Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Genetic diversity of the HLA-G coding region in Amerindian populations from the Brazilian Amazon: a possible role of natural selection

Genes & Immunity volume 14, pages 518–526 (2013)Cite this article

Subjects

Abstract

HLA-G has an important role in the modulation of the maternal immune system during pregnancy, and evidence that balancing selection acts in the promoter and 3′UTR regions has been previously reported. To determine whether selection acts on the HLA-G coding region in the Amazon Rainforest, exons 2, 3 and 4 were analyzed in a sample of 142 Amerindians from nine villages of five isolated tribes that inhabit the Central Amazon. Six previously described single-nucleotide polymorphisms (SNPs) were identified and the Expectation-Maximization (EM) and PHASE algorithms were used to computationally reconstruct SNP haplotypes (HLA-G alleles). A new HLA-G allele, which originated in Amerindian populations by a crossing-over event between two widespread HLA-G alleles, was identified in 18 individuals. Neutrality tests evidenced that natural selection has a complex part in the HLA-G coding region. Although balancing selection is the type of selection that shapes variability at a local level (Native American populations), we have also shown that purifying selection may occur on a worldwide scale. Moreover, the balancing selection does not seem to act on the coding region as strongly as it acts on the flanking regulatory regions, and such coding signature may actually reflect a hitchhiking effect.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

References

  1. Pyo CW, Williams LM, Moore Y, Hyodo H, Li SS, Zhao LP et al. HLA-E, HLA-F, and HLA-G polymorphism: genomic sequence defines haplotype structure and variation spanning the nonclassical class I genes. Immunogenetics 2006; 58: 241–251.

    Article  CAS  PubMed  Google Scholar 

  2. Hviid TV . HLA-G in human reproduction: aspects of genetics, function and pregnancy complications. Hum Reprod Update 2006; 12: 209–232.

    Article  CAS  PubMed  Google Scholar 

  3. Rizzo R, Vercammen M, van de Velde H, Horn PA, Rebmann V . The importance of HLA-G expression in embryos, trophoblast cells, and embryonic stem cells. Cell Mol Life Sci 2011; 68: 341–352.

    Article  CAS  PubMed  Google Scholar 

  4. Deschaseaux F, Delgado D, Pistoia V, Giuliani M, Morandi F, Durrbach A . HLA-G in organ transplantation: towards clinical applications. Cell Mol Life Sci 2011; 68: 397–404.

    Article  CAS  PubMed  Google Scholar 

  5. Carosella ED, Gregori S, Rouas-Freiss N, LeMaoult J, Menier C, Favier B . The role of HLA-G in immunity and hematopoiesis. Cell Mol Life Sci 2011; 68: 353–368.

    Article  CAS  PubMed  Google Scholar 

  6. Amiot L, Ferrone S, Grosse-Wilde H, Seliger B . Biology of HLA-G in cancer: a candidate molecule for therapeutic intervention? Cell Mol Life Sci 2011; 68: 417–431.

    Article  CAS  PubMed  Google Scholar 

  7. Fujii T, Ishitani A, Geraghty DE . A soluble form of the HLA-G antigen is encoded by a messenger ribonucleic acid containing intron 4. J Immunol 1994; 153: 5516–5524.

    CAS  PubMed  Google Scholar 

  8. LeMaoult J, Krawice-Radanne I, Dausset J, Carosella ED . HLA-G1-expressing antigen-presenting cells induce immunosuppressive CD4+ T cells. Proc Natl Acad Sci USA 2004; 101: 7064–7069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Rouas-Freiss N, Goncalves RM, Menier C, Dausset J, Carosella ED . Direct evidence to support the role of HLA-G in protecting the fetus from maternal uterine natural killer cytolysis. Proc Natl Acad Sci USA 1997; 94: 11520–11525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ristich V, Liang S, Zhang W, Wu J, Horuzsko A . Tolerization of dendritic cells by HLA-G. Eur J Immunol 2005; 35: 1133–1142.

    Article  CAS  PubMed  Google Scholar 

  11. Hviid TV, Hylenius S, Rorbye C, Nielsen LG . HLA-G allelic variants are associated with differences in the HLA-G mRNA isoform profile and HLA-G mRNA levels. Immunogenetics 2003; 55: 63–79.

