GENETIC-VARIATION AND EVOLUTIONARY STABILITY OF THE FMR1-CGG-REPEAT IN 6 CLOSED HUMAN-POPULATIONS

In an attempt to understand the allelic diversity and mutability of th e human FMR1 CGG repeat, we have analyzed the AGG substructure of this locus within six genetically-closed populations (Mbuti pygmy, Baka py gmy, E. surui, Karitiana, Mayan, and Hutterite), Most alleles (61/92 o r 66%) possessed two AGG interspersions occurring with a periodicity o f one AGG every nine or ten CGG repeats, indicating that this pattern is highly conserved in all human populations. Significant differences in allele distribution were observed among the populations for rare va riants possessing fewer Or more AGG interruptions than the canonical F MR1 CGG repeat sequence. Comparisons of expected heterozygosity of the FMR1 CGG repeat locus with 30 other microsatellite loci, demonstrated remarkably similar levels of polymorphism within each population, sug gesting that most FMR1 CGG repeat alleles mutate at rates indistinguis hable from other microsatellite loci. A single allele (1 out of 92) wa s identified with a large uninterrupted tract of pure repeats (42 pure CGG triplets). Retrospective pedigree analysis indicated that this al lele had been transmitted unstably. Although such alleles mutate rapid ly and likely represent evolving premutations, our analysis suggests t hat in spite of the estimated frequency of their occurrence, these uns table alleles do not significantly alter the expected heterozygosity o f the FMR1 CGG repeat in the human population. (C) 1996 Wiley-Liss, In c.