Abstract
The existence of a tradeoff between the reproductive success and immunity was demonstrated in the works conducted on wild and laboratory animals. Therefore, individuals with an increased reproductive capacity but with decreased immunity could be selected in the process of domestication. A decreased reactivity of the immune system could subsequently become inheritable by fixation of the genes with unfavorable mutations in the population. The aim of the investigation was to study (1) the genotype and allele frequencies of the rs340283541 single nucleotide polymorphism (SNP) in the lymphotoxin beta (LTB) cytokine gene in domestic pigs and wild boars; (2) the mRNA expression for this gene in mini pigs with different genotypes; and (3) to perform the bioinformatic analysis of a potential functional role of this SNP. The GG genotype frequency in the boar sample was significantly lower than this genotype frequency in the combined sample from different domestic pig breeds and populations. The level of the LTB gene mRNA expression in a lymph node in mini pigs with GG genotype had a trend towards an increase (p < 0.06) as compared with the A allele carriers. The rs340283541 SNP is located within the conservative sequence motif revealed in 12 mammalian species (that indirectly indicates important functional role of SNP). By means of the context analysis, it was detected that the A allele contains potential binding sites for the BRN-2 and AP-1 transcription factors, while the G allele contains those for the RFX1, ISGF3 (ISRE site), and USF (that are expressed in the immune system cells). Thus, an increase in the frequency of the rs340283541 SNP (located in the LTB gene 3'-region) GG genotype occurred in the process of pig domestication. The GG genotype is probably associated with an increased level of the LTB gene mRNA expression in the lymph node tissue. An increase in the expression level in pigs with the GG genotype can be associated with generation of the RFX1, ISRE, and USF binding sites and/or damage of the BRN-2 and AP-1 binding sites. It is also possible that the rs340283541 polymorphism is in linkage disequilibrium with another functionally significant mutation.
Similar content being viewed by others
References
Aitnazarov, R.B., Yudin, N.S., Nikitin, S.V., Yermolaev, V.I., and Voevoda, M.I., Identification of whole genomes of endogenous retroviruses in Siberian miniature pigs, Russ. J. Genet., Appl. Res., 2014, vol. 4, no. 6, pp. 523–525.
Ananko, E.A., Kondrakhin, Y.V., Merkulova, T.I., and Kolchanov, N.A., Recognition of interferon-inducible sites, promoters, and enhancers, BMC Bioinf., 2007, vol. 8, p. 56.
Ardia, D.R., Parmentier, H.K., and Vogel, L.A., The role of constraints and limitation in driving individual variation in immune response, Functional Ecology, 2011, vol. 25, no. 1, pp. 61–73. doi 10.1111/j.1365-2435.2010.01759.x
Balenger, S.L. and Zuk, M., Testing the Hamilton-Zuk hypothesis: Past, present, and future, Integr. Comp. Biol., 2014, vol. 54, no. 4, pp. 601–613. doi 10.1093/icb/icu059
Belyaev, D.K., Destabilizing selection as a factor of variability in domestication, Priroda (Moscow, Russ. Fed.), 1979, vol. 2, pp. 36–45.
Belyaev, D.K., Destabiliziruyushchii otbor kak faktor domestikatsii. Genetika i blagosostoyanie chelovechestva (Destabilizing Selection as a Factor of Domestication. Genetics and Human Well-Being), Moscow, 1981.
Corre, S. and Galibert, M.D., USF as a key regulatory element of gene expression, Med. Sci. (Paris), 2006, vol. 22, no. 1, pp. 62–67.
Crooks, G.E., Hon, G., Chandonia, J.M., and Brenner, S.E., Weblogo: A sequence logo generator, Genome Res., 2004, vol. 14, no. 6, pp. 1188–1190.
Crowe, P.D., VanArsdale, T.L., Walter, B.N., Ware, C.F., Hession, C., Ehrenfels, B., Browning, J.L., Din, W.S., Goodwin, R.G., and Smith, C.A., A lymphotoxin-beta-specific receptor, Science, 1994, vol. 264, no. 5159, pp. 707–710.
Cui, C.Y., Hashimoto, T., Grivennikov, S.I., Piao, Y., Nedospasov, S.A., and Schlessinger, D., Ectodysplasin regulates the lymphotoxin-beta pathway for hair differentiation, Proc. Natl. Acad. Sci. U.S.A., 2006, vol. 103, no. 24, pp. 9142–9147.
