Fine-Scale Mapping of HLA-C Haplotype Structural Diversity Using SNP Crossover Regions Flanked by Transposable...

The human major histocompatibility complex (MHC) is characterized by extreme polymorphism, with HLA-C contributing to pathogen defence, disease susceptibility, and transplantation outcomes. Beyond allelic diversity, and variation, the evolutionary restructuring of haplotypes influences functional diversity across the region. This study analysed HLA-C haplotypes in the context of transposable element (TE) architecture and single-nucleotide polymorphism (SNP) patterns to identify conserved modules and ancestral recombination boundaries.

Paired genomic alignments of fully phased homozygous lymphoblastoid cell lines carrying 36 haplotypes of HLA-C*01-C*07, C*12, and C*16 allelic groups were performed using Mauve to define locally co-linear blocks. SNP density plots were generated to visualize transitions between SNP-rich and SNP-poor regions. Six diverse HLA-C*07 haplotypes (linked to HLA-B*07, *08, *18, *49, *57 and *58) were examined as a primary case study. Particular focus was placed on crossover zones where SNP transitions coincided with TE boundaries, indicating putative ancestral recombination breakpoints.

Comparative analyses revealed extensive structural variation among C*07 haplotypes and across the broader C*01-C*16 series. The C*07:02 homologs exhibited significantly higher SNP density (mean = 1.87 ± 0.44 SNPs/kb, n = 10) than C*07:01 and C*07:18 homologs (mean = 0.29 ± 0.21 SNPs/kb, n = 20; p < 0.001). Abrupt SNP transitions frequently aligned with SINE, LINE, and LTR elements (e.g., Alu, L1, L2, HERV), marking recurrent TE-associated junctions. These breakpoints defined shared homozygous HLA-C segments spanning ∼4 kb to ∼4 Mb, consistent with mosaic haplotype evolution through recombination of conserved modules.

HLA-C haplotypes exhibit modular mosaic structures shaped by recurrent recombination at TE-associated crossover zones. Thus, MHC haplotypes may share the same HLA-C allele, yet differ in the surrounding HLA-B and class I genomic organization, preserving or disrupting co-adapted functional units. Incorporating haplotypic mosaicism, rather than focusing solely on allelic polymorphism, may improve models of immune variation, disease risk, and translation matching.