    CAS  PubMed  Google Scholar 

  12. Ober C, Aldrich CL, Chervoneva I, Billstrand C, Rahimov F, Gray HL et al. Variation in the HLA-G promoter region influences miscarriage rates. Am J Hum Genet 2003; 72: 1425–1435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Donadi EA, Castelli EC, Arnaiz-Villena A, Roger M, Rey D, Moreau P . Implications of the polymorphism of HLA-G on its function, regulation, evolution and disease association. Cell Mol Life Sci 2011; 68: 369–395.

    Article  CAS  PubMed  Google Scholar 

  14. Solier C, Mallet V, Lenfant F, Bertrand A, Huchenq A, Le Bouteiller P . HLA-G unique promoter region: functional implications. Immunogenetics 2001; 53: 617–625.

    Article  CAS  PubMed  Google Scholar 

  15. Castelli EC, Mendes-Junior CT, Deghaide NH, de Albuquerque RS, Muniz YC, Simoes RT et al. The genetic structure of 3′untranslated region of the HLA-G gene: polymorphisms and haplotypes. Genes Immun 2010; 11: 134–141.

    Article  CAS  PubMed  Google Scholar 

  16. Castelli EC, Moreau P, Oya e Chiromatzo A, Mendes-Junior CT, Veiga-Castelli LC, Yaghi L et al. In silico analysis of microRNAS targeting the HLA-G 3′ untranslated region alleles and haplotypes. Hum Immunol 2009; 70: 1020–1025.

    Article  CAS  PubMed  Google Scholar 

  17. Tan Z, Shon AM, Ober C . Evidence of balancing selection at the HLA-G promoter region. Hum Mol Genet 2005; 14: 3619–3628.

    Article  CAS  PubMed  Google Scholar 

  18. Castelli EC, Mendes-Junior CT, Veiga-Castelli LC, Roger M, Moreau P, Donadi EA . A comprehensive study of polymorphic sites along the HLA-G gene: implication for gene regulation and evolution. Mol Biol Evol 2011; 28: 3069–3086.

    Article  CAS  PubMed  Google Scholar 

  19. Meyer D, Thomson G . How selection shapes variation of the human major histocompatibility complex: a review. Ann Hum Genet 2001; 65 (Pt 1): 1–26.

    Article  CAS  PubMed  Google Scholar 

  20. Mendes-Junior CT, Castelli EC, Moreau P, Simoes AL, Donadi EA . Absence of the HLA-G*0113N allele in Amerindian populations from the Brazilian Amazon region. Hum Immunol 2010; 71: 428–431.

    Article  CAS  PubMed  Google Scholar 

  21. Mendes-Junior CT, Castelli EC, Simoes AL, Donadi EA . Absence of the HLA-G*0105N allele in Amerindian populations from the Brazilian Amazon Region: a possible role of natural selection. Tissue Antigens 2007; 70: 330–334.

    Article  CAS  PubMed  Google Scholar 

  22. Ober C, Aldrich CL . HLA-G polymorphisms: neutral evolution or novel function? J Reprod Immunol 1997; 36: 1–21.

    Article  CAS  PubMed  Google Scholar 

  23. Suarez MB, Morales P, Castro MJ, Fernandez V, Varela P, Alvarez M et al. A new HLA-G allele (HLA-G*0105N) and its distribution in the Spanish population. Immunogenetics 1997; 45: 464–465.

    Article  CAS  PubMed  Google Scholar 

  24. Lajoie J, Jeanneau A, Faucher MC, Moreau P, Roger M . Characterisation of five novel HLA-G alleles with coding DNA base changes. Tissue Antigens 2008; 72: 502–504.

    Article  CAS  PubMed  Google Scholar 

  25. Pfeiffer KA, Fimmers R, Engels G, van der Ven H, van der Ven K . The HLA-G genotype is potentially associated with idiopathic recurrent spontaneous abortion. Mol Hum Reprod 2001; 7: 373–378.

    Article  CAS  PubMed  Google Scholar 

  26. Aldrich CL, Stephenson MD, Karrison T, Odem RR, Branch DW, Scott JR et al. HLA-G genotypes and pregnancy outcome in couples with unexplained recurrent miscarriage. Mol Hum Reprod 2001; 7: 1167–1172.

    Article  CAS  PubMed  Google Scholar 

  27. Moreau P, Contu L, Alba F, Lai S, Simoes R, Orru S et al. HLA-G gene polymorphism in human placentas: possible association of G*0106 allele with preeclampsia and miscarriage. Biol Reprod 2008; 79: 459–467.

