Skip to main content
SpringerLink
Log in

Positive selection in the SLC11A1 gene in the family Equidae

  • Original Article
  • Published:
Immunogenetics Aims and scope Submit manuscript

Abstract

Immunity-related genes are a suitable model for studying effects of selection at the genomic level. Some of them are highly conserved due to functional constraints and purifying selection, while others are variable and change quickly to cope with the variation of pathogens. The SLC11A1 gene encodes a transporter protein mediating antimicrobial activity of macrophages. Little is known about the patterns of selection shaping this gene during evolution. Although it is a typical evolutionarily conserved gene, functionally important polymorphisms associated with various diseases were identified in humans and other species. We analyzed the genomic organization, genetic variation, and evolution of the SLC11A1 gene in the family Equidae to identify patterns of selection within this important gene. Nucleotide SLC11A1 sequences were shown to be highly conserved in ten equid species, with more than 97 % sequence identity across the family. Single nucleotide polymorphisms (SNPs) were found in the coding and noncoding regions of the gene. Seven codon sites were identified to be under strong purifying selection. Codons located in three regions, including the glycosylated extracellular loop, were shown to be under diversifying selection. A 3-bp indel resulting in a deletion of the amino acid 321 in the predicted protein was observed in all horses, while it has been maintained in all other equid species. This codon comprised in an N-glycosylation site was found to be under positive selection. Interspecific variation in the presence of predicted N-glycosylation sites was observed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4):248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ates O, Kurt S, Bozkurt N, Karaer H (2010) NRAMP1 (SLC11A1) variants: genetic susceptibility to multiple sclerosis. J Clin Immunol 30:583

    Article  CAS  PubMed  Google Scholar 

  • Barnes I, Duda A, Pybus OG, Thomas MG (2010) Ancient urbanization predicts genetic resistance to tuberculosis. Evolution 65(3):842

    Article  PubMed  Google Scholar 

  • Barton CH, Biggs TE, Baker ST, Bowen H, Atkinson PGP (1999) Nramp1: a link between intracellular iron transport and innate resistance to intracellular pathogens. J Leukoc Biol 66:757

    CAS  PubMed  Google Scholar 

  • Bayele HK, Peyssonnaux C, Giatromanolaki A, Arrals-Silva WW, Mohamed HS, Collins H et al (2007) HIF-1 regulates heritable variation and allele expression phenotypes of the macrophage immune response gene SLC11A1 from a Z-DNA-forming microsatellite. Blood 110(8):3039

    Article  CAS  PubMed  Google Scholar 

  • Blackwell, J.M. (1989) The macrophage resistance gene Lsh/Ity/Bcg. Research in Immunology, 140, 767. (Convenor, 27th Forum in Immunology).

  • Blackwell JM, Roberts CW, Roach TIA, Alexander J (1994) Influence of macrophage resistance gene Lsh/Ity/Bcg (candidate Nramp) on Toxoplasma gondii infection in mice. Clin Exp Immunol 97:107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blackwell JM, Searle S, Goswami T, Miller EN (2000) Understanding the multiple functions of Nramp1. Microbes Infect 2:317

    Article  CAS  PubMed  Google Scholar 

  • Blackwell JM, Goswami T, Evans CAW, Sibthorpe D, Papo N, White JK et al (2001) SLC11A1 (formerly NRAMP1) and disease resistance. Cell Microbiol 3(12):773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bradley DJ (1977) Gentic control of Leishmania populations within the host II Genetic control of acute susceptibility of mice to L donovani infections. Clin Exp Immunol 30:130

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cellier MF (2013) Cell-Type Specific Determinants of NRAMP1 Expression in Professional Phagocytes. Biology 2:233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chapman SJ, Hill A (2012) Human genetic susceptibility to infectious disease. Nat Rev Genet 13(3):175

    CAS  PubMed  Google Scholar 

  • Dinkel H, Van Roey K, Michael S, Davey NE, Weatheritt RJ, Born D et al (2014) The eukaryotic linear motif resourse ELM: 10 years and counting. Nucleic Acids Res 42(Database issue):D259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feng DF, Johnson MS, Doolittle RF (1985) Aligning amino acid sequences: comparison of commonly used method. J Mol Evol 21:112

    Article  CAS  Google Scholar 

  • Forbes JR, Gros P (2001) Divalent-metal transport by NRAMP proteins at the interface of host-pathogen interactions. Trends Microbiol 9(8):397

