A pan-MHC reference graph with 246 fully contiguous phased sequences

The major histocompatibility complex (MHC) is a region of the human genome that is key to immune system function but sometimes refractory to genomic analyses due to extreme polymorphism and structural variation. We performed targeted long-read sequencing and de novo assembly of MHC to create 246 highly accurate, fully contiguous, and phased full-length sequences, mostly from data provided by the Human Pangenome Reference Consortium (HPRC). We identified alleles at high resolution across 39 loci including the class I and II HLA (human leukocyte antigen) genes, discovering 1,246 putative novel allele sequences. We identified copy number variation in the C4A and C4B genes and found significant linkage disequilibrium between C4A[~]C4B haplotypes and 14 MHC loci. We build our sequences into a novel "pan-MHC" reference graph, and we demonstrate that this improves the accuracy of short-read variant calling. Our haplotypes and graph contain significantly more population diversity than preexisting MHC sequences, thus improving the prospects for global health equity in this clinically important genomic region.