Fig 4. Positive selection at the LRP5 locus.

(A). A 140 kb region on chromosome 6 that spans LRP5 showing GENCODE (Version 19) transcript annotation. Positions of 11 candidate regulatory variants and DNase I Hypersensitivity Clusters are shown along with the −log₁₀ of the combined p-values from frequency-spectrum-based analysis in three continental populations. The significance threshold is indicated by the dashed line and two non-overlapping 10 kb windows have a significant combined p-value in CHB. (B). A closer look at the 3’ selected region in East Asians (highlighted in blue). The region contains both variants with the highest derived allele frequency in East Asians (rs649772 and rs671494) that lie in a DNase I hypersensitivity cluster and show ENCODE chromatin state segmentation associated with enhancer binding in several cell lines. In osteoblasts the variants lie within the histone sequence variant, H2A.Z, that determines accessibility of the transcription start site (dark bands) and there are additional H3K4me1 and H3K27ac histone modifications upstream of the variant. The candidate regulatory variant site also shows binding for many transcription factors. The lower part of the panel shows median joining haplotype networks in a ~20 kb region that is in high LD (r² ≥ 0.95) in CHB. Phased haplotypes generated by the 1000 Genomes Project were used to construct this network. The derived alleles for the regulatory variants rs649772 and rs671494 lie on the branch leading towards the most frequent haplotype found in East Asians and shows a star like expansion typical of a selection signal. The non-synonymous variant rs3736228 (red line) that is associated with bone mineral density in genome wide association studies lies on a separate branch.