Insights on the HLA-G Evolutionary History Provided by a Nearby Alu Insertion

Abstract

The AluyHG element belongs to the AluYb8 subfamily. It is a polymorphic insertion, located approximately 20 kb from the HLA-G 3'-untranslated region (3'-UTR), which has been used for evolution studies because it exhibits identity for descendants and it is still polymorphic in the human genome. To understand the evolutionary mechanisms acting on HLA-G, we evaluated the presence or absence of the AluyHG element, associating this variable site with others observed at HLA-G coding, 3'-UTR, or both regions in four distinct populations (Brazilian, French, Congolese, and Senegalese). The results were compared with the 1000Genomes Consortium data. The worldwide AluyHG frequencies showed an increment, starting lower in Africa and increasing following distance and time of human dispersion out of Africa. The same haplotype pattern was observed in all populations, indicating that most of the HLA-G haplotypes already detected were originated earlier in Africa, before Homo sapiens dispersion. The AluyHG insertion was associated with the G*01:01:01:01/UTR-1 haplotype, with rare recombinants. Despite its high frequency in worldwide populations, the G*01:01:01:01/UTR-1 haplotype should be very recent. The low frequency of recombinants indicates that the rate of recombination at the HLA-G gene is very low.

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

“…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].…”

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

“…Moreover, the methodology used for ELISA should also be considered, since we used an in-house ELISA instead of a commercial one. It is noteworthy that two recently published median-joining networks of HLA-G 3’UTR haplotypes that consider both the frequency and the number of mutations separating each haplotypes [25, 47], have shown that UTR-1 (associated with higher luciferase activity herein), and UTR-5/-7 (associated with lower luciferase activity herein) are the most distant ones.…”

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

“…Limited protein diversity has indeed been described at the HLA-G coding region in human populations. 7,12,21,[62][63][64] Although the HLA-G region presents several variation sites, the majority of them are either intronic or synonymous substitutions, yielding only 16 different full-length proteins and two truncated molecules (null alleles), of which only five are frequently observed in worldwide populations. 7,21 One of them, the full-length molecule known as G*01:01, largely predominates over the others, representing about 60% of all HLA-G coding haplotypes.…”