Molecular Evolution of Antigen-Processing Genes in Salamanders: Do They Coevolve withMHCClass I Genes?

Abstract

Proteins encoded by Antigen Processing Genes (APGs) prepare antigens for presentation by the Major Histocompatibility Complex class I (MHC I) molecules. Coevolution between APGs and MHC I genes has been proposed as the ancestral gnathostome condition. The hypothesis predicts a single highly expressed MHC I gene and tight linkage between APGs and MHC I. In addition, APGs should evolve under positive selection, a consequence of the adaptive evolution in MHC I. The presence of multiple highly expressed MHC I genes in some teleosts, birds, and urodeles appears incompatible with the coevolution hypothesis. Here, we use urodele amphibians to test two key expectations derived from the coevolution hypothesis: i) the linkage between APGs and MHC I was studied in Lissotriton newts, and ii) the evidence for adaptive evolution in APGs was assessed using 42 urodele species comprising 21 genera from seven families. We demonstrated that five APGs (PSMB8, PSMB9, TAP1, TAP2 and TAPBP) are tightly linked (< 0.5 cM) to MHC I. Although all APGs showed some codons under episodic positive selection, we did not find a pervasive signal of positive selection expected under the coevolution hypothesis. Gene duplications, putative gene losses, and divergent allelic lineages detected in some APGs demonstrate considerable evolutionary dynamics of APGs in salamanders. Overall, our results indicate that if coevolution between APGs and MHC I occurred in urodeles, it would be more complex than envisaged in the original formulation of the hypothesis.

Coevolution between MHC Class I and Antigen-Processing Genes in Salamanders

“…Salamanders exhibit a combination of features that makes them a suitable model to test the coevolution hypothesis. At least some APGs are polymorphic in certain species ( Huang et al 2013 ; Fijarczyk et al 2018 ; Palomar et al 2021 ), as expected under the coevolution model. On the other hand, salamanders studied so far have multiple highly expressed MHC-I genes ( Sammut et al 1999 ; Fijarczyk et al 2018 ; Palomar et al 2021 ).…”

“…With both coevolving partners exhibiting high levels of polymorphism, an efficient system would require little or no recombination between them—frequent recombination would impose a heavy genetic load, separating coadapted alleles and thereby reducing the fitness of recombinant haplotypes ( Kaufman 1999 ). Tight linkage between APG and MHC-I enables coevolution and is thus a key prediction of the hypothesis that has been confirmed in several vertebrate groups, such as frogs ( Ohta et al 2006 ), salamanders ( Palomar et al 2021 ), and birds ( Kaufman et al 1999 ). Mammals are a notable exception ( Horton et al 2004 ), where generalist APGs serve all MHC-I alleles, presumably after the linkage between MHC-I and APGs was broken by an inversion ( Kaufman 2015 ).…”

“…Tapasin stabilizes an empty MHC-I molecule and ensures loading of high-affinity peptides. The collective term antigen-processing genes (APGs) is used for the genes encoding PSMB, TAP, and TAPBP proteins (e.g., McConnell et al 2016 ; Palomar et al 2021 ). Finally, the antigen–MHC-I complex moves via a secretory pathway to the cell surface.…”

“…In this view, coevolution may be considered as an ancestral state that limits the flexibility of the adaptive immune response by restricting the number of classical MHC-I genes. However, evidence for multiple expressed MHC-I genes has accumulated in nonmammalian vertebrates: fishes ( Nonaka and Nonaka 2010 ; McConnell et al 2014 ; Grimholt et al 2015 ), amphibians ( Sammut et al 1999 ; Fijarczyk et al 2018 ; Palomar et al 2021 ), and birds ( Drews and Westerdahl 2019 ). At least some species in these groups maintain tight linkage between MHC-I and APGs ( McConnell et al 2016 ; Palomar et al 2021 ).…”

“…However, evidence for multiple expressed MHC-I genes has accumulated in nonmammalian vertebrates: fishes ( Nonaka and Nonaka 2010 ; McConnell et al 2014 ; Grimholt et al 2015 ), amphibians ( Sammut et al 1999 ; Fijarczyk et al 2018 ; Palomar et al 2021 ), and birds ( Drews and Westerdahl 2019 ). At least some species in these groups maintain tight linkage between MHC-I and APGs ( McConnell et al 2016 ; Palomar et al 2021 ). This suggests that either coevolution was relaxed in these species, or coevolution does not preclude establishment, following gene duplication, of multiple highly expressed MHC-I genes.…”