    Article  CAS  PubMed  Google Scholar 

  • Forbes JR, Gros P (2003) Iron, manganese, and cobalt transport by Nramp1 (SLC11A1) and Nramp2 (Slc11a2) expressed at the plasma membrane. Blood 102(5):1884

    Article  CAS  PubMed  Google Scholar 

  • Goswami T, Bhattacharjee A, Babal P, Searle S, Moore E, Li M, Blackwell JM (2001) Natural-resistance-associated macrophage protein 1 is an H+ / bivalent cation antiporter. Biochem J 354(Pt 3):511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gruenheid S, Gros P (2000) Genetic susceptibility to intracellular infections: Nramp1, macrophage function and divalent cations transport. Curr Opin Microbiol 3(1):43

    Article  CAS  PubMed  Google Scholar 

  • Gupta, R., Jung, E. & Brunak, S. (2004) Prediction of N-glycosytarion sites in human proteins. In preparation. Server available at http://www.cbs.dtu.dk/services/NetNGlyc/ .

  • Hall TA (1999) BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucleic Acids Symp Ser 41:95

    CAS  Google Scholar 

  • Horin P, Matiasovic J (1999) Evidence for the existence of an NRAMP1 gene in the horse. Archiv für Tierzucht (Dummersdorf) 42:130

    CAS  Google Scholar 

  • Huang J, Zhao Y, Shiraigol W, Li B, Bai D, Ye W et al (2014) Analysis of horse genomes provides insight into the diversification and adaptive evolution of karyotype. Sci Rep 4:4958

    CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson EE, Wessling-Resnick M (2012) Iron metabolism and the innate immune response to infection. Microbes Infect 14:207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jónsson H, Schubert M, Sequin-Orlando A, Ginolhac A, Petersen L, Fumagalli M et al (2014) Speciation with gene flow in equids despite extensive chromosomal plasticity. Proc Natl Acad Sci U S A 111(52):18655

    Article  PubMed  PubMed Central  Google Scholar 

  • Karlsson EK, Kwiatkowski DP, Sabeti PC (2014) Natural selection and infectious disease in human populations. Nat Rev Genet 15(6):379

    Article  CAS  PubMed  Google Scholar 

  • Kim DS, Hahn Y (2015) The acquisition of novel N-glycosylation sites in conserved proteins during human evolution. BMC Bioinf 16:29

    Article  CAS  Google Scholar 

  • Kosakovsky Pond SL, Frost SDW (2005a) A Genetic Algorithm Approach to Detecting Lineage-Specific Variation in Selection Pressure. Mol Biol Evol 22(3):478

    Article  Google Scholar 

  • Kosakovsky Pond, S.L. & Frost, S.D.W. (2005) Datamonkey: rapid detection of selective pressure on individual sites of codon alignments. Bioinformatics, doi: 10.1093/bioinformatics/bti320

  • Kosakovsky Pond SL, Posada D, Gravenor MB, Woelk CH, Frost SD (2006) GARD: a genetic algorithm for recombination detection. Bioinformatics 22(24):3096

    Article  PubMed  Google Scholar 

  • Kosakovsky Pond SL, Murrell B, Fourment M, Frost SDW, Delport W, Scheffler K (2008) A random effects branch-site model for detecting episodic diversifying selection. Mol Biol Evol 24(1):1

    Google Scholar 

  • Lemos de Matos A, McFadden G, Esteves PD (2013) Evolution of viral sensing RIG-I-like receptor genes in Leporidae genera Orytolagus, Sylvilagus, and Lepus. Immunogenetics 66:43

    Article  PubMed  Google Scholar 

  • Li X, Yang Y, Zhou F, Zhang Y, Lu H, Jin Q, Gao L (2011) SLC11A1 (NRAMP1) polymorphisms and tuberculosis susceptibility: updated systematic review and metaanalysis. PLoS One 6(1):e15831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matiašovic J, Kubíčková S, Musilová P, Rubeš J, Hořín P (2002) Characterization of the NRAMP1 (SLC11A1) gene in the horse (Equus caballus L.). Eur J Immunogenet 29:423

    Article  PubMed  Google Scholar 

  • McLaren W, Pritchard B, Rios D, Chen Y, Flicek P, Cunningham F (2010) Deriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor. Bioinformatics 26(16):2069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Montalbetti N, Simonin A, Kovacs G, Hediger MA (2013) Mammalian iron transporters: families SLC11 and SLC40. Mol Asp Med 34:270–287

    Article  CAS  Google Scholar 

  • Nergadze SG, Lupotto M, Pellanda P, Santagostino M, Vitelli V, Giulotto E (2010) Mitochondrial DNA insertion in the nuclear horse genome. Anim Genet 41(2):176