    Article  CAS  PubMed  Google Scholar 

  28. Berger DS, Hogge WA, Barmada MM, Ferrell RE . Comprehensive analysis of HLA-G: implications for recurrent spontaneous abortion. Reprod Sci 2010; 17: 331–338.

    Article  CAS  PubMed  Google Scholar 

  29. Aldrich C, Wambebe C, Odama L, Di Rienzo A, Ober C . Linkage disequilibrium and age estimates of a deletion polymorphism (1597DeltaC) in HLA-G suggest non-neutral evolution. Hum Immunol 2002; 63: 405–412.

    Article  CAS  PubMed  Google Scholar 

  30. Ober C, Aldrich C, Rosinsky B, Robertson A, Walker MA, Willadsen S et al. HLA-G1 protein expression is not essential for fetal survival. Placenta 1998; 19: 127–132.

    Article  CAS  PubMed  Google Scholar 

  31. Mendes-Junior CT, Castelli EC, Simoes RT, Simoes AL, Donadi EA . HLA-G 14-bp polymorphism at exon 8 in Amerindian populations from the Brazilian Amazon. Tissue Antigens 2007; 69: 255–260.

    Article  CAS  PubMed  Google Scholar 

  32. Veit TD, Cazarolli J, Salzano FM, Schiengold M, Chies JA . New evidence for balancing selection at the HLA-G locus in South Amerindians. Genet Mol Biol 2012; 35 (4 (suppl)): 919–923.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Salzano FM, Callegari-Jacques SM . South American Indians: a case study in evolution. Oxford University Press: New York, 1988.

    Google Scholar 

  34. Atay GA, Arsan S, Atasay B, Ensari A, Aysev D . The possible role of intrauterine infections in unexplained second trimester abortions and macerated stillbirths: a study from a single center. J Perinatol 2004; 24: 679–685.

    Article  PubMed  Google Scholar 

  35. Petersson K, Norbeck O, Westgren M, Broliden K . Detection of parvovirus B19, cytomegalovirus and enterovirus infections in cases of intrauterine fetal death. J Perinat Med 2004; 32: 516–521.

    Article  PubMed  Google Scholar 

  36. Harrison GA, Humphrey KE, Jakobsen IB, Cooper DW . A 14 bp deletion polymorphism in the HLA-G gene. Hum Mol Genet 1993; 2: 2200.

    Article  CAS  PubMed  Google Scholar 

  37. Rousseau P, Le Discorde M, Mouillot G, Marcou C, Carosella ED, Moreau P . The 14 bp deletion-insertion polymorphism in the 3′ UT region of the HLA-G gene influences HLA-G mRNA stability. Hum Immunol 2003; 64: 1005–1010.

    Article  CAS  PubMed  Google Scholar 

  38. Excoffier L, Slatkin M . Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 1995; 12: 921–927.

    CAS  PubMed  Google Scholar 

  39. Stephens M, Smith NJ, Donnelly P . A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978–989.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Castelli EC, Mendes-Junior CT, Donadi EA . HLA-G alleles and HLA-G 14 bp polymorphisms in a Brazilian population. Tissue Antigens 2007; 70: 62–68.

    Article  CAS  PubMed  Google Scholar 

  41. Neel JV, Gershowitz H, Mohrenweiser HW, Amos B, Kostyu DD, Salzano FM et al. Genetic studies on the Ticuna, an enigmatic tribe of Central Amazonas. Ann Hum Genet 1980; 44: 37–54.

    Article  CAS  PubMed  Google Scholar 

  42. Mendes-Junior CT, Simoes AL . Mitochondrial DNA variability among eight Tikuna villages: evidence for an intratribal genetic heterogeneity pattern. Am J Phys Anthropol 2009; 140: 526–531.

    Article  PubMed  Google Scholar 

  43. Salzano FM, Callegari-Jacques SM, Neel JV . Genetic demography of the Amazonian Ticuna Indians. J Hum Evol 1980; 9: 179–191.

    Article  Google Scholar 

  44. Mestriner MA, Simoes AL, Salzano FM . New studies on the esterase D polymorphism in South American Indians. Am J Phys Anthropol 1980; 52: 95–101.

