Selection signature reveals genes associated with susceptibility loci affecting respiratory disease due to pleiotropic and hitchhiking effect in Chinese indigenous pigs

  • Xu, Zhong (Department of Animal Science, School of Agriculture and Biology, Shanghai Jiao Tong University) ;
  • Sun, Hao (Department of Animal Science, School of Agriculture and Biology, Shanghai Jiao Tong University) ;
  • Zhang, Zhe (Department of Animal Science, School of Agriculture and Biology, Shanghai Jiao Tong University) ;
  • Zhang, Cheng-Yue (Department of Animal Science, School of Agriculture and Biology, Shanghai Jiao Tong University) ;
  • Zhao, Qing-bo (Department of Animal Science, School of Agriculture and Biology, Shanghai Jiao Tong University) ;
  • Xiao, Qian (Department of Animal Science, School of Agriculture and Biology, Shanghai Jiao Tong University) ;
  • Olasege, Babatunde Shittu (Department of Animal Science, School of Agriculture and Biology, Shanghai Jiao Tong University) ;
  • Ma, Pei-Pei (Department of Animal Science, School of Agriculture and Biology, Shanghai Jiao Tong University) ;
  • Zhang, Xiang-Zhe (Department of Animal Science, School of Agriculture and Biology, Shanghai Jiao Tong University) ;
  • Wang, Qi-Shan (Department of Animal Science, School of Agriculture and Biology, Shanghai Jiao Tong University) ;
  • Pan, Yu-Chun (Department of Animal Science, School of Agriculture and Biology, Shanghai Jiao Tong University)
  • Received : 2018.09.03
  • Accepted : 2019.01.14
  • Published : 2020.02.01


Objective: Porcine respiratory disease is one of the most important health problems causing significant economic losses. To understand the genetic basis for susceptibility to swine enzootic pneumonia (EP) in pigs, we detected 102,809 single nucleotide polymorphisms in a total of 249 individuals based on genome-wide sequencing data. Methods: Genome comparison of susceptibility to swine EP in three pig breeds (Jinhua, Erhualian, and Meishan) with two western lines that are considered more resistant (Duroc and Landrace) using cross-population extended haplotype homozygosity and F-statistic (FST) statistical approaches identified 691 positively selected genes. Based on quantitative trait loci, gene ontology terms and literature search, we selected 14 candidate genes that have convincible biological functions associated with swine EP or human asthma. Results: Most of these genes were tested by several methods including transcription analysis and candidate genes association study. Among these genes: cytochrome P450 1A1 and catenin beta 1 (CTNNB1) are involved in fertility; transforming growth factor beta receptor 3 plays a role in meat quality traits; Wnt family member 2, CTNNB1 and transcription factor 7 take part in adipogenesis and fat deposition simultaneously; plasminogen activator, urokinase receptor (completely linked to AXL receptor tyrosine kinase, r2 = 1) plays an essential role in the successful ovulation of matured oocytes in pigs; colipase like 2 (strongly linked to SAM pointed domain containing ETS transcription factor, r2 = 0.848) is involved in male fertility. Conclusion: These adverse genes susceptible to swine EP may be selected while selecting for economic traits (especially reproduction traits) due to pleiotropic and hitchhiking effect of linked genes. Our study provided a completely new point of view to understand the genetic basis for susceptibility or resistance to swine EP in pigs thereby, provides insight for designing sustainable breed selection programs. Finally, the candidate genes are crucial due to their potential roles in respiratory diseases in a large number of species, including human.


