PMC:4502373 / 26357-33919 JSONTXT

{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/4502373","sourcedb":"PMC","sourceid":"4502373","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4502373","text":"Genomic regions and candidate genes for stature\nTable 1 shows a summary of the significant regions in each cohort with comparison to respective reference populations within the European and African categories. It also shows the number of regions harboring candidate genes associated with stature, which were found in human GWAS (Table S4). Overall, out of 9 and 17 significant genomic regions within the European and African cohorts, 7 (77.8%) and 5 (29.4%) were co-located with candidate gene regions that harbor stature-associated genes. The remaining 2 and 12 significant genomic regions in European and African cohorts, respectively, were identified outside the known candidate gene regions. Overall, 46% (n = 12 out of 26) of all significant CSS were co-located with candidate gene regions, this proportion is much higher as compared to the 7% expected by chance alone as described above (Figure S3).\nFigure 3 shows a summary comparison of empirical and permuted cohort results. Overall, 8.3% of the significant regions based on permuted CSS in five sets (i.e., 20 permuted cohorts) contained stature-associated loci (Figure 3) that was in agreement with the 7% expected by chance (Figure S3). On average, only 6.7% and 9.8% of significant regions of permuted CSS from European and African cohorts had stature-associated genes as compared to 77.8% and 29.4% of empirical regions, respectively.\nFigure 3 Comparison of empirical and permuted CSS scores for localization of significant regions harboring stature-associated genes. Horizontal lines, labeled with cohorts (European large = 100%, European small = 60%, African small = 37.5%, and African large = 22.2%), indicate the percentage of significant genomic regions from each cohort that localized the stature associated genes. Vertical bars show the distribution of significant regions (%) harboring stature-associated genes in five sets of permutation cohorts that mimicked the empirical cohorts in matching colors. The Circos image (Figure 4) represents all 26 significant genomic regions, names of important candidate genes for bovine stature (Table 2), and the locations of all the orthologous genes from human GWAS (Table S4). Table 2 shows the list of those 12 genomic regions that harbor 30 candidate genes, which have previously been associated with stature in human GWAS and other species. The results from the major contrasting cohorts, especially large and small cohorts of European Bos taurus, supported the strategy of finding candidate gene regions by grouping phenotypically alike breeds. All the significant signatures of selection (four out of four) identified in the European large cohort contained known candidate genes in multiple species (Table 2) within region 1 (gene: DUSP23), region 6 (NCAPG, LCORL), region 10 (TGS1, LYN, RPS20, MOS, PLAG1, CHCHD7, SDR16C5, RDHE2, PENK), and region 11 (POLR2A). However, in cattle, only regions 6 and 10 have previously been investigated in relation to stature. In the European small cohort, three out of the four significant genomic regions, i.e., region 3 (PKN2), region 5 (ATP5G2, ATF7), and region 7 (CAMLG, DDX46, TXNDC15, CATSPER3, PITX1) harbor candidate genes that were previously reported to be associated with human height.\nFigure 4 Circos image showing localization of genome-wide significant regions and candidate genes across all cohorts. The inner circle shows a bovine chromosome (29 autosomes) ideogram. The first outer circle, labeled as Stature Loci, shows the location of 134 loci listed in Table S4, and each red dot represents a stature-associated candidate gene (clustered red dots, within a locus, located on top of each other represent multiple neighboring candidate genes implicated in the same or different GWAS studies). Two circles, in the middle, labeled as EUROPEAN COHORTS and AFRICAN COHORTS show cohort-wise genomic regions identified by top 0.1% CSS (legends in the center for cohort-wise colored bars). The outer track shows genomic locations of 30 candidate genes within the 12 significant signatures of selection linked to bovine stature. Gene colors indicate whether they were identified in European (green) or African (purple) cattle types.\nTable 2 Significant selection regions that harbor candidate genes for stature identified by composite selection signals in all analyses of European and African cohorts\nRegion BTA Location (Mb) Top 0.1 (1)% SNPs Candidate Genes Candidate Population Source of Discovery (References)\n1 3 9.35–10.06 1 (15) DUSP23 European large Human (Lanktree et al. 2011)\n2 3 24.00–24.83 1 (9) SPAG17 African large Human (Weedon et al. 2008; Kim et al. 2010)\n3 3 50.62–56.96 5 (47) PKN2 European small Human (Lanktree et al. 2011)\n4 3 105.09–106.96 11 (30) SCMH1 African large Human (Weedon et al. 2008)\n5 5 26.88–27.50 4 (8) ATP5G2, ATF7 European small Human (Okada et al. 2010)\n6 6 38.29–39.75 10 (29) NCAPG, LCORL European large Human, cattle, and horse (Gudbjartsson et al. 2008; Weedon et al. 2008; Soranzo et al. 2009; Lango Allen et al. 2010; Okada et al. 2010; Pryce et al. 2011)\n7 7 43.42–46.75 20 (36) CAMLG, DDX46, TXNDC15, CATSPER3, PITX1a European small Human (Gudbjartsson et al. 2008)\n8 8 83.05–83.89 3 (13) FBP2, PTCH1 African small Human and cattle (Weedon et al. 2008; Kim et al. 2010; Lanktree et al. 2011; Pryce et al. 2011)\n9 10 59.38–59.97 1 (12) CYP19A1 African small Human (Okada et al. 2010; Lanktree et al. 2011)\n10 14 24.79–28.25 21 (66) TGS1, LYN, RPS20, MOS, PLAG1, CHCHD7, SDR16C5, RDHE2, PENK European large Human, cattle, and horse (Gudbjartsson et al. 2008; Soranzo et al. 2009; Okada et al. 2010; Lango Allen et al. 2010; Lettre et al. 2008; Pryce et al. 2011)\n11 19 27.64–28.63 6 (16) POLR2A European large Human (Lanktree et al. 2011)\n12 19 48.01–49.01 1 (14) WDR68, MAP3K3, LYK5, GH1 African small Human (Gudbjartsson et al. 2008; Soranzo et al. 2009; Lanktree et al. 2011)\na Candidate gene locus is localized slightly over 1 Mb in the surrounding of a significant region. In the African cohorts, several significant signatures of selection regions did not contain known stature-associated candidate genes. Consequently, the percentage of selection regions with known candidate genes was lower, i.e., 29.4%, which is almost one-third of that of European cohorts (77.8%). Despite that, this percentage in the African cohorts was almost three-times more than that of the likelihood of occurrence by chance. Nevertheless, we identified five candidate gene regions (2, 4, 8, 9, and 12) in African cohorts that contain important genes for stature, as reported by multiple human GWAS (Table 2).\nFinally, Figure S5 compares the distribution of CSS and its component tests (FST, ΔDAF, and XP-EHH) at the 12 candidate regions harboring stature-associated genes. These comparisons show that the CSS scores are not being derived from one particular component selection test. The results also suggest that the three component tests provide complementary evidence to each other at the candidate regions. However, it is evident that many of these candidate regions would not have been detected with any of the component selection tests, particularly regions 1, 2, 5, 8, 9, and 12. These results provide overwhelming support for the CSS strategy, suggesting that it is a robust and efficient method for combining complementary evidence to detect the historical signatures of selection for complex traits, which otherwise cannot be detected by available tests of 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