OR23 Whole gene analysis of HLA-A, -B and -C alleles observed in 100,000 individuals demonstrate distinct evolutionary and selection patterns in each Class I gene

Abstract

Aim Classical HLA Class I genes (HLA-A, -B and -C) is thought to be evolved from ancestral gene(s) via duplication events and considered to be homologous. Exon 2 and 3 of those genes encodes Antigen Recognition Sites (ARS). These exons are highly polymorphic and it was believed due to positive selection. We have analyzed over 100,000 human samples that were whole gene sequenced for HLA-A, -B and -C and contained 1188, 1237 and 1185 unique patterns for each gene respectively. Methods We performed whole gene HLA Class I gene sequencing on PacificBio platform as described earlier (Cereb et al. Hum Immunol. 2015 Dec;76(12):963–74). Mean values of nonsynonymous and synonymous divergence (dN and dS, respectively) for all codons for all pairwise comparisons among alleles were determined using SNPGenie, an implementation of the Nei-Gojobori method (Nei and Gojobori, Mol. Biol. Evol. 3:418–426.) for use with next-generation sequencing data (Mol. Biol. Evol. 3:418–426.). Results In summary regarding positive selection, the following exons give signatures of positive selection: (1) HLA-A exons 2, 3, and 5 (weak); (2) HLA-B exons 2 and 3 (weak); and (3) HLA-C exons 1, 6, and 7. Regarding HLA-C, this seems quite revolutionary, and may help to explain previous studies that failed to identify evidence of positive selection specifically favoring amino acid charge differences in the peptide binding residues (PBR) of HLA-C only. HLA-C has the most extreme signatures of positive selection heretofore observed, but in non-PBR exons: dN/dS for exon 1 is 17.94, and dN/dS for exon 7 is 19.02 — both very high values. However, it is noteworthy that these huge ratios are not due to a great increase in dN, but rather to a great decrease in d. By contrast, PBR exons 2 and 3 have overall signatures of weak purifying selection at the HLA-C locus.Overall values for dN at HLA-A, -B, and -C are 0.0305, 0.0306, and 0.0240, respectively. Overall values for dS are 0.0395, 0.0344, and 0.0300, respectively. Therefore, in terms of selectively neutral diversity, diversity is greatest in HLA-A, less in -B, and least in -C. Conclusions Whole gene sequencing of HLA Class I will provide us the foundation to understand the evolutionary forces shaping the regions and the functions of various regions of those genes. N. Cereb: 6. Stock Shareholder; Company/Organization; PacBio and Hitogenetics. C.W. Nelson: 2. Consultant; Company/Organization; Histogenetics. S. Yang: 6. Stock Shareholder; Company/Organization; PacBio and Histogenetics.