43.6?0.9 68.8?4.9 24.7?5.2 61.2?7.1 6.9?1.0 24.8?5.3 0.16?.Flanking SNPs of SNPs OAR2_88062818.1 35257.1 s26286.1 AR3_165050963.1 s59995.1 AR5_53435489.1 OAR6_6402059.1?OAR6_55087517_X.1 OAR6_57796972.1 AR6_58069886.1 OAR6_70844973.1 AR6_81183719.1 OAR6_127397796.1 33220.1 OAR10_29159858.1 AR10_29381795.1 s39429.1 AR13_55448085.1 OAR13_74074760.1 AR13_80614774_X.1 s59907.1 AR16_27501072.1 s25636.1 73670.1 OAR24_8063846.1 18520.1 OAR25_25923466.1 AR25_48288071_X.1 OAR26_222715_X.1 54858.Number 97 68 48 860 7 180 58 7 104 97 13 34 44 353Raw P-value 0.034 0.029 0.007 0.000 0.049 0.016 0.026 0.044 0.006 0.025 0.043 0.039 0.042 0.008 0.q-value 0.574 0.545 0.213 0.000 0.604 0.389 0.52 0.598 0.192 0.524 0.598 0.591 0.598 0.249 0.Guti rez-Gil et al.8 83.1?5.3 Mb 153.4?54.5 Mb ?39.3?9.5 Mb ?69.9?0.5 Mb ??48.9?2.0 Mb ??????Fariello et al.7 81.2?7.3 Mb 151.4?56.9 Mb 47.3?9.3 Mb 35.9?8.3 Mb ?67.9?0.3 Mb ?29.4?9.7 Mb 43.3?1.2 ??????10 13 16 17 24 25Table 2. LDN193189 msds putative selective sweeps identified in the hapFLK-based analysis. Those sweeps consistently found with BayeScan are shown in bold. In the two columns at the right part of the table, we show evidence of positional concordance with previously reported selective sweeps7,8. CHR = chromosome. (Table 2, Fig. 4), positional coincidences were identified on Oar3 (150?54 Mb), Oar6 (4.3?9.9 Mb), and Oar13 (68.8?4.9 Mb). Next, we will examine more thoroughly a set of physiological and positional candidate genes whose patterns of variation could have been potentially modified by selection. Selective sweep on Oar3. The Oar3 (150?54 Mb) region co-localizes with a pleiotropic bovine quantitative trait locus (QTL) for birth weight, calving ease direct, marbling and ribeye muscle area20 as well as with a second bovine QTL for fat yield21. There are several genes that may explain the existence of a selective sweep in this genomic region. The high mobility group AT-hook 2 (HMGA2, 153.7 Mb) gene is particularly relevant becauseScientific RepoRts | 6:27296 | DOI: 10.1038/srepwww.nature.com/scientificreports/Figure 4. A detailed view of the putative selective sweeps on Oar3, Oar6 and Oar13 detected with the HapFLK statistic and confirmed with BayeScan. The red and blue lines indicate the thresholds of significance set at 0.05 before (nominal P-value) and after (q-value) correction for multiple testing, respectively. Genomic coordinates and statistical significance (-log10 P-values) are plotted in the x- and y-axis, respectively. The approximate location of the candidate genes discussed in the current work is indicated (in Mb).polymorphism at this transcriptional regulator has been associated with height in humans and body size in horses and dogs20. Moreover, the inactivation of HMGA2 in mouse leads to the pygmy phenotype, characterized by a substantial decrease in body size and adiposity and defective spermatogenesis22,23. Another gene of interest is the WNT Inhibitory Factor 1 (WIF1, 154.5 Mb) locus, that encodes a molecule inhibiting extracellular WNT signaling, and that has been identified as positively selected in domestic cattle24. Interestingly, the WNT effector pathway is essential for the LDN193189MedChemExpress LDN193189 initiation of embryonic mammary organogenesis and the maintenance of stem cells, and it may also regulate post-natal ductal and alveolar development25. Finally, it is worth to mention the methionine sulfoxide reductase B3 (MSRB3, 154.2 Mb) and the LEM domain containing 3 (LEMD3, 154.4 Mb) loci, that