World distribution of A111T polymorphism in SLC24A5. The origins of sampled populations are indicated (+). Contours of global frequencies of SLC24A5^A111T are shaded according to the frequency/color scale to the right. Frequency data by population that were used for this figure are tabulated in Table S1.

Genomic region surrounding SLC24A5. The first three panels show SNPs (red symbols, SNPs used for haplotype analysis in HapMap Phase 3, Release 27, also listed in Table S2; black symbols, additional SNPs genotyped in fewer HapMap populations, or flanking SNPs not analyzed here). SNPs monomorphic in the original four HapMap population samples (CEU, CHB, JPT, YRI) are omitted. Top, SNP heterozygosity in CEU, calculated from allele frequencies, illustrating the region of diminished variation in this European sample. Middle, SNP allele frequency difference between CEU and YRI, showing several SNPs with extremely high frequency differentiation (Δf ≥ 0.8); rs1426654 is circled. Beneath is a recombination map showing boundaries of blocks used for haplotype analysis (A through D). Region C, as described in text, is the core region containing SLC24A5. Bottom, positions of SLC24A5 and other genes in region, with common coordinates (NCBI build B36) used for all panels. The centromere is to left.

Core-region haplotypes defined using 16 SNPs. (A) Diagram showing relationships between common haplotypes C1 through C11. SNPs that differ between adjacent haplotypes are labeled by nickname (SNP c1 through c16, keyed to Table S2). Haplotype C1 contains ancestral alleles for each SNP in this series. Haplotype C11 carries the derived Thr-111 allele of SLC24A5 (rs1426654, SNP c11). The only duplicated transition in this diagram is for SNP c1 (rs1834640). Note that analysis of additional SNPs reveals cases in which adjacent haplotypes in the diagram do not have ancestor-descendent relationships (compare ). (B) Histograms showing the distribution of haplotypes in several HapMap populations. The three East Asian populations are combined, as are CEU and TSI. Indeterminate C2/C3 in TSI indicated. MEX and ASW are not depicted. The frequency scale is split at 0.2.

Phylogenetic relationships among core haplotype clusters. Haplotypes were deduced from 1000 Genomes data by the use of 156 polymorphisms with frequency ≥1%. (A) Haplotypes having frequencies ≥0.5% (representing 78% of total) are depicted. Complete dataset is found in File S1. Sets of haplotypes corresponding to those deduced using 16 SNPs are enclosed within red boxes and labeled C1 through C11. C8, which constituted <0.5%, is not shown. Two variants of C3 differ at an indel that shows evidence of recurrent mutation and for which the ancestral state is unknown. Values within each circle indicate number of occurrences. Gray and yellow shading indicates haplotypes that are predominantly African or East Asian (in this dataset), respectively. Numbers of polymorphic differences on each branch are indicated if greater than one. Inclusion of lower frequency polymorphisms would raise the number of C1-specific variants to 26, whereas C4-specific variants would increase to 11. Early haplotype lineage divergence, depicted within the dashed circle, provides evidence for multiple recombination events that are not resolved in this phylogeny. The numbers within the dashed circle represent number of polymorphic differences from the ancestral state; this involves 31 polymorphisms that have derived alleles shared by more than one lineage. (B) Relationships among early diverging branches supported by 21 polymorphisms. (C) Alternative relationships among early diverging branches supported by 5 polymorphisms. The ancestral state is represented by the open circle in B and C.

Relationships between local haplotypes in B and C regions. For each HapMap population, the distribution of haplotype combinations is shown as a heat map (scale on right). Recurrent recombination between core- and B-region is apparent. Predominant association of C11 with B6 contrasts with associations of C10 (B2) and C9 (B2, B7). Counts are shown in File S2.

Generation of haplotype C11. Recombination between chromosomes containing C10 (white) and C3 (shaded) is indicated by X. The crossover product represented by the solid line is the precursor to C11; the reciprocal recombinant represented by the dotted line is not recovered. Ancestral alleles are represented by open symbols, and derived alleles are solid black, where rs12441154, rs1834640 (c1), rs2675345 (c2), rs57108441, and rs1426654 (c11) are represented by the triangle, square, triangle, circle, and star, respectively. The B6 haplotype (here defined by 6 SNPs), just to the left of the C region, is that most commonly found in phase with the C3 allele, as indicated; B2 and B3 are most commonly in phase with C10. Subsequent mutation at rs1426654, represented by the black star, produced the predominant SLC24A5^A111T-containing haplotype, C11, which is globally associated with B6. 1000 Genomes Project data localize the crossover to the 0.9-kb interval between rs57108441 and rs78729596. Flanking regions are not shown. Note that the final product is identical under an alternate model in which mutation precedes recombination.