EVOLUTION OF THE FRIEDREICH ATAXIA TRINUCLEOTIDE REPEAT EXPANSION - FOUNDER EFFECT AND PREMUTATIONS

Friedreich's ataxia,the most frequent inherited ataxia, is caused, in the vast majority of cases, by large GAA repeat expansions in the firs t intron of the frataxin gene. The normal sequence corresponds to a mo derately polymorphic trinucleotide repeat with bimodal size distributi on. Small normal alleles have approximately eight to nine repeats wher eas a more heterogeneous mode of large normal alleles ranges from 16 t o 34 GAA. The latter class accounts for approximate to 17% of normal a lleles. To identify the origin of the expansion mutation, we analyzed linkage disequilibrium between expansion mutations or normal alleles a nd a haplotype of five polymorphic markers within or close to the frat axin gene; 51% of the expansions were associated with a single haploty pe, and the other expansions were associated with haplotypes that coul d be related to the major one by mutation at a polymorphic marker or b y ancient recombination. Of interest, the major haplotype associated w ith expansion is also the major haplotype associated with the larger a lleles 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 allel es (42 and 60 GAA) that underwent cataclysmic expansion to pathologica l range in a single generation. This stepwise evolution to large trinu cleotide expansions already was suggested for myotonic dystrophy and f ragile X syndrome and may relate to a common mutational mechanism, des pite sequence motif differences.