Balancing immunity and tolerance: genetic footprint of natural selection in the transcriptional regulatory region of HLA-G

Gineau, Laure; Luisi, Pierre; Castelli, Erick C.; Milet, Jacqueline; Courtin, David; Cagnin, N; Patillon, Blandine; Laayouni, Hafid; Moreau, Philippe; Donadi, Eduardo Antônio; Garcia, André; Sabbagh, Audrey

doi:10.1038/gene.2014.63

Cited by 27 publications

(50 citation statements)

References 87 publications

(108 reference statements)

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“…The DNA methylation status of the HLA-G locus is also important to control the HLA-G transcriptional activity [16]. To date at least 35 single nucleotide variations (SNV) have been listed in the worldwide population, which define a total of 68 haplotypes of the 1.4 kb regulatory region [17–21]. Variable sites might influence the expression of HLA-G by affecting the differential binding of some transcription factors and might influence the methylation of DNA [7].…”

Section: Introductionmentioning

confidence: 99%

Haplotypes of the HLA-G 3’ Untranslated Region Respond to Endogenous Factors of HLA-G+ and HLA-G- Cell Lines Differentially

et al. 2017

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The immune checkpoint HLA-G prevents maternal rejection of the fetus and contributes in cancer invasion and acceptance of allografts. The 5’ and 3’ regulatory regions of the HLA-G gene are polymorphic and balancing selection probably maintains this variability. It is proposed that nucleotide variations may affect the level of HLA-G expression. To investigate this issue we aimed to analyze how haplotypes of the 3’ untranslated region (3’UTR) with highest worldwide frequencies, namely UTR-1, UTR-2, UTR-3, UTR-4, UTR-5, UTR-18 and UTR-7, impact the expression of a luciferase reporter gene in vitro. Experiments performed with the HLA-G positive cell lines JEG-3 (choricarcinoma) and FON (melanoma), and with the HLA-G negative cell lines M8 (melanoma) and U251MG (glioblastoma) showed that the HLA-G 3’UTR polymorphism influences the response to endogenous cellular factors and may vary according to the cell type. UTR-5 and UTR-7 impact the activity of luciferase the most whereas UTR-2, UTR-3, UTR-4, and UTR-18 have intermediate impact, and UTR-1 has the lowest impact. These results corroborate the previous associations between amounts of plasma sHLA-G levels and 3’UTR haplotypes in healthy individuals and reinforce that 3’UTR typing may be a predictor of the genetic predisposition of an individual to express different levels of HLA-G.

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Section: Introductionmentioning

confidence: 99%

Haplotypes of the HLA-G 3’ Untranslated Region Respond to Endogenous Factors of HLA-G+ and HLA-G- Cell Lines Differentially

et al. 2017

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“…Signature of balancing selection has been disclosed at both flanking regulatory regions . Notwithstanding, due to the strong linkage disequilibrium across the entire HLA‐G gene, thus encompassing the 5′ URR, coding and 3′ UTR segments, it is not possible to unequivocally establish the actual targets of balancing selection and if any segment merely reflects a hitchhiking effect . Even so, balancing selection may result in the maintenance of different HLA‐G lineages, associated with different expression patterns over time .…”

Section: The Hla‐g Gene and Hla‐g Moleculementioning

confidence: 99%

The role of HLA‐G in parasitic diseases

Sabbagh

Sonon

Sadissou

et al. 2018

HLA

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Little attention has been devoted to the role of HLA-G gene and molecule on parasitic disorders, and the available studies have focused on malaria, African and American trypanosomiasis, leishmaniosis, toxoplasmosis and echinococcosis. After reporting a brief description regarding the role of the cells of innate and adaptive immune system against parasites, we reviewed the major features of the HLA-G gene and molecule and the role of HLA-G on the major cells of immune system. Increased levels of soluble HLA-G (sHLA-G) have been observed in patients presenting toxoplasmosis and in the active phase of echinococcosis. In addition, increased sHLA-G has also been associated with increased susceptibility to malaria and increased susceptibility to develop human African trypanosomiasis (HAT). In contrast, decreased membrane-bound HLA-G has been reported in placenta of patients infected with Plasmodium falciparum and in heart and colon of patients presenting Chagas disease. The 3' untranslated region of the HLA-G gene has been the main focus of studies on malaria, HAT and Chagas disease, exhibiting distinct patterns of associations. Considering that HLA-G is an immune checkpoint molecule, inhibiting the activity of several cells of the immune system, the excessive neoexpression and the increased sHLA-G levels together with the decreased constitutive tissue expression of membrane-bound HLA-G may be detrimental to the host infected with parasite agents.

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“…14,29-31 Balancing selection favors genetic diversity by retaining variation in the population as a result of heterozygote advantage and frequency-dependent advantage. Despite rarer, a pertinent example is the HLA (also known as major histocompatibility complex ( MHC )) region, 32,33 where highly polymorphic loci play a central role in the recognition and presentation of antigens to the immune system. The high levels of polymorphism are the results of pathogen-driven balancing selection.…”

Section: Population Genetics Natural Selection and Adaptationmentioning

confidence: 99%

Population Genetics and Natural Selection in Rheumatic Disease

Ramos

2017

Rheumatic Disease Clinics of North America

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Synopsis Human genetic diversity is the result of population genetic forces. This genetic variation influences disease risk and contributes to health disparities. Natural selection is an important influence on human genetic variation. Since immune and inflammatory function genes are enriched for signals of positive selection, the prevalence of rheumatic disease risk alleles seen in different populations is partially the result of differing selective pressures (e.g., due to pathogens). This review summarizes the genetic regions associated with susceptibility to different rheumatic diseases and concomitant evidence for natural selection, including known agents of selection exerting selective pressure in these regions. Integrating rheumatic disease susceptibility studies with population genetics to investigate how natural selection has contributed to genetic variation that influences disease risk will help identify functional variants and elucidate biological mechanisms.

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Balancing immunity and tolerance: genetic footprint of natural selection in the transcriptional regulatory region of HLA-G

Cited by 27 publications

References 87 publications

Haplotypes of the HLA-G 3’ Untranslated Region Respond to Endogenous Factors of HLA-G+ and HLA-G- Cell Lines Differentially

Haplotypes of the HLA-G 3’ Untranslated Region Respond to Endogenous Factors of HLA-G+ and HLA-G- Cell Lines Differentially

The role of HLA‐G in parasitic diseases

Population Genetics and Natural Selection in Rheumatic Disease

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