Peptide specificity of the Amerindian B*3905 allotype: molecular insight into selection mechanisms driving HLA class I evolution in indigenous populations of the Americas

Abstract

HLA-B*3905 is apparently restricted to Amerindian populations and presents a wide geographical distribution, from Mexico to Argentina. It differs from B*3901, one of the founder HLA class I alleles of Central and South Amerindians, by a single nucleotide substitution leading to an Asp74Tyr change in the gene product. The peptide specificity of the B*3905 protein was characterized by pool sequence analysis of B*3905-bound peptides and by sequencing of a set of individual ligands, using electrospray ion trap mass spectrometry. The results indicate a double effect of the B*3905 mutation. First, pocket B specificity was shifted towards an increased preference for His at peptide position 2, which is the main anchor for B39-bound peptides, relative to B*3901. Second, at peptide position 3 acidic residues were favored, and aromatic residues disfavored, relative to B*3901. These features approach the peptide specificity of B*3905 to B*3801 and B*1509, allotypes absent from Central and South Amerindians. Together with B*3909, B*3905 is the second HLA-B39 subtype whose polymorphism results in a shift of peptide specificity towards that of HLA-B allotypes absent from these populations. This suggests that HLA-B39 evolution in Central and South America may be an antigen-driven adaptive response, leading to generate antigen-presenting properties absent from the HLA class I repertoire of the ancestral population.

Major Histocompatibility Complex Class I Molecules Bind Natural Peptide Ligands Lacking the Amino-terminal Binding Residue in Vivo

“…An NH 2 -terminally extended peptide, IHEPEPHIL, found in the same peptide pool (Fig. 1), had been previously reported as a natural B*3905 ligand (21). Thus, these results indicate that a peptide in the B*3905-bound pool lacks the P1 residue of another natural ligand from the same peptide pool.…”

“…The sequence of the latter peptide was confirmed by MS/MS fragmentation of the corresponding synthetic peptide. NH 2 -terminally extended counterparts of these peptides (EHGPN-PIL and EHAGVISVL) were known natural B*3905 ligands (21). A third peptide, with M ϭ 851.3 was detected in HPLC fraction N.145 (elution time: 71.5 min) from B*3905.…”

“…C1R transfectants expressing B*3901, B*3905, or B*3909 have been described previously (20,21). RMA-S is a TAP-deficient murine cell line (12).…”

Molecular variability in Amerindians: widespread but uneven information

“…At the serological level , using principal-components analysis and synthetic gene frequency maps, observed longitudinal and latitudinal clines suggesting ancient migration routes. The molecular investigations, on the other hand, indicated: (a) a limited amount of polymorphism compared to other ethnic groups, confirming serological data (for instance, Fernández-Viña et al 1997); (b) novel B locus variants, especially in South America (Cadavid and Watkins 1997); (c) the phenomenon of ''allele turnover'', that is, new alleles tend to supplant older alleles rather than supplementing them (Parham et al 1997); and (d) an antigen-driven evolution of HLA-B molecules of Central and South American Indians aimed at generating novel peptide specificities not provided by the limited repertoire of founder allotypes postulated to have been present in the first migrants to the continent (Yagüe et al 2000).…”

Molecular analysis of HLA‐DRB1, DQA1, DQB1, DQ promoter polymorphism and extended class I/class II haplotypes in the Seri Indians from Northwest Mexico

“…The analysis of these genes has been a valuable tool in unraveling the historical relationships between ethnic groups and has greatly increased the knowledge of the ancestry and migration patterns of many different populations including the Amerindian groups in America (9,10). Some evidence also exists regarding natural selection and the possible mechanisms responsible for the presence of particular alleles in certain environments (11–13). Native Americans are constitutionally susceptible to pathogens, as has been documented since the 16th century, after Columbus discovered America (14).…”