    Article  CAS  PubMed  Google Scholar 

  45. Mohrenweiser H, Neel JV, Mestriner MA, Salzano FM, Migliazza E, Simoes AL et al. Electrophoretic variants in three Amerindian tribes: the Baniwa, Kanamari, and Central Pano of western Brazil. Am J Phys Anthropol 1979; 50: 237–246.

    Article  CAS  PubMed  Google Scholar 

  46. Salzano FM, Jacques SM . Genetic demography of the Central Pano and Kanamari Indians of Brazil. Hum Biol 1979; 51: 551–564.

    CAS  PubMed  Google Scholar 

  47. Salzano FM . Molecular variability in Amerindians: widespread but uneven information. An Acad Bras Cienc 2002; 74: 223–263.

    Article  CAS  PubMed  Google Scholar 

  48. Parham P, Arnett KL, Adams EJ, Little AM, Tees K, Barber LD et al. Episodic evolution and turnover of HLA-B in the indigenous human populations of the Americas. Tissue Antigens 1997; 50: 219–232.

    Article  CAS  PubMed  Google Scholar 

  49. Tsuneto LT, Probst CM, Hutz MH, Salzano FM, Rodriguez-Delfin LA, Zago MA et al. HLA class II diversity in seven Amerindian populations. Clues about the origins of the Ache. Tissue Antigens 2003; 62: 512–526.

    Article  CAS  PubMed  Google Scholar 

  50. Moreau P, Dausset J, Carosella ED, Rouas-Freiss N . Viewpoint on the functionality of the human leukocyte antigen-G null allele at the fetal-maternal interface. Biol Reprod 2002; 67: 1375–1378.

    Article  CAS  PubMed  Google Scholar 

  51. Bamshad MJ, Mummidi S, Gonzalez E, Ahuja SS, Dunn DM, Watkins WS et al. A strong signature of balancing selection in the 5′ cis-regulatory region of CCR5. Proc Natl Acad Sci USA 2002; 99: 10539–10544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Nei M, Kumar S . Molecular Evolution and Phylogenetics. Oxford University Press: New York, USA, 2000.

    Google Scholar 

  53. Harris EE, Meyer D . The molecular signature of selection underlying human adaptations. Am J Phys Anthropol 2006; Suppl 43: 89–130.

    Article  PubMed  Google Scholar 

  54. Stephens JC, Schneider JA, Tanguay DA, Choi J, Acharya T, Stanley SE et al. Haplotype variation and linkage disequilibrium in 313 human genes. Science 2001; 293: 489–493.

    Article  CAS  PubMed  Google Scholar 

  55. Simonsen KL, Churchill GA, Aquadro CF . Properties of statistical tests of neutrality for DNA polymorphism data. Genetics 1995; 141: 413–429.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhai W, Nielsen R, Slatkin M . An investigation of the statistical power of neutrality tests based on comparative and population genetic data. Mol Biol Evol 2009; 26: 273–283.

    Article  CAS  PubMed  Google Scholar 

  57. Ptak SE, Przeworski M . Evidence for population growth in humans is confounded by fine-scale population structure. Trends Genet 2002; 18: 559–563.

    Article  PubMed  Google Scholar 

  58. Fagundes NJ, Ray N, Beaumont M, Neuenschwander S, Salzano FM, Bonatto SL et al. Statistical evaluation of alternative models of human evolution. Proc Natl Acad Sci USA 2007; 104: 17614–17619.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Amos W, Hoffman JI . Evidence that two main bottleneck events shaped modern human genetic diversity. Proc Biol Sci 2010; 277: 131–137.

    Article  CAS  PubMed  Google Scholar 

  60. Flajollet S, Poras I, Carosella ED, Moreau P . RREB-1 is a transcriptional repressor of HLA-G. J Immunol 2009; 183: 6948–6959.

    Article  CAS  PubMed  Google Scholar 

  61. Moreau P, Flajollet S, Carosella ED . Non-classical transcriptional regulation of HLA-G: an update. J Cell Mol Med 2009; 13: 2973–2989.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Higuchi R . Simple and rapid preparation of samples for PCR. In: Erlich HA (ed) PCR Technology: Principles and Applications for DNA Amplification. Stockton Press: New York, NY, USA, 1989, pp 31–38.

