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. 2005 Sep;1(3):e41.
doi: 10.1371/journal.pgen.0010041. Epub 2005 Sep 30.

Positive selection of a pre-expansion CAG repeat of the human SCA2 gene

Fuli Yu  1 , Pardis C Sabeti, Paul Hardenbol, Qing Fu, Ben Fry, Xiuhua Lu, Sy Ghose, Richard Vega, Ag Perez, Shiran Pasternak, Suzanne M Leal, Thomas D Willis, David L Nelson, John Belmont, Richard A Gibbs
Affiliations

Positive selection of a pre-expansion CAG repeat of the human SCA2 gene

Fuli Yu et al. PLoS Genet. 2005 Sep.

Abstract

A region of approximately one megabase of human Chromosome 12 shows extensive linkage disequilibrium in Utah residents with ancestry from northern and western Europe. This strikingly large linkage disequilibrium block was analyzed with statistical and experimental methods to determine whether natural selection could be implicated in shaping the current genome structure. Extended Haplotype Homozygosity and Relative Extended Haplotype Homozygosity analyses on this region mapped a core region of the strongest conserved haplotype to the exon 1 of the Spinocerebellar ataxia type 2 gene (SCA2). Direct DNA sequencing of this region of the SCA2 gene revealed a significant association between a pre-expanded allele [(CAG)8CAA(CAG)4CAA(CAG)8] of CAG repeats within exon 1 and the selected haplotype of the SCA2 gene. A significantly negative Tajima's D value (-2.20, p < 0.01) on this site consistently suggested selection on the CAG repeat. This region was also investigated in the three other populations, none of which showed signs of selection. These results suggest that a recent positive selection of the pre-expansion SCA2 CAG repeat has occurred in Utah residents with European ancestry.

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Conflict of interest statement

Competing interests. The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Haplotype Block Size Distribution of Human Chromosome 12 in CEU
The haplotype blocks were defined by D′ confidence interval [16] and binned according to their sizes. The inset provides the ungrouped distribution of the haplotype blocks larger than 100 kb.
Figure 2
Figure 2. LD Patterns and Haplotypes of the Largest Block on Human Chromosome 12 in CEU (A), CHB (B), JPT (C), and YRI (D)
Pair-wise LD of common SNPs (MAF > 0.05) is expressed as D′, with red indicating strong LD. The figure also shows the haplotype blocks of 1 Mb intervals in both upstream and downstream of the largest block. Schematic position of the SCA2 gene is shown.
Figure 3
Figure 3. Mapping the Locus that is Under Positive Selection to the SCA2 Gene Using the EHH Approach
The mapped core region consists of 7 markers (rs593226, rs616513, rs653178, rs695871, rs3809274, rs1544396, and rs9300319). (A) The relative gene positions, EHH × distance and REHH × distance plots. (B) Four core haplotypes [TCGGGAT (39%), TCAGGAT (22%), CAACCGC (20%), and CCAGGAT (7%)]. The common SNPs are highlighted in yellow. The ancestral alleles predicted as the chimp alleles were shown on the top. (C) Haplotype bifurcation plots of the four core haplotypes.
Figure 4
Figure 4. Schematic of the SCA2 gene, (CAG)n, and the 7 SNPs (rs593226, rs616513, rs653178, rs695871, rs3809274, rs1544396, and rs9300319) in the Core Region
Figure 5
Figure 5. REHH × Frequency Distribution of CEU Chromosome 12
REHH was calculated at 0.25 cM distances on both sides for all possible core haplotypes from CEU Chromosome 12 and represented with blue dots and given with 50th, 75th, 90th, and 95th percentiles. REHH values of CH-1 were represented with brown dots.
Figure 6
Figure 6. LD of CAG repeat in SCA2 gene with the 7 Adjacent SNPs (rs593226, rs616513, rs653178, rs695871, rs3809274, rs1544396, and rs9300319)
Different alleles of CAG repeat were recoded as such: 1 = (CAG)8CAA(CAG)4CAA(CAG)8 allele; 2 = all the other alleles; 0 = failed.
See this image and copyright information in PMC

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