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).
A total of 616 chromosomes from control individuals of all major continental groups, and six individuals affected by either Creutzfeldt-Jakob disease (CJD) or fatal familial insomnia (FFI), were typed with a new single-reaction protocol method and were also sequenced, with total reproducibility to screen variation at important positions (385A>G: M129V and 655G>A: E219K) in the human prion protein gene (PRNP). We have found, for the first time, that 129V allele is highly represented in some populations from the Americas, and that 129M and 129V are in similar frequencies in Africa. The 129M susceptibility allele was found at high frequencies in Old World populations, very high in the Pacific (~81%) and up to 93% in Central and East Asia, but at a low frequency (~30%) in Native Americans. The protective 219L allele was restricted to Asian and Pacific populations. Susceptibility alleles exhibit marked geographic differences in frequency, and thus, differences in probability to develop prion diseases. © 2003 Wiley-Liss, Inc.KEY WORDS: prion; PRNP; SNP; population genetics; Creutzfeldt-Jakob disease; CJD; fatal familial insomnia; FFI INTRODUCTIONFamilial Creutzfeldt-Jakob disease (CJD; MIM# 123400), fatal familial insomnia (FFI; MIM# 600072) and Gerstmann-Sträussler-Scheinker disease (GSD; MIM# 137440) are frequently caused by mutations in the prion gene ( PRNP; MIM# 176640; GenBank U29185) in codons 200, 178 and 102. CJD can also be sporadic (representing 85% of the cases) or acquired, which includes iatrogenic CJD, kuru and variant CJD. In these cases some polymorphic positions, codons 129 (385A>G: M129V) and 219 (655G>A: E219K) of the PRNP are particularly important for susceptibility to prion diseases.Codon 129 is known to be implicated in the development of sporadic Laplanche et al., 1994;Salvatore et al., 1994;Alperovitch et al., 1999], acquired (iatrogenic, ; kuru, [Lee et al., 2001]) and variant CJD [Zeidler and Ironside, 2000], with increased susceptibility observed for the M/M 2 Soldevila et al.genotype. This finding was interpreted as suggesting that dimerization of the prion protein is an important element in the pathogenesis of CJD and that this is more likely to occur in Met homozygotes than in heterozygotes. The relative frequencies of the codon 129 alleles in Europeans were estimated to be 68% M and 32% V [Owen et al., 1990]. Similar frequencies were obtained in other studies of normal European populations Bratosiewicz et al., 2001]. The frequency of 129M allele is higher in Japanese (95.8%; [Doh-ura et al., 1991]), Han Chinese (98.5%; [Tsai et al., 2001]), Turkish (74%; [Erginel-Unaltuna et al., 2001]) and in Cretans (75.5%; [Plaitakis et al., 2001]). The importance of codon 129 was highlighted in this last study, where an increased incidence of sporadic Creutzfeldt-Jakob disease was associated with a high rate of M homozygosity. These data is the first to relate a high regional incidence rate for sCJD to the distribution of PRNP 129 genotypes. To date, all studies of PRNP codon 129 have mainly focuse...
Several human neurodegenerative disorders are caused by the expansion of polymorphic trinucleotide repeat regions. Many of these loci are functional short tandem repeats (STRs) located in brain-expressed genes, and their study is thus relevant from both a medical and an evolutionary point of view. The aims of our study are to infer the comparative pattern of variation and evolution of this set of loci in order to show species-specific features in this group of STRs and on their potential for expansion (therefore, an insight into evolutionary medicine) and to unravel whether any human-specific feature may be identified in brain-expressed genes involved in human disease. We analyzed the variability of the normal range of seven expanding STR CAG/CTG loci (SCA1, SCA2, SCA3-MJD, SCA6, SCA8, SCA12, and DRPLA) and two nonexpanding polymorphic CAG loci (KCNN3 and NCOA3) in humans, chimpanzees, gorillas, and orangutans. The study showed a general conservation of the repetitive tract and of the polymorphism in the four species and high heterogeneity among loci distributions. Humans present slightly larger alleles than the rest of species but a more relevant difference appears in variability levels: Humans are the species with the largest variance, although only for the expanding loci, suggesting a relationship between variability levels and expansion potential. The sequence analysis shows high levels of sequence conservation among species, a lack of correspondence between interruption patterns and variability levels, and signs of conservative selective pressure for some of the STR loci. Only two loci (SCA1 and SCA8) show a human specific distribution, with larger alleles than the rest of species. This could account, at the same time, for a human-specific trait and a predisposition to disease through expansion.