    Chapter  Google Scholar 

  63. Hviid TV, Hylenius S, Hoegh AM, Kruse C, Christiansen OB . HLA-G polymorphisms in couples with recurrent spontaneous abortions. Tissue Antigens 2002; 60: 122–132.

    Article  CAS  PubMed  Google Scholar 

  64. Guo SW, Thompson EA . Performing the exact test of Hardy-Weinberg proportion for multiple alleles. Biometrics 1992; 48: 361–372.

    Article  CAS  PubMed  Google Scholar 

  65. Rousset F . genepop'007: a complete re-implementation of the genepop software for Windows and Linux. Mol Ecol Resour 2008; 8: 103–106.

    Article  PubMed  Google Scholar 

  66. Raymond M, Rousset F . An exact test for population differentiation. Evolution 1995; 49: 1280–1283.

    Article  PubMed  Google Scholar 

  67. Excoffier L, Lischer HE . Arlequin suite ver 3.5: a new series of programs to perform population genetics analyses under Linux and Windows. Mol Ecol Resour 2010; 10: 564–567.

    Article  PubMed  Google Scholar 

  68. Excoffier L, Slatkin M . Incorporating genotypes of relatives into a test of linkage disequilibrium. Am J Hum Genet 1998; 62: 171–180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Excoffier L, Smouse PE, Quattro JM . Analysis of molecular variance inferred from metric distances among DNA haplotypes: application to human mitochondrial DNA restriction data. Genetics 1992; 131: 479–491.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Ewens WJ . The sampling theory of selectively neutral alleles. Theor Popul Biol 1972; 3: 87–112.

    Article  CAS  PubMed  Google Scholar 

  71. Watterson GA . The homozygosity test of neutrality. Genetics 1978; 88: 405–417.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Slatkin M . An exact test for neutrality based on the Ewens sampling distribution. Genet Res 1994; 64: 71–74.

    Article  CAS  PubMed  Google Scholar 

  73. Lancaster A, Nelson MP, Meyer D, Thomson G, Single RM . PyPop: a software framework for population genomics: analyzing large-scale multi-locus genotype data. Pac Symp Biocomput 2003; 8: 514–525.

    Google Scholar 

  74. Tajima F . Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 1989; 123: 585–595.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Nei M, Gojobori T . Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol Biol Evol 1986; 3: 418–426.

    CAS  PubMed  Google Scholar 

  76. Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S . MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 2011; 28: 2731–2739.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. McDonald JH, Kreitman M . Adaptive protein evolution at the Adh locus in Drosophila. Nature 1991; 351: 652–654.

    Article  CAS  PubMed  Google Scholar 

  78. Librado P, Rozas J . DnaSP v5: a software for comprehensive analysis of DNA polymorphism data. Bioinformatics 2009; 25: 1451–1452.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Simone Kashima, Sandra Rodrigues, Rochele Azevedo, Evandra Strazza Rodrigues and Adriana Marques for technical assistance. We thank Cynthia Maria de Campos Prado Manso and Elettra Greene for assistance with the English language. This study was supported by CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico—Brazil) grant 475670/2007-8, CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo) grant 2013/19382-0 and FAEPA (Fundação de Apoio ao Ensino, Pesquisa e Assistência do HCFMRP-USP). CTM-J was supported by post-doctoral fellowships from CNPq/Brazil (150996/2005-5) and from FAPESP/Brazil (07/58391-4), and is currently supported by a Research fellowship from CNPq/Brazil (305493/2011-6). ECC was supported by a post-doctoral fellowship from FAPESP/Brazil (07/58420-4).

Author information

Authors and Affiliations

  1. Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil

    C T Mendes-Junior

  2. Departamento de Patologia, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista Júlio de Mesquita Filho, Botucatu, Brazil

    E C Castelli

  3. Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil

    D Meyer

  4. Departamento de Genética, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil

    A L Simões

  5. Divisão de Imunologia Clínica, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil

    E A Donadi

Authors
  1. C T Mendes-Junior
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E C Castelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Meyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A L Simões
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E A Donadi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C T Mendes-Junior.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Mendes-Junior, C., Castelli, E., Meyer, D. et al. Genetic diversity of the HLA-G coding region in Amerindian populations from the Brazilian Amazon: a possible role of natural selection. Genes Immun 14, 518–526 (2013). https://doi.org/10.1038/gene.2013.47

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2013.47

Keywords

This article is cited by

Search

Advanced search

Quick links