Haplotype analysis at the FRAXA locus in the Japanese population

Abstract

Fragile X syndrome, one of the most common human genetic diseases, is characterized by a unique genetic mechanism which involves dynamic mutation in a heritable unstable DNA sequence, a p(CCG)n repeat, in the FRAXA locus. It has recently been suggested that a few founder chromosomes are responsible for most fragile X mutations in the Caucasian population. In order to investigate the origin of the fragile X mutations in the Japanese population, we analyzed haplotypes of the FRAXA locus in 40 unrelated fragile X chromosomes and 142 normal X chromosomes in Japanese males, by using two polymorphic AC repeats, FRAXAC1 and FRAXAC2, which flank the fragile site. This analysis provided evidence for founder fragile X chromosomes in the Japanese population, similar to that in Caucasians, although different haplotypes are involved. The distribution of normal allele size of the p(CCG)n repeat among the X chromosomes in the Japanese population is very similar to that reported for Caucasians, except that the most frequent copy number (n = 28) is one copy less than that in Caucasians and that there is an additional peak at 35 copies. There is significant correlation between FRAXAC alleles and the p(CCG)n repeat copy number in non-fragile X chromosomes, however, alleles with more than 31 copies of the p(CCG)n repeat do not segregate with either of the fragile X common FRAXAC haplotypes.

Genetic diversity at the FMR1 locus in the Indonesian population

“…The FRAXAC1-106 bp allele was present in 62 % of the total Indonesian population compared with 15-22 % in the Caucasian population Kunst et al 1996). In all Asian populations studied to date, the 106 bp allele has approximately twice the frequency of the 108 bp allele, whereas in Caucasians and Africans the 108 bp allele predominates (Richards et al 1994 ;Zhong et al 1994 ;Chiurazzi et al 1996 b ;Poon et al 1999). Despite the similar trends, the observed differences in the allele frequencies between the Malay and Chinese populations reached statistical significance for the FMR1 CGG repeat and FRAXAC1, while the Melanesian Indonesian subgroup is even more divergent.…”

“…Although the frequencies of non-106 and 108 bp FRAXAC1 and 200 bp DXS548 alleles are low in Indonesians (3 % and 1 % respectively) studies of allele diversity in Chinese and Japanese have shown that these populations have a much more restricted allele repertoire at these loci (Zhong et al 1994 ;Richards et al 1994 ;Poon et al 1999). We speculate that this may be the result either of the presence of indigenous populations in Sundaland prior to the Austronesian migration from Taiwan\southern China 5000-6000 years ago, or due to other genetic admixtures from migrations and colonisations from the Indian subcontinent, southern Asia and Oceania.…”

“…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).…”

FMRI CGG Repeats:Reference Levels and Race-Ethnic Variation in Women With Normal Fertility (Study of Women’s Health Across the Nation)

“…These reports include cohorts from Asia, Europe, and North America. The modal repeat length is 29 and 30 CGGs in most of these reports, with the exception of 2 Japanese studies (modal value was 27 or 28 CGG repeats), 14,19 a study of Canadian newborns (modal value was 28), 16 and a study of Israeli men (modal value of 27). 12 Five of these articles reported separate results for females.…”

Analysis of FMR1 (CGG)n alleles and FRAXA microsatellite haplotypes in the population of Greenland: implications for the population of the New World from Asia

“…This is very similar to distributions reported for Asian populations. [20][21][22] Comparison of (CGG) n allele sizes and linked DXS548-FRAXAC1 haplotypes showed that 85% of alleles with 29-31 CGG were linked to haplotype 7-3 Analysis of FRAXA alleles in the population of Greenland t and 88% of alleles with 35-37 CGG were linked to haplotype 6-4 ( Figure 1). …”