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 (...

Anticipating how epidemics will spread across landscapes requires understanding host dispersal events that are notoriously difficult to measure. Here, we contrast host and virus genetic signatures to resolve the spatiotemporal dynamics underlying geographic expansions of vampire bat rabies virus (VBRV) in Peru. Phylogenetic analysis revealed recent viral spread between populations that, according to extreme geographic structure in maternally inherited host mitochondrial DNA, appeared completely isolated. In contrast, greater population connectivity in biparentally inherited nuclear microsatellites explained the historical limits of invasions, suggesting that dispersing male bats spread VBRV between genetically isolated female populations. Host nuclear DNA further indicated unanticipated gene flow through the Andes mountains connecting the VBRV-free Pacific coast to the VBRV-endemic Amazon rainforest. By combining Bayesian phylogeography with landscape resistance models, we projected invasion routes through northern Peru that were validated by real-time livestock rabies mortality data. The first outbreaks of VBRV on the Pacific coast of South America could occur by June 2020, which would have serious implications for agriculture, wildlife conservation, and human health. Our results show that combining host and pathogen genetic data can identify sex biases in pathogen spatial spread, which may be a widespread but underappreciated phenomenon, and demonstrate that genetic forecasting can aid preparedness for impending viral invasions.Desmodus | zoonotic disease | forecasting | sex bias | spatial dynamics

Genes of the major histocompatibility complex (MHC) in vertebrates are integral for effective adaptive immune response and are associated with sexual selection. Evidence from a range of vertebrates supports MHC-based preference for diverse and dissimilar mating partners, but evidence from human mate choice studies has been disparate and controversial. Methodologies and sampling peculiarities specific to human studies make it difficult to know whether wide discrepancies in results among human populations are real or artefact. To better understand what processes may affect MHC-mediated mate choice across humans and nonhuman primates, we performed phylogenetically controlled meta-analyses using 58 effect sizes from 30 studies across seven primate species. Primates showed a general trend favouring more MHC-diverse mates, which was statistically significant for humans. In contrast, there was no tendency for MHC-dissimilar mate choice, and for humans, we observed effect sizes indicating selection of both MHC-dissimilar and MHC-similar mates. Focusing on MHC-similar effect sizes only, we found evidence that preference for MHC similarity was an artefact of population ethnic heterogeneity in observational studies but not among experimental studies with more control over sociocultural biases. This suggests that human assortative mating biases may be responsible for some patterns of MHC-based mate choice. Additionally, the overall effect sizes of primate MHC-based mating preferences are relatively weak (Fisher's Z correlation coefficient for dissimilarity Zr = 0.044, diversity Zr = 0.153), calling for careful sampling design in future studies. Overall, our results indicate that preference for more MHC-diverse mates is significant for humans and likely conserved across primates.