Supported by : National Natural Science Foundation of China


  1. Simionatto S, Marchioro SB, Maes D, Dellagostin OA. Mycoplasma hyopneumoniae: from disease to vaccine development. Vet Microbiol 2013;165:234-42. vetmic.2013.04.019
  2. Hong SJ. The role of Mycoplasma pneumoniae infection in asthma. Allergy Asthma Immunol Res 2012;4:59-61.
  3. Okamura T, Onodera W, Tayama T, et al. A genome-wide scan for quantitative trait loci affecting respiratory disease and immune capacity in Landrace pigs. Anim Genet 2012;43:721-9.
  4. Huang X, Huang T, Deng W, et al. Genome-wide association studies identify susceptibility loci affecting respiratory disease in Chinese Erhualian pigs under natural conditions. Anim Genet 2017;48:30-7.
  5. Fang X, Zhao W, Fu Y, et al. Difference in susceptibility to mycoplasma pneumonia among various pig breeds and its molecular genetic basis. Sci Agric Sin 2015;48:2839-47.
  6. Sabeti PC, Varilly P, Fry B, et al. Genome-wide detection and characterization of positive selection in human populations. Nature 2007;449:913-8.
  7. Weir BS, Cockerham CC. Estimating F-statistics for the analysis of population structure. Evolution 1984;38:1358-70.
  8. Jeong H, Song KD, Seo M, et al. Exploring evidence of positive selection reveals genetic basis of meat quality traits in Berkshire pigs through whole genome sequencing. BMC Genet 2015;16: 104.
  9. Taye M, Lee W, Caetano-Anolles K, et al. Whole genome detection of signature of positive selection in African cattle reveals selection for thermotolerance. Anim Sci J 2017;88: 1889-901.
  10. Yuan Z, Liu E, Liu Z, et al. Selection signature analysis reveals genes associated with tail type in Chinese indigenous sheep. Anim Genet 2017;48:55-66.
  11. Li Z, Chen J, Wang Z, et al. Detection of selection signatures of population-specific genomic regions selected during domestication process in Jinhua pigs. Anim Genet 2016;47:672-81.
  12. Wang Z, Chen Q, Yang Y, et al. Genetic diversity and population structure of six Chinese indigenous pig breeds in the Taihu Lake region revealed by sequencing data. Anim Genet 2015;46:697-701.
  13. Zhang Z, Wang Z, Yang Y, et al. Identification of pleiotropic genes and gene sets underlying growth and immunity traits: a case study on Meishan pigs. Animal 2016;10:550-7.
  14. Chen Q, Ma Y, Yang Y, et al. Genotyping by genome reducing and sequencing for outbred animals. PloS One 2013;8:e67500.
  15. Purcell S, Neale B, Todd-Brown K, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007;81:559-75. 10.1086/519795
  16. Li B, Du L, Xu X, et al. Transcription analysis on response of porcine alveolar macrophages to co-infection of the highly pathogenic porcine reproductive and respiratory syndrome virus and Mycoplasma hyopneumoniae. Virus Res 2015;196:60-9.
  17. Tsui KH, Chung LC, Wang SW, Feng TH, Chang PL, Juang HH. Hypoxia upregulates the gene expression of mitochondrial aconitase in prostate carcinoma cells. J Mol Endocrinol 2013;51:131-41.
  18. Fang X, Liu X, Meng C, et al. Breed-linked polymorphisms of porcine toll-like receptor 2 (TLR2) and TLR4 and the primary investigation on their relationship with prevention against Mycoplasma pneumoniae and bacterial LPS challenge. Immunogenetics 2013;65:829-34.
  19. Fang X, Zhao W, Xu J, et al. CYP1A1 mediates the suppression of major inflammatory cytokines in pulmonary alveolar macrophage (PAM) cell lines caused by Mycoplasma hyponeumoniae. Dev Comp Immunol 2016;65:132-8.
  20. Gao L, Millstein J, Siegmund KD, et al. Epigenetic regulation of AXL and risk of childhood asthma symptoms. Clin Epigenetics 2017;9:121.
  21. Zhou T, Huang X, Zhou Y, et al. Associations between Th17-related inflammatory cytokines and asthma in adults: A Case-Control Study. Sci Rep 2017;7:15502. s41598-017-15570-8
  22. Kurz T, Hoffjan S, Hayes MG, et al. Fine mapping and positional candidate studies on chromosome 5p13 identify multiple asthma susceptibility loci. J Allergy Clin Immunol 2006;118: 396-402.
  23. Valenta T, Hausmann G, Basler K. The many faces and functions of beta-catenin. EMBO J 2012;31:2714-36.
  24. Li N, Li S, Wang Y, et al. Decreased expression of WNT2 in villi of unexplained recurrent spontaneous abortion patients may cause trophoblast cell dysfunction via downregulated Wnt/beta-catenin signaling pathway. Cell Biol Int 2017;41:898-907.
  25. Zhu Y, Wang W, Wang X. Roles of transcriptional factor 7 in production of inflammatory factors for lung diseases. J Transl Med 2015;13:273.
  26. Liu Z, Chen X, Wu Q, Song J, Wang L, Li G. miR-125b inhibits goblet cell differentiation in allergic airway inflammation by targeting SPDEF. Eur J Pharmacol 2016;782:14-20.
  27. Ingram JL, Slade D, Church TD, et al. Role of matrix metalloproteinases-1 and -2 in interleukin-13-suppressed elastin in airway fibroblasts in asthma. Am J Respir Cell Mol Biol 2016; 54:41-50.
  28. Al-Alwan LA, Chang Y, Mogas A, et al. Differential roles of CXCL2 and CXCL3 and their receptors in regulating normal and asthmatic airway smooth muscle cell migration. J Immunol 2013;191:2731-41.
  29. Intraraksa Y, Engen RL, Switzer WP. Pulmonary and hematologic changes in swine with Mycoplasma hyopneumoniae pneumonia. Am J Vet Res 1984;45:474-7.
  30. Yoo S, Takikawa S, Geraghty P, et al. Integrative analysis of DNA methylation and gene expression data identifies EPAS1 as a key regulator of COPD. PLoS Genet 2015;11:e1004898.
  31. Wang L, Lingappan K, Jiang W, et al. Disruption of cytochrome P4501A2 in mice leads to increased susceptibility to hyperoxic lung injury. Free Radic Biol Med 2015;82:147-59.
  32. Ptak A, Ludewig G, Gregoraszczuk EL. A low halogenated biphenyl (PCB3) increases CYP1A1 expression and activity via the estrogen receptor beta in the porcine ovary. J Physiol Pharmacol 2008;59:577-88.
  33. Kiewisz J, Kaczmarek MM, Andronowska A, Blitek A, Ziecik AJ. Gene expression of WNTs, beta-catenin and E-cadherin during the periimplantation period of pregnancy in pigs--involvement of steroid hormones. Theriogenology 2011;76:687-99.
  34. Grzesiak M, Knapczyk-Stwora K, Duda M, Slomczynska M. Elevated level of 17beta-estradiol is associated with overexpression of FSHR, CYP19A1, and CTNNB1 genes in porcine ovarian follicles after prenatal and neonatal flutamide exposure. Theriogenology 2012;78:2050-60.
  35. Diaz J, Warren L, Helfner L, et al. Obesity shifts house dust mite-induced airway cellular infiltration from eosinophils to macrophages: effects of glucocorticoid treatment. Immunol Res 2015;63:197-208.
  36. Blaha M, Nemcova L, Kepkova KV, Vodicka P, Prochazka R. Gene expression analysis of pig cumulus-oocyte complexes stimulated in vitro with follicle stimulating hormone or epidermal growth factor-like peptides. Reprod Biol Endocrinol 2015; 13:113.
  37. Lu X, Ding F, Lian Z, et al. An epididymis-specific secretory protein Clpsl2 critically regulates sperm motility, acrosomal integrity, and male fertility. J Cell Biochem 2018;119:4760-74.