Djebali, S., Davis, C.A., Merkel, A., Dobin, A., Lassmann, T., Mortazavi, A., Tanzer, A., Lagarde, J., Lin, W., Schlesinger, F., Xue, C., Marinov, G.K., Khatun, J., Williams, B.A., et al., Landscape of transcription in human cells, Nature, 2012, vol. 489, no. 7414, pp. 101–108. doi 10.1038/nature11233
Ellmann, L., Joshi, M.B., Resink, T.J., Bosserhoff, A.K., and Kuphal, S., BRN2 is a transcriptional repressor of CDH13 (T-cadherin) in melanoma cells, Lab Invest., 2012, vol. 92, no. 12, pp. 1788–1800. doi 10.1038/labinvest.2012.140
Fontes, J.D., Jabrane-Ferrat, N., and Peterlin, B.M., Assembly of functional regulatory complexes on MHC class II promoters in vivo, J. Mol. Biol., 1997, vol. 270, no. 3, pp. 336–345.
Goodall, J., Martinozzi, S., Dexter, T.J., Champeval, D., Carreira, S., Larue, L., and Goding, C.R., Brn-2 expression controls melanoma proliferation and is directly regulated by beta-catenin, Mol. Cell Biol., 2004, vol. 24, no. 7, pp. 2915–2922.
Heringstad, B., Chang, Y.M., Gianola, D., and Klemetsdal, G., Genetic association between susceptibility to clinical mastitis and protein yield in Norwegian dairy cattle, J. Dairy Sci., 2005, vol. 88, no. 4, pp. 1509–1514.
Heringstad, B., Klemetsdal, G., and Steine, T., Selection responses for disease resistance in two selection experiments with Norwegian red cows, J. Dairy Sci., 2007, vol. 90, no. 5, pp. 2419–2426.
Hess, J., Angel, P., and Schorpp-Kistner, M., AP-1 subunits: Quarrel and harmony among siblings, J. Cell Sci., 2004, vol. 117, no. 25, pp. 5965–5973.
Ignatieva, E.V., Podkolodnaya, O.A., Orlov, Yu.L., Vasiliev, G.V., and Kolchanov, N.A., Regulatory genomics: Combined experimental and computational approaches, Russ. J. Genet., 2015, vol. 51, no. 4, pp. 334–352.
Kel-Margoulis, O.V., Romashchenko, A.G., Kolchanov, N.A., Wingender, E., and Kel, A.E., COMPEL: A database on composite regulatory elements providing combinatorial transcriptional regulation, Nucleic Acids Res., 2000, vol. 28, no. 1, pp. 311–315.
Kessler, D.S., Veals, S.A., Fu, X.Y., and Levy, D.E., Interferon-alpha regulates nuclear translocation and DNAbinding affinity of ISGF3, a multimeric transcriptional activator, Genes Dev., 1990, vol. 4, no. 10, pp. 1753–1765.
Kim, J.Y., Moon, S.M., Ryu, H.J., Kim, J.J., Kim, H.T., Park, C., Kim, K., Oh, B., and Lee, J.K., Identification of regulatory polymorphisms in the TNF-TNF receptor superfamily, Immunogenetics, 2005, vol. 57, no. 5, pp. 297–303.
Kolchanov, N.A., Ignatieva, E.V., Ananko, E.A., Podkolodnaya, O.A., Stepanenko, I.L., Merkulova, T.I., Pozdnyakov, M.A., Podkolodny, N.L., Naumochkin, A.N., and Romashchenko, A.G., Transcription regulatory regions database (TRRD): Its status in 2002, Nucleic Acids Res., 2002, vol. 30, no. 1, pp. 312–317.
Levitsky, V.G., Ignatieva, E.V., Ananko, E.A., Turnaev, I.I., Merkulova, T.I., Kolchanov, N.A., and Hodgman, T.C., Effective transcription factor binding site prediction using a combination of optimization, a genetic algorithm and discriminant analysis to capture distant interactions, BMC Bioinf., 2007, vol. 8, p. 481.
Loos, R.J. and Yeo, G.S., The bigger picture of FTO: The first GWAS-identified obesity gene, Nat. Rev. Endocrinol., 2014, vol. 10, no. 1, pp. 51–61. doi 10.1038/nrendo.2013.227
Merkulova, T.I., Ananko, E.A., Ignatieva, E.V., and Kolchanov, N.A., Transcription regulatory codes of eukaryotic genomes, Russ. J. Genet., 2013, vol. 49, no. 1, pp. 29–45.
