FXN protomutations are the source of pathogenic expanded GAA alleles in Friedreich ataxia and explain its unequal population distribution.

Friedreich ataxia (FRDA) is a recessive condition that is typically caused by inheriting an expanded GAA repeat (usually > 500 triplets) in the FXN gene from both parents who are heterozygous carriers of the expanded (E) allele. E alleles, which are evolutionarily derived from non-pathogenic long normal (LN) alleles (≥12 triplets), occasionally arise de novo via intergenerational expansion of premutation alleles (34-60 triplets). However, why FRDA susceptibility is limited to Eurasians, and how the prevalence of E alleles is sustained in susceptible populations are incompletely understood. Sequencing of the FXN locus revealed two major subclasses of E alleles, which have originated from a subset of Eurasian LN alleles, termed protomutations. Haplotype identity, the observed size continuum of protomutation-premutation-E alleles, and evidence of intergenerational instability in a protomutation allele, together support a dynamic relationship wherein protomutations can transition to premutation and E alleles. Consistent with the exclusive prevalence of FRDA in Eurasia, protomutations are absent in sub-Saharan Africa, where E alleles did not develop despite a relatively high prevalence of LN alleles. However, genetic admixture has introduced a slight risk of FRDA in African Americans. Analysis of ancient DNAs revealed that protomutations have existed in Europe and Western Asia for thousands of years, with evidence of spread to Europe via early Neolithic farmers. These data indicate that FXN protomutations serve as a reservoir for the generation of premutation and E alleles, and for millennia have sustained the geographically-defined population distribution of FRDA.