Insights into HLA-G Genetics Provided by Worldwide Haplotype Diversity

Abstract

Human leukocyte antigen G (HLA-G) belongs to the family of non-classical HLA class I genes, located within the major histocompatibility complex (MHC). HLA-G has been the target of most recent research regarding the function of class I non-classical genes. The main features that distinguish HLA-G from classical class I genes are (a) limited protein variability, (b) alternative splicing generating several membrane bound and soluble isoforms, (c) short cytoplasmic tail, (d) modulation of immune response (immune tolerance), and (e) restricted expression to certain tissues. In the present work, we describe the HLA-G gene structure and address the HLA-G variability and haplotype diversity among several populations around the world, considering each of its major segments [promoter, coding, and 3′ untranslated region (UTR)]. For this purpose, we developed a pipeline to reevaluate the 1000Genomes data and recover miscalled or missing genotypes and haplotypes. It became clear that the overall structure of the HLA-G molecule has been maintained during the evolutionary process and that most of the variation sites found in the HLA-G coding region are either coding synonymous or intronic mutations. In addition, only a few frequent and divergent extended haplotypes are found when the promoter, coding, and 3′UTRs are evaluated together. The divergence is particularly evident for the regulatory regions. The population comparisons confirmed that most of the HLA-G variability has originated before human dispersion from Africa and that the allele and haplotype frequencies have probably been shaped by strong selective pressures.

HLA-E coding and 3′ untranslated region variability determined by next-generation sequencing in two West-African population samples

“…This close association between coding and regulatory region haplotypes was already observed for other non-classical HLA class I gene, such as HLA-G [51][52][53]. It should be noticed that even though a given HLA-E coding allele is associated with more stable mRNA or protein molecules, we should consider that the regulatory regions may influence expression levels by a myriad of mechanisms, including differential transcriptional factor binding [52] and differential microRNA binding [54]. The influence of the regulatory regions at the non classical HLA class I transcription levels has been explored and documented [reviewed at [52]].…”

“…For example, E ⁄ :01:01:01:01 and E ⁄ 01:03:05 were mainly associated with 3UTR-1 and E ⁄ 01:03:02:01 was mainly associated with 3UTR-2 considering both African populations pooled together. This close association between coding and regulatory region haplotypes was already observed for other non-classical HLA class I gene, such as HLA-G [51][52][53]. It should be noticed that even though a given HLA-E coding allele is associated with more stable mRNA or protein molecules, we should consider that the regulatory regions may influence expression levels by a myriad of mechanisms, including differential transcriptional factor binding [52] and differential microRNA binding [54].…”

“…It should be noticed that even though a given HLA-E coding allele is associated with more stable mRNA or protein molecules, we should consider that the regulatory regions may influence expression levels by a myriad of mechanisms, including differential transcriptional factor binding [52] and differential microRNA binding [54]. The influence of the regulatory regions at the non classical HLA class I transcription levels has been explored and documented [reviewed at [52]]. Despite the relationship between the coding and 3 0 UTR haplotypes, LD patterns depicted along the HLA-E gene indicate that the majority of SNP pairs are in complete LD (D 0 = 1) in both populations, and globally higher levels of LD were detected mostly between positions +424 and +756, and between these SNPs and other frequent variations.…”

14-bp Insertion/Deletion Polymorphism of the HLA-G gene in Breast Cancer among Women from North Western Iran

“…Compared with the classical HLA class-I molecules, limited HLA-G coding region polymorphisms have been reported in the human population, whereas a relatively higher degree of variation is known in its promoter and 3´untranslated region (3´-UTR) (Castelli et al, 2014;Kuroshli et al, 2014). The HLA-G 3´-UTR contains regulatory elements included polyadenylation signals and AU-rich sequences (Castelli et al, 2010), which play important role in the spatial and temporal expression of HLA-G (Gonzalez et al, 2012).…”

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

“…7,8 In contrast, the HLA-G 5′URR has been poorly studied. Only a few reports have surveyed sequence variation in this gene region in healthy individuals, 4,9,12,[18][19][20][21] providing limited knowledge of the worldwide genetic diversity at this regulatory gene segment. Similarly, there have been few attempts to associate HLA-G 5′URR variations with modulation of HLA-G expression and susceptibility to diseases.…”