Advances in the Evolutionary Understanding of MHC Polymorphism

Abstract

Proteins encoded by the classical major histocompatibility complex (MHC) genes incite the vertebrate adaptive immune response by presenting peptide antigens on the cell surface. Here, we review mechanisms explaining landmark features of these genes: extreme polymorphism, excess of nonsynonymous changes in peptide-binding domains, and long gene genealogies. Recent studies provide evidence that these features may arise due to pathogens evolving ways to evade immune response guided by the locally common MHC alleles. However, complexities of selection on MHC genes are simultaneously being revealed that need to be incorporated into existing theory. These include pathogen-driven selection for antigen-binding breadth and expansion of the MHC gene family, associated autoimmunity trade-offs, hitchhiking of deleterious mutations linked to the MHC, geographic subdivision, and adaptive introgression. MHC: The Enigma ContinuesThe MHC is a gene-dense region in jawed vertebrate genomes enriched for immunity genes. The classical MHC genes, which will be the subject of this review, encode glycoproteins that bind peptides, both self and non-self, inside the cell and deliver them to the surface for inspection by T cells and natural killer (NK) cells [1,2] (Boxes 1 and 2). This antigen presentation is a crucial step in the adaptive immune response as it allows self/non-self discrimination by T cells, ultimately facilitating the recognition of infecting pathogens. The feature that distinguishes classical MHC genes (MHC genes hereafter) from other genes in the MHC region is their extreme polymorphism, with dozens to hundreds of allelic variants segregating in natural populations [3][4][5]. The polymorphism is most pronounced in the peptide-binding domain (PBD; see Glossary), in particular at peptidebinding sites (PBSs), amino-acid residues interacting directly with antigens [6]. Consequently, molecules coded by different MHC alleles differ in their antigen-binding profiles [7,8], which in turn affect susceptibility to disease [9][10][11]. Polymorphism apparently evolves adaptively, as evidenced by the high relative nonsynonymous substitution rate within the PBD [12], particularly at PBSs [6,13,14], as well as by large short-term selection coefficients (Figure 1). High polymorphism coupled with evidence for positive selection has made MHC genes an attractive model for studying how selection can promote and maintain genetic variation in natural populations.Evidence is accumulating, as has long been suspected based on the function of MHC proteins, that pathogens impose significant selection on MHC (Figure 1) and, importantly, drive MHC allele frequency changes in natural populations [3,15]. However, the specific selection mechanisms that shape the extraordinary diversity of MHC genes are still controversial (Figure 2, Key Figure ). An associated question is whether these mechanisms can explain the evolutionary persistence of MHC allelic lineages for a much longer time than expected under neutrality, leading to transspecies polymorphism (...

Rapid Evolution of Parasite Resistance via Improved Recognition and Accelerated Immune Activation and Deactivation

“…These self/non-self-recognition systems are known to evolve rapidly and can lead to varying outcomes in the arms race between hosts and parasites in different contexts. Given this, they may be a widespread mechanism generating rapid variation in infection outcomes between individuals and populations, even under short evolutionary timescales (Radwan et al 2020). For large macroparasites, such as helminths, it is known that dendritic cells play a central role in recognition and initiation of an immune response (Motran et al 2018).…”

Post-copulatory genetic matchmaking: HLA-dependent effects of cervical mucus on human sperm function

“…The observed effects of partners' HLA dissimilarity on sperm function could potentially arise at least through two evolutionary mechanisms. First, as highlighted above, cervical mucus -mediated selection towards HLA-dissimilar males may represent an evolutionary strategy that ensures the ‘production' of offspring that have broad (or optimal) antigen recognition capability and thus better ability to fight against infections [ 82 ]. Supporting this possibility, pathogens have been widely assumed to be the strongest selective agent in human evolution (e.g.…”

The impact of bottlenecks and inbreeding on the genome of the endangered Pyrenean desman

“…The genomic sequences of individuals of an endangered species like the Pyrenean desman can also help determine the functional genomic features of particular specimens, to gain a better understanding of their genomic health (Steiner et al 2013;Díez-del-Molino et al 2018). In this work, we have characterized two groups of proteins from multigenic families in which high levels of diversity are essential, both at the inter-and intra-locus levels: the class I major histocompatibility complex (Hughes and Yeager 1998;Radwan et al 2020) and the olfactory receptors (Alonso et al 2008;Hughes et al 2018). The analysis of the genetic diversity in these revealed interesting differences between the individuals sequenced.…”

“…Proteins that directly interact with the environment are particularly interesting in the context of genetic diversity as these require a high degree of inter-and intra-locus variability to function properly. Two protein families are key in this regard: the major histocompatibility complex (MHC), which is one of the principal components of the immune system (Abduriyim et al 2019;Radwan et al 2020); and the olfactory receptors (OR), which involves the largest multigene family in mammals (Hughes et al 2018). Due to balancing selection, a huge diversity of alleles is found in some MHC genes, consequently raising heterozygosity in these particular loci (Vandiedonck and Knight 2009).…”