Detailed analysis of a 1.1 Mb genomic region surrounding the <i>VKORC1</i> gene locus in East Asia.

<p>The boundaries of the region displayed (chr16:30,271,572-31,391,123; UCSC human genome build hg18) were chosen so as to include the three clusters of significant scores detected in East Asia by the selection tests in the 2 Mb region centered on <i>VKORC1</i> (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0053049#pone-0053049-g003" target="_blank">Figure 3</a>). (<b>A</b>) <b>Name and location of genes.</b> Exons are displayed as blue boxes and the transcribed strand is indicated with an arrow. Genes located in the block of strong LD encompassing <i>VKORC1</i> and including the SNPs in the red box shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0053049#pone-0053049-g004" target="_blank">Figure 4C</a>, are highlighted in the grey area. (<b>B</b>) <b>XP-EHH results in East Asia.</b> The significance of the XP-EHH scores (−log₁₀ empirical <i>p</i>-value) are shown for individual SNPs with a MAF ≥0.01 in East Asia. Horizontal dashed lines indicate 0.05 and 0.01 chromosome-wide significance levels. Recombination hotspots detected in HapMap Phase II data are indicated by red vertical dotted lines. The data and methods used to derive these hotspots are available from the HapMap website (<a href="http://www.hapmap.org/" target="_blank">http://www.hapmap.org/</a>) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0053049#pone.0053049-McVean1" target="_blank">[83]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0053049#pone.0053049-Winckler1" target="_blank">[84]</a>. (<b>C</b>) <b>LD plot.</b> Pairwise LD values, depicted as <i>D</i>’, are shown for SNPs with a MAF ≥0.01 in East Asia. <i>D</i>’ values are displayed in different colors from yellow to red for <i>D</i>’ = 0 to <i>D</i>’ = 1, respectively. The red box highlights SNPs included in the LD block encompassing <i>VKORC1.</i> The plot was produced using the snp.plotter R package <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0053049#pone.0053049-Luna1" target="_blank">[74]</a>.</p

Results of the inter-regional <i>F_ST</i>, intra-regional <i>F_ST</i>, XP-EHH and iHS tests in the seven geographic regions.

a<p>Derived allele frequency estimated at the global level.</p>b<p><i>F_ST</i> estimated at the inter-regional level, <i>i.e.</i> between a given geographic region and the remaining ones.</p>c<p><i>P</i>-values are derived from the genome-wide empirical distribution of <i>F_ST</i> values.</p>d<p><i>F_ST</i> estimated at the intra-regional level, <i>i.e.</i> among populations within a region.</p>e<p><i>P</i>-values are derived from the empirical distribution of the iHS and XP-EHH scores along the chromosome 16.</p>*<p><i>p</i><0.05; ** <i>p</i><0.01; *** <i>p</i><0.005.</p><p>NA: Not Applicable (for iHS: when a gap>200 kb between successive SNPs is found in the region in the region delimited by the SNPs where the EHH value drops below 0.05 around the core SNP).</p

Distribution of –log₁₀ (<i>p-</i>values) for four selection tests across a 2 Mb region centered on <i>VKORC1</i>.

<p>A black vertical line indicates the physical position of <i>VKORC1</i> on chromosome 16. Horizontal red dotted and dashed lines show 0.05 and 0.01 chromosome-wide significance levels, respectively. The selection tests (inter-regional <i>F_ST</i>, XP-CLR, XP-EHH and iHS, respectively) were separately applied in each of the seven geographic regions.</p

Atypical patterns of genetic differentiation observed for <i>VKORC1</i> SNPs.

<p>Genome-wide empirical distributions of <i>F_ST</i> values were constructed from 644,143 SNPs having a MAF ≥0.001 at the global level. Individual values of <i>F_ST</i> calculated for each of the seven <i>VKORC1</i> SNPs are plotted against their global MAF. The functional rs9923231 SNP is shown in red. The 50^th, 95^th and 99^th percentiles are indicated as dotted, dashed and full red lines, respectively.</p

Transcriptome Sequencing from Diverse Human Populations Reveals Differentiated Regulatory Architecture

<div><p>Large-scale sequencing efforts have documented extensive genetic variation within the human genome. However, our understanding of the origins, global distribution, and functional consequences of this variation is far from complete. While regulatory variation influencing gene expression has been studied within a handful of populations, the breadth of transcriptome differences across diverse human populations has not been systematically analyzed. To better understand the spectrum of gene expression variation, alternative splicing, and the population genetics of regulatory variation in humans, we have sequenced the genomes, exomes, and transcriptomes of EBV transformed lymphoblastoid cell lines derived from 45 individuals in the Human Genome Diversity Panel (HGDP). The populations sampled span the geographic breadth of human migration history and include Namibian San, Mbuti Pygmies of the Democratic Republic of Congo, Algerian Mozabites, Pathan of Pakistan, Cambodians of East Asia, Yakut of Siberia, and Mayans of Mexico. We discover that approximately 25.0% of the variation in gene expression found amongst individuals can be attributed to population differences. However, we find few genes that are systematically differentially expressed among populations. Of this population-specific variation, 75.5% is due to expression rather than splicing variability, and we find few genes with strong evidence for differential splicing across populations. Allelic expression analyses indicate that previously mapped common regulatory variants identified in eight populations from the International Haplotype Map Phase 3 project have similar effects in our seven sampled HGDP populations, suggesting that the cellular effects of common variants are shared across diverse populations. Together, these results provide a resource for studies analyzing functional differences across populations by estimating the degree of shared gene expression, alternative splicing, and regulatory genetics across populations from the broadest points of human migration history yet sampled.</p></div

RNA-sequencing summary.

<p>RNA-sequencing summary.</p

Differential expression across human populations.

<p>Bottom plots show exon positions indicated by rectangles to physical position scale. Red rectangles are differentially expressed exons. Upper plots show the median conditionally quantile normalized (CQN) expression values per population of each exon in horizontal lines. Diagonal lines connect each exon. Each exon corresponds one-to-one with the transcript structure shown below but have been scaled evenly to the width of the plot for ease of visualization. Population orders on the right correspond with the order of expression values of the last exon. A) Expression by population of the uc002yzh.3 transcript of MX1. B) Expression by population of the uc001lui.3 transcript of LSP1.</p

Analysis of genetic and expression divergence among individuals and populations.

<p>A) F_ST matrix with 100*F_ST values shown in the upper half and B) tree generated via hierarchical clustering. C–F) Principal components analysis (PCA) of genetic (C and D) and expression (E and F) values. Genetic values are from exome variants, which were called from high coverage (96X) sequence data.</p

Collection sites for genome-, exome-, and RNA-sequenced human lymphoblastoid cell lines (LCLs).

<p>LCLs were immortalized from the populations highlighted above, as described previously <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004549#pgen.1004549-Cann1" target="_blank">[21]</a>, and the genomes, exomes, and transcriptomes were sequenced. Founder effect and migration paths have been reproduced from <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004549#pgen.1004549-Henn2" target="_blank">[53]</a> to highlight the breadth of human migration history across which these LCLs were sampled.</p

Comparison between eQTL correlations (ρ²) discovered in HapMap3 vs replicated in HGDP.

<p>* indicates p<0.05, ** indicates p<0.01, *** indicates p<0.001. ρ² values in this dataset were filtered to the same minimum threshold as in the HapMap3 study for consistency.</p