Fine‐Scale Mapping of HLA‐C Haplotype Structural Diversity Using SNP Crossover Regions Flanked by Transposable Element Markers in Homozygous Cell Lines

Background/Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.