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Greenlandic Inuit show genetic signatures of diet and climate adaptation

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Science  18 Sep 2015:
Vol. 349, Issue 6254, pp. 1343-1347
DOI: 10.1126/science.aab2319
  • Fig. 1 Results from a genome-wide scan for positive selection.

    (A) PBS values in windows of 20 SNPs, using a step size of 5 SNPs. The 99.5th and 99.9th percentiles of the empirical distribution are shown as red dashed horizontal lines. Names of genes associated with the highest peaks are shown. (B) Evolutionary trees underlying the strongest signal of selection. The bottom panel shows genomic-average branch lengths based on FST (fixation index, a measure of population genetic differentiation) for GI, CEU and CHB branches (bottom); the top panel shows branch lengths for the SNPs in the window with the highest PBS values, indicating substantial changes in allele frequencies along the GI branch.

  • Fig. 2 The effect of rs7115739 and rs174570 on weight and height.

    (A) The effect of rs7115739 on weight in the Greenlandic cohorts IHIT and B99. Shown is the mean value stratified by the genotypes of rs7115739 (top) and the estimated effect of carrying one and two copies of the derived allele, respectively (bottom). The effect-size estimates are adjusted for admixture and other confounding factors and were obtained using a linear mixed model applied to untransformed phenotype measurements. Unlike the estimates in the text and table S10, the estimates shown here were obtained without assuming an additive effect. Error bars, ±1 SE. (B) As in (A), but for height. (C) Effect sizes for height for the derived allele of rs7115739 in three Greenlandic cohorts and seven European cohorts (SDC, Steno Diabetes Center). Point estimates are shown as points and 95% confidence intervals are shown as horizontal bars. For each of the two geographic regions, the results from a meta-analysis of all the cohorts from the region are also shown. N indicates the number of individuals analyzed; DAF, derived allele frequency. For the Greenlandic cohorts, the effect sizes were estimated from height measurements that were quantile-transformed to a standard normal distribution. For the European cohorts, height was analyzed as sex-specific standard (z) scores. Hence, the effect sizes from the two geographic regions are not directly comparable. (D) As in (C), but for rs174570.

  • Fig. 3 Results of testing for association between the fatty acids in the omega-3 and omega-6 synthesis pathways and each of two SNPs, rs7115739 and rs174570.

    The omega-6 (top) and omega-3 (bottom) synthesis pathways are depicted with circles for each fatty acid and arrows for each synthesis step. For each fatty acid, P values for tests of association and effect directions for the derived allele are illustrated by the colors on the left (rs7115739) and right (rs174570) halves of the circle. Green text indicates in which of the synthesis steps FADS1 and FADS2 play a role. Arrows outside the boxes are simplified indications of where different types of diet enter the two pathways.

  • Table 1

    Annotation for the top six SNPs under positive selection in Greenlandic Inuit. DAFs for each population (CEU, CHB, and GI) and PBS values are reported, along with the genomic position for each SNP.

    Position*Reference SNP
    identification number
    AllelesDAFPBS
    CEUCHBGI
    chr11:61627960rs74771917C/T0.0250.160.982.67
    chr11:61631510rs3168072A/T0.0170.180.982.64
    chr11:61632310rs12577276A/G0.0170.180.982.64
    chr11:61641717rs7115739G/T0.0170.220.982.54
    chr11:61624414rs174602C/T0.800.730.012.11
    chr11:61597212rs174570C/T0.160.340.992.056

    *Positions refer to human genome assembly hg19. Alleles are coded as ancestral/derived states.

    Supplementary Materials

    • Greenlandic Inuit show genetic signatures of diet and climate adaptation

      Matteo Fumagalli, Ida Moltke, Niels Grarup, Fernando Racimo, Peter Bjerregaard, Marit E. Jørgensen, Thorfinn S. Korneliussen, Pascale Gerbault, Line Skotte, Allan Linneberg, Cramer Christensen, Ivan Brandslund, Torben Jørgensen, Emilia Huerta-Sánchez, Erik B. Schmidt, Oluf Pedersen, Torben Hansen, Anders Albrechtsen, Rasmus Nielsen

      Materials/Methods, Supplementary Text, Tables, Figures, and/or References

      Download Supplement
      • Materials and Methods
      • Supplementary Text
      • Figs. S1 to S14
      • Captions for Tables S1 to S17
      Tables S1 to S17
      Table S1. Population Branch Statistic (PBS) values for all SNPs in the SNP-chip data set. Minor allele frequencies (MAF) are reported for the overall minor allele for Greenlandic Inuit (GI), East Asians (CHB) and Europeans (CEU)

      Table S2. Candidate regions under positive selection in Greenlandic Inuit (GI) based on analyses of the SNP-chip data set.

      Table S3. Summary statistics of candidate genes under positive selection based on top PBS entries using either the SNP-chip or the exome sequencing data set. Bold numbers represent values below the 5th percentile of the empirical distribution for Tajima’s D and Fu and Li’s metrics. Genes having less than 2 SNPs, as well as open reading frame entries, were not reported.

      Table S4. Population Branch Statistic (PBS) values for all SNPs in the exome-sequencing data set. Non-reference allele frequencies (AF) are reported for Greenlandic Inuit (GI), East Asians (CHB) and Europeans (CEU).

      Table S5. Candidate regions under positive selection, based on PBS analysis, in Greenlandic Inuit (GI) using the exome sequencing data set.

