Transposon-mediated death of an ancestral A-23-like allele: evolution of TCR-positioning motifs in the HLA-A lineage

Abstract

HLA-A alleles are characterized by tandem arginine and histidine/arginine motifs (i.e., R65 and H151R motifs) present on the α1- and α2-helix, respectively. In crystallographic structures, α/β T-cell receptors (TCR) contact both motifs and appear to be geometrically positioned for alloreactivity. Herein, bioinformatics of "dual-motif" MHC A-like alleles were investigated across phylogeny. While A-like alleles with the R65 motif are widespread, the H151R motif has segregated out of most species. Surprisingly, an uncharacterized orf in tarsiers (Loc-103275158) encodes R151 within a truncated A-23-like gene, which is in frame with short footprints of Tc5 and Tigger transposons (TE); the extant tarsier A-23 allele is totally missing exon-3 and part of exon-4; together, suggesting TE-mediated inactivation of an intact/ancestral A-23 allele. Since the only other (non-human) dual-motif A-like alleles are in gorilla, chimpanzee, and the Florida manatee, we speculate that dual-motif A alleles first emerged in the Afrotherian lineage and reappeared during the evolution of higher primates.

TE-domestication and horizontal transfer in a putative Nef-AP1mu mimic of HLA-A cytoplasmic domain re-trafficking

“…[32][33][34] Given the role of GTPases in intracellular immunity to T. gondii, 34 it is an intriguing hypothesis that protozoans may have fortuitously enhanced immunity against retroviral pathogens. That such complexity is seemingly recapitulated within an MHC-I structural gene 4 is profound, and might suggest a previously unrecognized level of evolutionary interplay between these two types of pathogens and the genesis of the human adaptive immune system. Figure. 1, suggest intermediate species as hosts for protozoan vectors of the tigger TE.…”

“…Moreover, the full a3 domain, and the C-terminus of a nominal MHC-I, are encoded in the 3 0 -sequence of Loc-103275158. 4,16 Indeed, there are several unique features to this uncharacterized orf (Fig. 1).…”

“…[12][13][14][15] During the study of the HLA-A23 lineage in early primates, we encountered a surprising example of domestication involving the DNA transposon, tigger-1. 4,15 In the tarsier, Tarsius syrichta, an apparent deletion of an ancestral/intact A23 allele led to exon-3 (encodes the a2 domain) being completely absent, and exon-4 almost absent (only the last two b-strands of the a3 domain remains encoded). 4 By contrast, a highly unusual, uncharacterized orf in T. syrichta (Loc-103275158) displays a complete deletion of exon-2 (encodes a1) and contains only part of exon-3 (~from the structurally crucial "kink" in the a2 helix at R151 16 to the end of the a2 domain; this is encoded by exon-5 in the orf).…”

“…4,15 In the tarsier, Tarsius syrichta, an apparent deletion of an ancestral/intact A23 allele led to exon-3 (encodes the a2 domain) being completely absent, and exon-4 almost absent (only the last two b-strands of the a3 domain remains encoded). 4 By contrast, a highly unusual, uncharacterized orf in T. syrichta (Loc-103275158) displays a complete deletion of exon-2 (encodes a1) and contains only part of exon-3 (~from the structurally crucial "kink" in the a2 helix at R151 16 to the end of the a2 domain; this is encoded by exon-5 in the orf). Moreover, the full a3 domain, and the C-terminus of a nominal MHC-I, are encoded in the 3 0 -sequence of Loc-103275158.…”

“…Surprisingly, an uncharacterized orf in T. syrichta (Loc-103275158) encoded R151, but within a truncated A-23 like gene containing 5 0 -and 3 0 -footprints of the transposon (TE), tigger-1; the extant tarsier A-23 allele is totally missing exon-3 and part-of exon-4; together, suggesting TE-mediated inactivation of an intact/ancestral A-23 allele (Murray, 2015a). 4 The unique Loc-103275158 orf encodes a putative 15-exon transcript with no apparent paralogs throughout phylogeny. However, an HLA-A11 like gene in M. leucophaeus with a shortened C-terminal domain, and an HLA-A like orf in C. atys with two linked a1/a2/a3 domains, both contain a second transmembrane segment, which is conserved in Loc-103275158.…”