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

Abstract

Proteins encoded by Antigen Processing Genes (APGs) provide MHC class I (MHC-I) with antigenic peptides. In mammals, polymorphic multigenic MHC-I family is served by monomorphic APGs, whereas in certain non-mammalian species both MHC-I and APGs are polymorphic and coevolve within stable haplotypes. Coevolution was suggested as an ancestral gnathostome feature, presumably enabling only a single highly expressed classical MHC-I gene. In this view coevolution, while optimizing some aspects of adaptive immunity, would also limit its flexibility by preventing the expansion of classical MHC-I into a multigene family. However, some non-mammalian taxa, such as salamanders, have multiple highly expressed MHC-I genes, suggesting either that coevolution is relaxed or that it does not prevent the establishment of multigene MHC-I. To distinguish between these two alternatives we use salamanders (30 species from 16 genera representing six families) to test, within a comparative framework, a major prediction of the coevolution hypothesis: the positive correlation between MHC-I and APGs diversity. We found that MHC-I diversity explained both within-individual and species-wide diversity of two APGs, TAP1 and TAP2, supporting their coevolution with MHC-I, while no consistent effect was detected for the other three APGs (PSMB8, PSMB9 and TAPBP). Our results imply that while coevolution occurs in salamanders, it does not preclude the expansion of the MHC-I gene family. Contrary to the previous suggestions, non-mammalian vertebrates thus may be able to accommodate diverse selection pressures with flexibility granted by rapid expansion or contraction of the MHC-I family, while retaining the benefits of coevolution between MHC-I and TAPs.

Salamanders reveal novel trajectories of amphibian MHC evolution

“…All amplicon sequence data analyzed in this study were taken from Palomar et al. (2021) where the detailed sequencing and genotyping results can be found. Genotyping repeatability averaged over all species was 91.4% for exon 2 and 97.4% for exon 3.…”

“…Data on MHC‐I polymorphism analyzed here were taken from Palomar et al. (2021). MHC‐I polymorphism was assessed in 30 salamander species representing 16 genera and six Urodela families.…”

“…In most cases, transcriptomes of multiple individuals from a genus or species were available for primer design. Details of amplification, sequencing, and genotyping are in Palomar et al (2021). Sequences that exhibited signatures of nonfunctionality, that is, frameshift-causing indels or internal stop codons, were excluded from the analysis (an average of 5.6% in exon 2 and 4.4% in exon 3 per species).…”

“…The Urodela alignments covered amino acid positions 8-79 (exon 2) and 109-162 (exon 3) of the human HLA-A protein α domain. For a detailed summary of variation within species, see Palomar et al (2021).…”

“…In the present study, we take advantage of a large comparative dataset of MHC-I variation in 30 species representing six out of nine extant families (Palomar et al 2021). This dataset was collected using standardized methodology, with primers targeting variable exons 2 and 3 designed based on transcriptome sequences of (typically) multiple species from the focal genera, amplicon sequencing using Illumina technology, and genotyping using established standards (Sebastian et al 2016).…”