      Table S6. Significantly enriched gene ontology categories based on the ranking of the maximum PBS score of human genes (P < 0.01, FDR q-value < 0.1, enrichment score > 5).

      Table S7. Association test results for top 1 PBS SNP (rs74771917) and 13 metabolic and anthropometric phenotypes in two Greenlandic cohorts (IHIT and B99). The results are based on testing for association using an additive linear mixed model. All the phenotypes were quantile-transformed to a standard normal distribution before they were analyzed. βSD is the estimated effect size for the quantile-transformed data and β is the effect size estimated for the untransformed data. P-values below 0.05 are marked in red. The βs are the effects of the derived allele (the major allele in Greenlandic Inuit.)

      Table S8. Association test results for top 2 PBS SNP (rs3168072) and 13 metabolic and anthropometric phenotypes in two Greenlandic cohorts (IHIT and B99). The results are based on testing for association using an additive linear mixed model. All the phenotypes were quantile-transformed to a standard normal distribution before they were analyzed. βSD is the estimated effect size for the quantile-transformed data and β is the effect size estimated for the untransformed data. P-values below 0.05 are marked in red. The βs are the effects of the derived allele (the major allele in Greenlandic Inuit.)

      Table S9. Association test results for top 3 PBS SNP (rs12577276) and 13 metabolic and anthropometric phenotypes in two Greenlandic cohorts (IHIT and B99). The results are based on testing for association using an additive linear mixed model. All the phenotypes were quantile-transformed to a standard normal distribution before they were analyzed. βSD is the estimated effect size for the quantile-transformed data and β is the effect size estimated for the untransformed data. P-values below 0.05 are marked in red. The βs are the effects of the derived allele (the major allele in Greenlandic Inuit.)

      Table S10. Association test results for top PBS SNP 4 (rs7115739) and 13 metabolic and anthropometric phenotypes in two Greenlandic cohorts (IHIT and B99). For height results for BBH are also shown. The results are based on testing for association using an additive linear mixed model. All the phenotypes were quantile-transformed to a standard normal distribution before they were analyzed. βSD is the estimated effect size for the quantile-transformed data and β is the effect size estimated for the untransformed data. P-values below 0.05 are marked in red. The βs are the effects of the derived allele (the major allele in Greenlandic Inuit.)

      Table S11. Association test results for top 5 PBS SNP (rs174602) and 13 metabolic and anthropometric phenotypes in two Greenlandic cohorts (IHIT and B99). The results are based on testing for association using an additive linear mixed model. All the phenotypes were quantile-transformed to a standard normal distribution before they were analyzed. βSD is the estimated effect size for the quantile-transformed data and β is the effect size estimated for the untransformed data. P-values below 0.05 are marked in red. The βs are the effects of the ancestral allele (the major allele in Greenlandic Inuit.)

      Table S12. Association test results for top 6 PBS SNP (rs174570) and 13 metabolic and anthropometric phenotypes in two Greenlandic cohorts (IHIT and B99). For height results for BBH are also shown. The results are based on testing for association using an additive linear mixed model. All the phenotypes were quantile-transformed to a standard normal distribution before they were analyzed. βSD is the estimated effect size for the quantile-transformed data and β is the effect size estimated for the untransformed data. P-values below 0.05 are marked in red. The βs are the effects of the ancestral allele (the major allele in Greenlandic Inuit.)

      Table S13. Association results between top 6 PBS SNPs and metabolic phenotypes in Europeans. Association analyses in individual cohorts were performed by linear regression combined by a fixed effect meta-analysis (see Supplementary Methods).

      Table S14.Results for testing if the effect on weight and height is the same in Greenlandic Inuit and in Europeans for top PBS SNP 4 (rs7115739) and 6 (rs174570). The column "P (M1 vs. M4)" contains the P-values for the tests. "β Inuit” and “β EU” contains ancestry specific effects size estimates measured in units of standard deviation. "Effect Inuit" and "Effect EU" are the estimated ancestry specific effect sizes based on untransformed phenotype values.

      Table S15. Association test results for top 4 PBS SNP (rs7115739) and 37 phenotypes related to red blood cell membrane fatty acid composition in the Greenlandic IHIT cohort. The results are based on testing for association using an additive linear mixed model. All phenotypes with less than 20% zero values (corresponding to not measurable) were quantile-transformed to a standard normal distribution before they were analyzed. The rest were transformed to case-control data. βSD is the estimated effect size for the transformed data and b is the effect size estimated for the untransformed data. P-values below 0.05 are marked in red. All βs are the effects of the derived allele (the major allele in Greenlandic Inuit).

      Table S16. Association test results for top 6 PBS SNP (rs174570) and 37 phenotypes related to red blood cell membrane fatty acid composition in the Greenlandic IHIT cohort. The results are based on testing for association using an additive linear mixed model. All phenotypes with less than 20% zero values (corresponding to not measurable) were quantile-transformed to a standard normal distribution before they were analyzed. The rest were transformed to case-control data. βSD is the estimated effect size for the transformed data and b is the effect size estimated for the untransformed data. P-values below 0.05 are marked in red. All βs are the effects of the derived allele (the major allele in Greenlandic Inuit).

      Table S17. eQTLs with FDR < 5% from European RNA-seq data (from the Geuvadis exon database). Significant SNPs with high PBS in the FADS region are reported. Highlighted in red are eQTLs with -log10 p-values > 10.

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