are involved in cell grow.43.6?0.9 68.8?4.9 24.7?5.2 61.2?7.1 6.9?1.0 24.8?5.3 0.16?.Flanking SNPs of SNPs OAR2_88062818.1 35257.1 s26286.1 AR3_165050963.1 s59995.1 AR5_53435489.1 OAR6_6402059.1?OAR6_55087517_X.1 OAR6_57796972.1 AR6_58069886.1 OAR6_70844973.1 AR6_81183719.1 OAR6_127397796.1 33220.1 OAR10_29159858.1 AR10_29381795.1 s39429.1 AR13_55448085.1 OAR13_74074760.1 AR13_80614774_X.1 s59907.1 AR16_27501072.1 s25636.1 73670.1 OAR24_8063846.1 18520.1 OAR25_25923466.1 AR25_48288071_X.1 OAR26_222715_X.1 54858.Number 97 68 48 860 7 180 58 7 104 97 13 34 44 353Raw P-value 0.034 0.029 0.007 0.000 0.049 0.016 0.026 0.044 0.006 0.025 0.043 0.039 0.042 0.008 0.q-value 0.574 0.545 0.213 0.000 0.604 0.389 0.52 0.598 0.192 0.524 0.598 0.591 0.598 0.249 0.Guti rez-Gil et al.8 83.1?5.3 Mb 153.4?54.5 Mb ?39.3?9.5 Mb ?69.9?0.5 Mb ??48.9?2.0 Mb ??????Fariello et al.7 81.2?7.3 Mb 151.4?56.9 Mb 47.3?9.3 Mb 35.9?8.3 Mb ?67.9?0.3 Mb ?29.4?9.7 Mb 43.3?1.2 ??????10 13 16 17 24 25Table 2. Putative selective sweeps identified in the hapFLK-based analysis. Those sweeps consistently found with BayeScan are shown in bold. In the two columns at the right part of the table, we show evidence of positional concordance with previously reported selective sweeps7,8. CHR = chromosome. (Table 2, Fig. 4), positional coincidences were identified on Oar3 (150?54 Mb), Oar6 (4.3?9.9 Mb), and Oar13 (68.8?4.9 Mb). Next, we will examine more thoroughly a set of physiological and positional candidate genes whose patterns of variation could have been potentially modified by selection. Selective sweep on Oar3. The Oar3 (150?54 Mb) region co-localizes with a pleiotropic bovine quantitative trait locus (QTL) for birth weight, calving ease direct, marbling and ribeye muscle area20 as well as with a second bovine QTL for fat yield21. There are several genes that may explain the existence of a selective sweep in this genomic region. The high mobility group AT-hook 2 (HMGA2, 153.7 Mb) gene is particularly relevant becauseScientific RepoRts | 6:27296 | DOI: 10.1038/srepwww.nature.com/scientificreports/Figure 4. A detailed view of the putative selective sweeps on Oar3, Oar6 and Oar13 detected with the HapFLK statistic and confirmed with BayeScan. The red and blue lines indicate the thresholds of significance set at 0.05 before (nominal P-value) and after (q-value) correction for multiple testing, respectively. Genomic coordinates and statistical significance (-log10 P-values) are plotted in the x- and y-axis, respectively. The approximate location of the candidate genes discussed in the current work is indicated (in Mb).polymorphism at this transcriptional regulator has been associated with height in humans and body size in horses and dogs20. Moreover, the inactivation of HMGA2 in mouse leads to the pygmy phenotype, characterized by a substantial decrease in body size and adiposity and defective spermatogenesis22,23. Another gene of interest is the WNT Inhibitory Factor 1 (WIF1, 154.5 Mb) locus, that encodes a molecule inhibiting extracellular WNT signaling, and that has been identified as positively selected in domestic cattle24. Interestingly, the WNT effector pathway is essential for the initiation of embryonic mammary organogenesis and the maintenance of stem cells, and it may also regulate post-natal ductal and alveolar development25. Finally, it is worth to mention the methionine sulfoxide reductase B3 (MSRB3, 154.2 Mb) and the LEM domain containing 3 (LEMD3, 154.4 Mb) loci, that are involved in cell grow.
