Evolution of HLA-F and its orthologues in primate species: a complex tale of conservation, diversification and inactivation

N Otting,N G De Groot,R E Bontrop

doi:10.1007/s00251-020-01187-1

Abstract

HLA-F represents one of the nonclassical MHC class I molecules in humans. Its main characteristics involve low levels of polymorphism in combination with a restricted tissue distribution. This signals that the gene product executes a specialised function, which, however, is still poorly understood. Relatively little is known about the evolutionary equivalents of this gene in nonhuman primates, especially with regard to population data. Here we report a comparative genetic analysis of the orthologous genes of HLA-F in various great ape, Old World monkey (OWM), and New World monkey (NWM) species. HLA-F-related transcripts were found in all subjects studied. Low levels of polymorphism were encountered, although the length of the predicted gene products may vary. In most species, one or two transcripts were discovered, indicating the presence of only one active F-like gene per chromosome. An exception was provided by a New World monkey species, namely, the common marmoset. In this species, the gene has been subject to duplication, giving rise to up to six F-like transcripts per animal. In humans, great apes, and OWM, and probably the majority of the NWM species, the evolutionary equivalents of the HLA-F gene experienced purifying selection. In the marmoset, however, the gene was initially duplicated, but the expansion was subjected afterwards to various mechanisms of genetic inactivation, as evidenced by the presence of pseudogenes and an array of genetic artefacts in a section of the transcripts.

Highlights

The classical HLA-A, -B, and -C molecules are highly polymorphic and are usually expressed on the cell surface of nucleated cells
Orthologues of the HLA-F gene are present in the great apes, Old World monkey (OWM), and New World monkey (NWM)
This illustrates that the F gene, which lacks exon 7, is old, and that a primordial structure was already present in a common ancestor that lived approximately 30 million years ago

Summary

Introduction

The classical HLA-A, -B, and -C molecules are highly polymorphic and are usually expressed on the cell surface of nucleated cells. The non-classical MHC class I molecules in humans are designated HLA-E, -F, and -G and are characterised by low levels of polymorphism These gene products display a restricted tissue distribution, and generally, but not exclusively, interact with receptors of the innate immune system; for example, HLA-E is a monitor for the manipulation of MHC class I expression by pathogens. In this particular example, the ligands are the CD94/NKG2 receptors, and interaction may augment or inhibit NK cell-mediated cytotoxicity and cytokine production (Lee et al 1998). HLA-G is expressed on trophoblast cells of the placenta and is considered to function as a tolerogenic immunoregulator during pregnancy (Shiroishi et al 2006; Persson et al 2017)

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