Mittelstadt, M.L. and Patel, R.C., AP-1 mediated transcriptional repreßsion of matrix metalloproteinase-9 by recruitment of histone deacetylase 1 in response to interferon ß, PLoS One, 2012, vol. 7, no. 8. doi 10.1371/journal. pone.0042152
van der Most, P.J., de Jong, B., Parmentier, H.K., and Verhulst, S., Trade-off between growth and immune function: A meta-analysis of selection experiments, Funct. Ecol., 2011, vol. 25, no. 1, pp. 74–80. doi 10.1111/j.1365-2435.2010.01800.x
Nakamura, T., Tashiro, K., Nazarea, M., Nakano, T., Sasayama, S., and Honjo, T., The murine lymphotoxin-beta receptor cDNA: Isolation by the signal sequence trap and chromosomal mapping, Genomics, 1995, vol. 30, no. 2, pp. 312–319.
Nedospasov, S.A. and Kuprash, D.V., Tumor necrosis factor and lymphotoxin: Physiological functions and importance for cytokine and anti-cytokine therapy, Russ. Mul’tidistsip. Zh., 2008, vol. 12, no. 1, pp. 69–76.
Onder, L., Danuser, R., Scandella, E., Firner, S., Chai, Q., Hehlgans, T., Stein, J.V., and Ludewig, B., Endothelial cell-specific lymphotoxin-ß receptor signaling is critical for lymph node and high endothelial venule formation, J. Exp. Med., 2013, vol. 210, no. 3, pp. 465–473. doi 10.1084/jem.20121462
Seddon, J.M., Berggren, K.T., and Fleeman, L.M., Evolutionary history of DLA class II haplotypes in canine diabetes mellitus through single nucleotide polymorphism genotyping, Tissue Antigens, 2010, vol. 75, no. 3, pp. 218–226. doi 10.1111/j.1399-0039.2009.01426.x
Sheldon, B.C. and Verhulst, S., Ecological immunology: Costly parasite defences and trade-offs in evolutionary ecology, Trends Ecol. Evol., 1996, vol. 11, no. 8, pp. 317–321.
Tierney, R., Kirby, H., Nagra, J., Rickinson, A., and Bell, A., The Epstein-Barr virus promoter initiating B-cell transformation is activated by RFX proteins and the B-cell-specific activator protein BSAP/Pax5, J. Virol., 2000, vol. 74, no. 22, pp. 10458–10467.
Trapezov, O.V., Darwinism and the lessons of practical breeding in Russia, Vavilovskii Zh. Genet. Sel., 2009, vol. 13, no. 2, pp. 249–297.
Zhang, G., Li, C., Li, Q., Li, B., Larkin, D.M., Lee, C., Storz, J.F., Antunes, A., Greenwold, M.J., Meredith, R.W., Odeen, A., Cui, J., Zhou, Q., Xu, L., Pan, et al., Comparative genomics reveals insights into avian genome evolution and adaptation, Science, 2014, vol. 346, no. 6215, pp. 1311–1320. doi 10.1126/science.1251385
Zhao, F.Q., Octamer-binding transcription factors: Genomics and functions, Front Biosci., 2013, vol. 18, pp. 1051–1071.
Author information
Authors and Affiliations
Corresponding author
Additional information
Original Russian Text © R.B. Aitnazarov, E.V. Ignatieva, N.E. Bazarova, V.G. Levitsky, S.P. Knyazev, Y. Gon, N.S. Yudin, 2015, published in Vavilovskii Zhurnal Genetiki i Selektsii, 2015, Vol. 19, No. 6, pp. 699–706.
Electronic supplementary material
13328_2016_204_MOESM1_ESM.pdf
The allele and genotype frequencies for SNP rs340283541 located in the 3’-flanking region of the LTB gene in pigs of domestic breeds and wild boars
Rights and permissions
About this article
Cite this article
Aitnazarov, R.B., Ignatieva, E.V., Bazarova, N.E. et al. Estimation of the role of single nucleotide polymorphism in lymphotoxin beta gene during pig domestication based on the bioinformatic and experimental approaches. Russ J Genet Appl Res 6, 816–824 (2016). https://doi.org/10.1134/S2079059716070017
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S2079059716070017