Authors:
C. Nelson (New York, New York, US)
E. Kim (Ossining, New York, US)
S. Choi (Ossining, New York, US)
S. Seo (Ossining, New York, US)
J. Ryu (Ossining, New York, US)
H. Kim (Ossining, New York, US)
S. Yang (Ossining, New York, US)
N. Cereb (Ossining, New York, US)
We have been sequencing whole gene HLA class I on a large scale at Histogenetics on PacBio RS II® platform since the beginning of July 2016. To date we have sequenced 150,000 samples for whole gene class I. We observed 1422, 1489 and 1443 unique sequences in HLA-A, -B and -C, respectively. We compared inter-allelic variation for each HLA class I gene (HLA-A, -B, -C) for 106,377 that were sequenced as of December 31st 2016. Here we present a summary of our findings for HLA-A alleles. Mean values of non-synonymous 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, 1986) for use with next-generation sequencing data (Nelson and Hughes, 2015; Nelson et al., 2015). Overall d (among unique alleles) for introns is 0.0236, as compared to overall dS for exons at 0.0392. Thus, neutral diversity among unique alleles is approximately 66% higher in exons than introns. This is consistent with the hypothesis that diversity at synonymous coding sites has been elevated as a result of linkage to non-synonymous sites, which experience over-dominant (positive balancing) selection. In contrast, intronic sites are less closely linked to non-synonymous coding sites than are synonymous coding sites, making them more likely to experience recombinational separation from coding sites and subsequent drift, which has acted to homogenize the sequences over evolutionary time. When we compared dN/dS ratios exons 2 and 3 are the only ones for which dN/dS substantially exceeds 1, consistent with over-dominant selection acting on peptide binding residues (PBR). However, We were surprised to see that, while exon 4 seems to experience strong purifying selection (dN/dS = 0.22), exon 5 is again higher (dN/dS=1.04; the only exon besides 2 and 3 with a ratio above 1). Since exon 5 does not encode the PBR, this ratio suggests either a relaxation of purifying selection or localized over-dominant selection. There have been reports that the transmembrane domains of HLA class I genes could be a determinant in Inhibition of a subset of Natural Killer Cells.
We will present similar analysis for HLA-B and -C and discuss evolutionary pathways and possible functionalities of various regions of class I genes.