Eur J Hum Genet. 2001 Sep;9(9):724-7.
Analysis of FMR1 (CGG)(n) alleles and DXS548-FRAXAC1 haplotypes in three European circumpolar populations: traces of genetic relationship with Asia.
Larsen LA1, Vuust J, Nystad M, Evseeva I, Van Ghelue M, Tranebjaerg L.
Fragile X syndrome, the most common form of inherited mental retardation, is caused by expansion of a (CGG)(n) repeat located in the FMR1 gene. The molecular factors involved in the mutation process from stable (CGG)(n) alleles towards unstable alleles are largely unknown, although family transmission studies and population studies have suggested that loss of AGG interruptions in the (CGG)(n) repeat is essential. We have analysed the AGG interspersion pattern of the FMR1 (CGG)(n) repeat and the haplotype distribution of closely located microsatellite markers DXS548 and FRAXAC1, in three circumarctic populations: Norwegians, Nenets and Saami. The data confirm the conservation, reported in all human populations studied so far, of an AGG interruption for each 9-10 CGG and support the stabilising effect of AGG interruptions. The data also indicate the existence of chromosomes of Asian origin in the Saami and Nenets population, thereby confirming a genetic relationship between Northern Europe and Asia. DXS548-FRAXAC1 haplotype frequencies were compared between 24 Norwegian fragile X males and 119 normal males. Significant linkage disequilibrium were found between the fragile X mutation and haplotype 6-4 and between normal (CGG)(n) alleles and haplotype 7-3.
…most of the (CGG)29 alleles found among the Nenets population were associated with haplotype 7-4, as in Asian populations,15 whereas most Caucasian (CGG)29 alleles are associated with haplotype 7-3.10
Asian populations are also characterised by a signifi- cant shortage of (CGG)n alleles of (CGG)S26 compared to Caucasian populations, as well as by the presence of alleles with the internal sequence of 9A9A6A9.13 Both the Saami and Nenets population had a lower frequency of (CGG)S26 alleles (9 and 13%, respectively) compared to Caucasian populations (about 20%), although the difference was not statistically significant. One allele with the internal sequence of 9A9A6A9 was found among the Saami population, but no such alleles were found in the Nenets or Norwegian samples. The 9A9A6A9 allele is found in approximately 20% of Greenlandic males.16
The distribution of (CGG)n alleles indicates genetic differences between the Saami and the Nenets population (Figure 1). The fact that the 29 CGG allele is the most abundant in Nenets and the presence of the 9A9A6A9 allele in the Saami indicate the presence of chromosomes of Asian origin in these populations. Our data also indicate that the degree of Asian admixture may be larger in the Nenets compared to the Saami. Although the last observation needs to be confirmed in additional studies based on a larger data set, our data are in agreement with a previous analysis of a Y-chomosomal T/C nucleotide polymorphism, suggesting a gene-flow from Asia towards Northern Europe, with a declining gradient.17
DXS548-FRAXAC1 haplotype 6-4 was the most frequent among 24 Norwegian fragile X males (Table 1). This is similar to reports from studies of the Danish,10 Swedish and Finnish population.12 However, inter-population differences are indicated by the frequency of haplotype 2-1, which is quadrupled in Norwegian fragile X males compared to the normal controls. This is similar to the Danish population,10 but different from both the Swedish and the Finnish population,12 where no differences in frequencies were reported.
In a previous study of the Danish population, 13.6% of the fragile X alleles were found associated with haplotype 7-3, and it was suggested that these alleles may have originated from a pool of unstable normal alleles with the internal sequence of 10A19.10 No alleles associated with haplotype 7- 3 were found among the fragile X patients in the Norwegian population, and no 10A19 alleles were found among 59 Norwegian normal males. Thus, the results from the analysis of DXS548-FRAXAC1 haplotypes and the AGG interspersion analysis show that the fragile X founder haplotypes may vary between populations and support that the CGG expansion associated with fragile X syndrome may originate from sub- populations of unstable alleles within the normal population.4