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Results: 5

1.
Figure 3

Figure 3. Haplotype Alignment of the Region Presenting Differing Variation Rates. From: Genetic Analysis of Completely Sequenced Disease-Associated MHC Haplotypes Identifies Shuffling of Segments in Recent Human History.

The alignment covers the centromeric side of the DR–DQ 158-kb DNA segment (left half, low variation) and the adjacent DNA segment (increased variation). Coordinates refer to Chromosome 6 build NCBI35. Rows represent the allelic state for 26 single chromosomes with the same DRB1*1501-DQA1*0102-DQB1*0602 (DR15–DQ6) haplotype at successive SNPs which are represented by columns (A, red; C, blue; G, orange; and T, green). Identity is interrupted at a position perfectly matching with a recombination hotspot coordinate [5,53] represented as hotspot number 2 in Figure 4.

James A Traherne, et al. PLoS Genet. 2006 January;2(1):e9.
2.
Figure 4

Figure 4. LD Structure around the HLA-DR Region. From: Genetic Analysis of Completely Sequenced Disease-Associated MHC Haplotypes Identifies Shuffling of Segments in Recent Human History.

High-resolution view of the HLA-DR region, as represented by GOLDsurfer three-dimensional view of D′ values [81]. The position of the 158-kb segment shared by identical by descent between COX and QBL is shown by a dashed white line. High LD areas (red blocks) are separated by LD breaks. The first LD break (1) corresponds to a recombination hotspot mapped between NOTCH4 and C6orf10 in the class II–III boundary region. Another LD break (2) is visualized at another recombination hotspot centromeric of HLA-DQB1 at the boundary of the SNP desert between COX and QBL. This is followed centromerically by a further four LD breaks corresponding to recombination hotspots mapped at BRD2/HLA-DOA interval, within HLA-DMB, within TAP2 and HLA-DQB2/-DOB interval [5,51,53]. An asterisk (*) indicates a region of depleted SNP data, likely owing to substantial genotyping failure in an area with an extreme level of polymorphism.

James A Traherne, et al. PLoS Genet. 2006 January;2(1):e9.
3.
Figure 5

Figure 5. Model of Haplotype Divergence over DR–DQ Region in Relation to Extended MHC Haplotypes. From: Genetic Analysis of Completely Sequenced Disease-Associated MHC Haplotypes Identifies Shuffling of Segments in Recent Human History.

(A) Divergence of DR–DQ region over tens of millions of years [73].
(B) Transfer of divergent blocks into other haplotypes by recombination. This does not need a double crossover but could occur by single crossovers separated in time.
(C) Relative expansion of ancestral DR–DQ haplotypic segments that may result from either positive selection or neutral processes. Black vertical stripes represent occasional SNP mutations occurring within the MHC including within the ancestral haplotypic segments. Small crosses represent crossovers occurring more frequently outside the conserved DR–DQ blocks relative to inside these blocks. However, allele or gene conversion may take place by closely spaced double crossovers, resulting in diversification of the peptide-binding groove without flanking recombination [87,88]. This model was predicted by Gaudieri et al. (1997) [63] based on incomplete sequence analysis.
(D) Examples of contemporary MHC haplotypes containing ancestral DR–DQ segments (data provided by www.allelefrequencies.net).

James A Traherne, et al. PLoS Genet. 2006 January;2(1):e9.
4.
Figure 2

Figure 2. Positional Distributions of Variations between COX and QBL in the HLA-DR Region. From: Genetic Analysis of Completely Sequenced Disease-Associated MHC Haplotypes Identifies Shuffling of Segments in Recent Human History.

MHC sequences were divided into 10-kb bins, and variations were calculated in each bin. Results are expressed as variations per 1 kb. Red and blue plots relate to SNP and DIP variations respectively.
Within a stretch of approximately 160 kb between HLA-DRB3 and HLA-DQB3, only 14 SNPs and six small DIPs, comprising 1 bp, 6 bp, 10 bp (five copies of a dinucleotide repeat), and 54 bp (two copies of 27 mer), were contained. None of the variations located to coding sequence or the defined promoter regions of the HLA class II genes [86].
Four 1-bp DIPs, labelled in grey, were identified between DRB1 and DQA1 where LR-PCR products were used to close a small gap resulting from clone deficit. These DIPs were located in polyA/T tracts in which the probability of Taq slippage in PCR products is much higher than in in-vivo amplified plasmid DNA such that their authenticity was questionable and they were excluded from analyses (Figure S2 shows one alignment of sequence traces with differing polyT tracts).

James A Traherne, et al. PLoS Genet. 2006 January;2(1):e9.
5.
Figure 1

Figure 1. Positional Distributions of Variations between PGF and QBL and COX and QBL. From: Genetic Analysis of Completely Sequenced Disease-Associated MHC Haplotypes Identifies Shuffling of Segments in Recent Human History.

(A) Shows the distribution for PGF and QBL and (B) shows COX and QBL. MHC sequences were divided into 10-kb bins, and variations were calculated in each bin. Results are expressed as variations per 1 kb. Red and blue plots relate to SNP and DIP variations respectively. The sequence is interrupted by five gaps, shown as green vertical bars, where BACs encompassing these regions could not be identified from the clone library, which by comparison with PGF comprise a total of approximately 317 kb. The lengths and gene content of these gaps were as follows, from left to right: 159 kb including OR2U1P to OR12D2; 51 kb containing HCP5; 26 kb containing C6orf26, C6orf27, and the three exons of 3′ end of MSH5; 53 kb containing CREBL1, FKBPL, and six exons of the 5′ end of TNXB; and 27 kb containing HLA-DOB. These gaps do not represent large genomic deletions within the QBL haplotype since exonic sequence from selected genes within these regions were successfully amplified from QBL genomic DNA and sequenced to confirm their identity. The grey shaded area at the telomeric end of the map represents sequence for which overlap was not obtained and was therefore outside the area that was compared.
Boundaries of the class I, II, and III regions are shown. The positions of RFP and KIFC1 that define the ends of the MHC haplotype sequencing project are indicated. Landmark genes are labelled in blue. Regions 1 and 2 are the RCCX module and the HLA-DRB region, respectively. The HLA-DRB3 and HLA-DQB3 region, which shows little variation between COX and QBL haplotypes, is shaded in orange.

James A Traherne, et al. PLoS Genet. 2006 January;2(1):e9.

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