Evolution of the Friedreich’s ataxia trinucleotide repeat expansion: Founder effect and premutations

Abstract

Friedreich's ataxia, the most frequent inherited ataxia, is caused, in the vast majority of cases, by large GAA repeat expansions in the first intron of the frataxin gene. The normal sequence corresponds to a moderately polymorphic trinucleotide repeat with bimodal size distribution. Small normal alleles have approximately eight to nine repeats whereas a more heterogeneous mode of large normal alleles ranges from 16 to 34 GAA. The latter class accounts for Ϸ17% of normal alleles. To identify the origin of the expansion mutation, we analyzed linkage disequilibrium between expansion mutations or normal alleles and a haplotype of five polymorphic markers within or close to the frataxin gene; 51% of the expansions were associated with a single haplotype, and the other expansions were associated with haplotypes that could be related to the major one by mutation at a polymorphic marker or by ancient recombination. Of interest, the major haplotype associated with expansion is also the major haplotype associated with the larger alleles in the normal size range and was almost never found associated with the smaller normal alleles. The results indicate that most if not all large normal alleles derive from a single founder chromosome and that they represent a reservoir for larger expansion events, possibly through ''premutation'' intermediates. Indeed, we found two such alleles (42 and 60 GAA) that underwent cataclysmic expansion to pathological range in a single generation. This stepwise evolution to large trinucleotide expansions already was suggested for myotonic dystrophy and fragile X syndrome and may relate to a common mutational mechanism, despite sequence motif differences.

Further evidence for a major ancient mutation underlying myotonic dystrophy from linkage disequilibrium studies in the Japanese population

“…They also proposed that alleles with 19-30 CTG repeats are always associated with the Alu insertion allele and these may serve as a reservoir for recurrent mutations to unstable alleles with 30-50 repeats. The situation is very similar to that proposed for Friedreich's ataxia (FRDA), where almost all large normal alleles (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34) in the Caucasian population stem from a single founder expansion (Cossée et al 1997). The ancestral haplotype hypothesis is further supported by the findings of Neville et al (1994), who performed a highresolution genetic analysis of the locus using polymerase chain reaction (PCR)-based assays of nine polymorphisms immediately flanking the DM repeat.…”

“…A reservoir pool with n ϭ 19-37 might be derived from n ϭ 5 alleles based on haplotypes. More recently, Cossée et al (1997) reported the evolution hypothesis of the FRDA (GAA) n expansion similar to DM. The model that we have described promises to be invaluable in studying triplet repeat expansion mechanisms.…”

Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders

“…26 The A467T and W748S mutations have effectively spread to many populations of European descent not only through heterozygous carriers of the mutation, but also through homozygous patients with adult-onset ataxia. Similarly, a global ancient founder chromosome has been found in Friedreich ataxia (MIM 229300), 27 which resembles MIRAS in its phenotype and pathogenesis, as a mitochondrial ataxia. An ancient world-wide ancestry of a founder allele is not, however, common among recessive diseases.…”

Identification of the Finnish founder mutation for diastrophic dysplasia (DTD)

“…A second possibility is that the chromosomes with the rare haplotype are more prone to mutation, although again there is no evidence to support such a hypothesis. Examples are known of chromosomes prone to triplet-repeat expansion in the germline 20 or to APC mutations in somatic cells, 21 but neither provides a close precedent for the case at hand. Finally, a third possibility is that the presence of multiple mutations on the rare haplotype is simply a matter of random chance.…”