Dynamics of CAG repeat loci revealed by the analysis of their variability

In order to understand the dynamics of the expressed single tandem repeat trinucleotides (most of them involved in pathological expansion), the diversity in 10 different loci (SCA1, SCA2, SCA3, SCA6, SCA8, SCA12, DRPLA, HD, KCNN3, and NCOA3) was analyzed in four major human groups (Africans, Europeans, Indians, and East Asians). The present analysis intends to disentangle population-based from genetic-based factors having shaped STR (trinucleotide) variation and to recognize, for each locus, the specific rate and pattern of mutation (bias toward expansion or contraction, constraints on allele size), and the footprints of selection. Population differences account for a very small part of the total variation, but a clear footprint appears of population growth after a bottleneck in all non-African populations, giving support to the out-of-Africa model of modern humans. Most of the diversity is found among loci, and different dynamics are inferred for each of them. SCA2 and SCA3 follow an unrestricted stepwise mutation model, while the rest of loci are found under allele size constrictions and a bias to expansion (SCA1, SCA6, HD, and KCNN3), contraction (SCA12, DRPLA, and NCOA3), or unbiased (SCA8).