    Article  CAS  PubMed  Google Scholar 

  • Neves JV, Wilson JM, Kuhl H, Reinhardt R, Castro LF, Rodrigues PN (2011) Natural history of SLC11 genes in vertebrates: tales from the fish world. BMC Evol Biol 11:106

    CAS  PubMed  PubMed Central  Google Scholar 

  • Orlando L, Ginolhac A, Zhang G, Froese D, Albrechtsen A, Stiller M et al (2013) Rechalibrating Equus evolution using the genome sequence of an early Middle Pleistocene horse. Nature 499(7456):74

    Article  CAS  PubMed  Google Scholar 

  • Ortutay C, Vihinen M (2012) Conserved and quickly evolving immunogenome genes have different evolutionary paths. Hum Mutat 33(10):1456

    Article  CAS  PubMed  Google Scholar 

  • Pinheiro A, Woof JM, Almeida T, Abrantes J, Alves PC, Gortázar C, Esteves PJ (2014) Leporid immunoglobulin G shows evidence of strong selective pressure on the hinge and CH3 domains. Open Biol 4:140088

    Article  PubMed  PubMed Central  Google Scholar 

  • Plant JE, Glynn A (1976) Genetics of resistance to infection with Salmonella typhimurium in mice. J Infect Dis 133:72

    Article  CAS  PubMed  Google Scholar 

  • Price SA, Bininda-Emonds ORP (2009) A comprehensive phylogeny of extant horses, rhinos and tapirs (Perissodactyla) through data combination. Zoosystematics Evolution 85:277

    Article  Google Scholar 

  • Purdie AC, Plain KM, Begg DJ, de Silva K, Whittington RJ (2011) Candidate gene and genome-wide association studies of Mycobacterium avium subsp. paratuberculosis infection in cattle and sheep: a review. Comp Immunol Microbiol Infect Dis 34:197

    Article  PubMed  Google Scholar 

  • Qanbari S, Strom TM, Haberer G, Weigend S, Gheyas AA, Turner F, Burt DW, Preisinger R, Gianola D, Simianer H (2012) A high resolution genome-wide scan for significant selective sweeps: an application to pooled sequence data in laying chickens. PLoS One 7(11):e49525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Risler JL, Delorme MO, Delacroix H, Henaut A (1988) Amino acid substitutions in structurally related proteins. A pattern recognition approach. Determination of a new and efficient scoring matrix. J Mol Biol 204:1019

    Article  CAS  PubMed  Google Scholar 

  • Rozen, S. & Skaletsky, H.J. (1998) Primer3. Code available at http://www-genome.wi.mit.edu/genome_software/other/primer3.html

  • Salinas-Delgado Y, Galaviz-Hernández C, Toral RG, Ávila Rejón CA, Reyes-Lopez MA, Martínez AR, Martínez-Aguilar G, Sosa-Macías M (2015) The D543N polymorphism of the SLC11A1/NRAMP1 gene is associated with treatment failure in male patients with pulmonary tuberculosis. Drug Metabol Personal Ther 30(3):211

    Article  CAS  PubMed  Google Scholar 

  • Schubert M, Jónsson H, Chang D, Der Sarkissian C, Ermini L, Ginolhac A et al (2014) Prehistoric genomes reveal the genetic foundation and cost of horse domestication. PNAS 111:E5661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Searle S, Blackwell JM (1999) Evidence for a functional repeat polymorphism in the promoter of the human NRAMP1 gene that correlates with autoimmune versus infectious disease susceptibility. J Med Genet 36:295

    CAS  PubMed  PubMed Central  Google Scholar 

  • Segond D, Dellagi A, Lanquar V, Rigault M, Patrit O, Thomine S, Expert D (2009) NRAMP genes function in Arabidopsis thaliana resistance to Erwinia chrysanthemi infection. Plant J 58:195

    Article  CAS  PubMed  Google Scholar 

  • Skamene E, Gros P, Forget A, Kongshaven PAL, StCharles C, Taylor BA (1982) Genetic regulation of resistance to intracellular pathogens. Nature 297:506

    Article  CAS  PubMed  Google Scholar 

  • Steiner CC, Ryder OA (2011) Molecular phylogeny and evolution of the Perissodactyla. Zool J Linnean Soc 163:1289

