility of variation at several geographic scales.…”

“…Several reports indicate differences among populations in the distribution of fragile X alleles into the normal, premutation and full-mutation size classes (see, for example, Arinami et al, 1993;Barros-Núñez et al, 2008;Hofstee et al, 1994;Nanba et al, 1995;Otsuka et al, 2010;Peprah et al 2010). Asian and non-Asian populations, in particular, have been reported to exhibit substantial differences, with markedly lower frequencies of premutation-and fullmutation carriers observed in Asian populations (Arinami et al, 1993;Hofstee et al, 1994;Nanba et al, 1995;Otsuka et al, 2010).…”

“…Asian and non-Asian populations, in particular, have been reported to exhibit substantial differences, with markedly lower frequencies of premutation-and fullmutation carriers observed in Asian populations (Arinami et al, 1993;Hofstee et al, 1994;Nanba et al, 1995;Otsuka et al, 2010). Here we assess statistical evidence for frequency differences between these groups, using data from several published, general-population studies.…”

Fragile X syndrome in Calcutta, India

“…A study by Arinami et al, 15 on nonretarded Japanese subjects, showed (CGG) 28 to be the most frequent allele in their population, and reports 16±18 on the Chinese population showed the most frequent allele to be (CGG) 29 among their normal subjects. A similar distribution pattern was observed by Richards et al 19 in a study on the different ethnic populations of the world.…”

Genetic diversity at the FMR1 locus in the Indonesian population

“…Among Asian populations these studies have been largely limited to the North Asian populations of China and Japan (Arinami et al 1993 ;Richards et al 1994 ;Zhong et al 1994 ;Poon et al 1999), although one study has reported the analysis of FMR1 and FRAXAC1 in 31 samples from the Kadazan population of Sabah, Malaysian Borneo (Kunst et al 1996). Comparison of published allele frequencies for short tandem repeats within the fragile X locus in North Asian, Caucasian and African populations have identified clear differences between these populations (Zhong et al 1994 ;Chiurazzi et al 1996 b).…”