Ample evidence has accumulated showing that different coding variants of the PRNP gene confer differential susceptibility for prion diseases. Here we evaluate the patterns of nucleotide variation in PRNP exon 2, which includes all the protein-coding sequence, by resequencing a worldwide sample of 174 humans for 2378 bp. In line with previous studies, we found two main haplotypes differentiated by nonsynonymous substitution in codon 129. Our analyses reveal the worldwide pattern of variation at the PRNP gene to be inconsistent with neutral expectations, indicating instead an excess of low-frequency variants, a footprint of the action of either positive or purifying selection. A comparison of neutrality test statistics for PRNP with other human genes indicates that the signal of positive selection on PRNP is stronger than expected from a possible confounding genome-wide background signal of population expansion. Two main conclusions arise from our analysis. First, the existence of an ancient, stable, balanced polymorphism that has been claimed in a previous study and related to cannibalism can be rejected and is shown to be due to ascertainment bias. Second, our results are consistent with a complex history of selection including mainly positive selection, even if short local periods of balancing selection (Kuru-like episodes), or even a weak purifying selection model, are consistent with our data.Transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of rare, subacute and fatal neurodegenerative disorders characterized by accumulation of the abnormal isoform of a host-encoded membrane protein. Human TSEs can be sporadic, acquired, or genetic, and include, among others, Creutzfeldt-Jakob disease (CJD), Kuru (a disease confined to a population in Papua-New Guinea), and variant CJD (vCJD), a concept coined to designate cases potentially caused by the human consumption of cattle suffering from bovine spongiform encephalopathy (BSE).The human prion protein (PrP) is a product of a single gene located on the short arm of Chromosome 20 (Prusiner 1991). It is encoded by a single exon of PRNP, exon 2. Variation in the gene sequence produces protein variants that are causative of genetic TSE diseases; the most common are at codons 200, 178, and 102. Other polymorphisms have been linked to differential susceptibility to the acquired TSE diseases, particularly those in codons 129 and 219 (Palmer et al. 1991;Laplanche et al. 1999;Soldevila et al. 2003).In the case of codon 219, it has been suggested that the Lys allele acts as a protective factor against sporadic CJD (Shibuya et al. 1998), and it has been shown to be restricted to Asian and Pacific regions (Soldevila et al. 2003).The common methionine/valine (Met/Val) polymorphism at codon 129 is generally considered to be the most important in genetic susceptibility to prion diseases. Up to 90% of sporadic CJD (sCJD) cases have occurred in individuals who are homozygous for either version of codon 129, Met-Met or Val-Val (Palmer et al. 1991). So far...
Monoamine oxidase A (MAOA) is the X-linked gene responsible for deamination and subsequent degradation of several neurotransmitters and other amines. Among other activities, the gene has been shown to play a role in locomotion, circadian rhythm, and pain sensitivity and to have a critical influence on behavior and cognition. Previous studies have reported a non-neutral evolution of the gene attributable to positive selection in the human lineage. To determine whether this selection was human-exclusive or shared with other species, we performed a population genetic analysis of the pattern of nucleotide variation in non-human species, including bonobo, chimpanzee, gorilla, and orangutan. Footprints of positive selection were absent in all analyzed species, suggesting that positive selection has been recent and unique to humans. To determine which human-unique genetic changes could have been responsible for this differential evolution, the coding region of the gene was compared between human, chimpanzee, and gorilla. Only one human exclusive non-conservative change is present in the gene: Glu151Lys. This human substitution affects protein dimerization according to a three-dimensional structural model that predicts a non-negligible functional shift. This is the only candidate position at present to have been selected to fixation in humans during an episode of positive selection. Divergence analysis among species has shown that, even under positive selection in the human lineage, the MAOA gene did not experience accelerated evolution in any of the analyzed lineages, and that tools such as K(a)/ K(s) would not have detected the selective history of the gene.
The cytotoxic T lymphocyte antigen 4 (CTLA4) acts as a potent negative regulator of T-cell response, and has been suggested as a pivotal candidate gene for autoimmune disorders such as Graves' disease, type 1 diabetes and autoimmune hypothyroidism, among others. Several single-nucleotide polymorphisms (SNPs) have been proposed as the susceptibility variants, or to be in strong linkage disequilibrium (LD) with the variant. Nevertheless, contradictory results have been found, which may be due to lack of knowledge of the genetic structure of CTLA4 and its geographic variation. We have typed 17 SNPs throughout the CTLA4 gene region in order to analyze the haplotype diversity and LD structure in a worldwide population set (1262 individuals from 44 populations) to understand the variation pattern of the region. Allele and haplotype frequency differentiation between populations is consistent with genomewide averages and points to a lack of strong population-specific selection pressures. LD is high and its pattern is not significantly different within or between continents. However, haplotype composition is significantly different between geographical groups. A continent-specific set of haplotype tagging SNPs has been designed to be used for future association studies. These are portable among populations, although their efficiency might vary depending on the population haplotype spectrum.
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