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

Abstract

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).

Spinocerebellar ataxias: microsatellite and allele frequency in unaffected and affected individuals

“…The widespread distribution of the wild-type MJD alleles is attributed to a high mutation rate, without any bias to expansion, which could explain the observed allelic frequencies. This is in accordance with a model that postulates the presence of a small number of mutational events from which most of the MJD cases worldwide have originated 20 and contrasts with findings for Huntington disease (HD) 21 , in which intermediate and expanded alleles are observed in the normal population. The results of these studies may corroborate the idea that there is a mechanism that maintains these diseases in the population and suggest the existence of a few founding chromosomes from which all families originated.…”

“…This corroborates the hypothesis that the Portuguese and African populations brought a pool of founding genes to Brazil with a common mutation in the SCA3 gene identified as the cause of MJD (SCA3) 37,[41][42][43] . However, other studies of the Portuguese population did not show any correlation between the frequency of the large normal alleles and the frequency of the disease [20][21][22][23] . There was no significant correlation between the frequency of MJD and the frequency of small, medium or large normal alleles in the SCA3 locus of the Portuguese population 23 .…”

“…Population genetic analysis of expansion diseases suggests a controversial pathogenic mechanism among them [20][21][22][23] . There is the hypothesis that most cases of new mutations that cause expansion diseases arise from the existence of a large number of normal repetitions or intermediate alleles in the non-affected population.…”

“…Moreover, it is believed that expanded alleles in MJD are maintained in the population over generations by presenting greater adaptive value 25 . Allelic frequencies in the normal population could explain the evolutionary mechanism to support expanded alleles through generations 20,23 .…”

Unexpanded and intermediate CAG polymorphisms at the SCA2 locus (ATXN2) in the Cuban population: evidence about the origin of expanded SCA2 alleles

“…Normal genetic polymorphism according to CAG repeat length (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) The normal CAG repeat size from 2695 (K-S, Po0.01) chromosomes of the Cuban NM population shows a modal distribution (Figure 1a) (mode and median¼22 CAG), with 22 28 The range of the CAG is distributed continuously from 13 to 31 CAG and encompasses almost all the expected allelic classes in this numeric series (17 observed/18 expected) -with a kurtosis of 11.66 and a variance of 3.04 vs 1.21 for other populations worldwide. 27 The allele with 13 CAG repeats is exclusively found in the Cuban population and that with 26 CAG in both Cuban and Czech populations.…”