    Article  Google Scholar 

  • Stienstra Y, van der Werf TS, Oosterom E, Nolte IM, van der Graaf WT, Etuaful S et al (2006) Susceptibility to Buruli ulcer is associated with the SLC11A1 (NRAMP1) D543N polymorhism. Genes Immun 7(3):185

    Article  CAS  PubMed  Google Scholar 

  • Takahashi K, Hasegawa Y, Abe T, Yamamoto T, Nakshima K, Imaizumi K, Shimokata K (2008) SLC11A1 (formerly NRAMP1) polymorphisms associated with multidrug-resistant tuberculosis. Tuberculosis 88:52

    Article  CAS  PubMed  Google Scholar 

  • Tamura K, Stecher G, Peterson D, Filipski A, Kumar S (2013) MEGA6: molecular evolutionary genetics analysis version 6.0. Mol Biol Evol 30:2725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taype CA, Castro JC, Accinelli RA, Herrera-Velit P, Shaw MA, Espinoza JR (2006) Association between SLC11A1 polymorphisms and susceptibility to different clinical forms of tuberculosis in the Peruvian population. Infect Genet Evol 6:361

    Article  CAS  PubMed  Google Scholar 

  • Techau ME, Valdez-Taubas J, Popoff JF, Francis R, Seaman M, Blackwell JM (2007) Evolution of differences in transport function in Slc11a family members. J Biol Chem 282(49):35646

    Article  CAS  PubMed  Google Scholar 

  • Trifonov VA, Musilova P, Kulemsina AI (2012) Chromosome evolution in Perissodactyla. Cytogenet Genome Res 137:208

    Article  CAS  PubMed  Google Scholar 

  • Vidal S, Tremblay ML, Govoni G, Gauthier S, Sebastiani G, Malo D, Skamene E, Olivier M, Jothy S, Gros P (1995) The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene. J Exp Med 182:655

    Article  CAS  PubMed  Google Scholar 

  • Vilstrup JT, Seguin-Orlando A, Stiller M, Ginolhac A, Raghavan M, Nielsen SC et al (2013) Mitochondrial phylogenomics of modern and ancient equids. PLoS One 8(2):e55950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Williams R, Ma X, Schott RK, Mohammad N, Ho CY, Li CF, Chang BSW, Demetriou M, Dennis JW (2014) Encoding asymmetry of the N-glycosylation motif facilitates glycoprotein evolution. PLoS ONE 9(1):e86088

    Article  PubMed  PubMed Central  Google Scholar 

  • Wlasiuk G, Nachman MW (2010) Adaptation and constraint at toll-like receptors in primates. Mol Biol Evol 27(9):2172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This study was supported by the Czech National Science Foundation project GACR 523/09/1972 and by the project “CEITEC – Central European Institute of Technology” (CZ.1.05/1.100/02.0068) from European Regional Development Fund. The authors would like to thank Petra Videnska for her assistance with the next-generation sequence analyses.

Author information

Authors and Affiliations

  1. Department of Animal Genetics, Research Group Immunogenomics, Ceitec VFU, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic

    Zuzana Bayerova, Eva Janova & Petr Horin

  2. Department of Immunology, Veterinary Research Institute, Brno, Czech Republic

    Jan Matiasovic

  3. Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Copenhagen, Denmark

    Ludovic Orlando

Authors
  1. Zuzana Bayerova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eva Janova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jan Matiasovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ludovic Orlando
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Petr Horin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Petr Horin.

Electronic Supplementary Materials

Below is the link to the electronic supplementary material.

ESM 1

(DOC 28 kb)

ESM 2

(DOC 64 kb)

ESM 3

(PDF 1576 kb)

ESM 4

(PDF 302 kb)

ESM 5

(DOC 38 kb)

ESM 6

(XLSX 23 kb)

ESM 7

(PDF 89 kb)

ESM 8

(XLSX 38 kb)

ESM 9

(PDF 290 kb)

ESM 10

(DOC 49 kb)

ESM 11

(PDF 90 kb)

ESM 12

(DOC 28 kb)

ESM 13

(DOC 39 kb)

ESM 14

(DOC 33 kb)

ESM 15

(DOC 26 kb)

ESM 16

(DOC 144 kb)

ESM 17

(DOC 26 kb)

ESM 18

(DOC 83 kb)

ESM 19

(DOC 49 kb)

ESM 20

(DOC 32 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bayerova, Z., Janova, E., Matiasovic, J. et al. Positive selection in the SLC11A1 gene in the family Equidae . Immunogenetics 68, 353–364 (2016). https://doi.org/10.1007/s00251-016-0905-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00251-016-0905-2

Keywords

Search

Navigation