Complete sequences of six major histocompatibility complex haplotypes, including all the major MHC class II...

Area of Science:

• Genomics and Bioinformatics
• Immunogenetics
• Human Genetics

Background:

• Accurate immunogenetic reference panels are crucial for population-scale immunogenomics.
• The Major Histocompatibility Complex (MHC) is a highly polymorphic genomic region linked to immune diseases and therapeutic responses.
• Complex genetic variation and lack of resolved MHC reference haplotypes hinder accurate analysis.

Purpose of the Study:

• To resolve and add alternative MHC reference haplotypes to the human reference genome.
• To provide a structurally accurate genotyping graph for the complete MHC region.
• To improve the analysis of genetic variation within the medically important MHC region.

Main Methods:

• Integration of Illumina, Nanopore, and PacBio HiFi sequencing technologies.
• Application of bespoke bioinformatics pipelines for haplotype assembly.
• Analysis of seven diverse samples from the 1000 Genomes Project for read remapping.

Main Results:

• Six alternative MHC reference haplotypes were assembled, including DR1, DR4, DR2, DR3, and six C4 region variants.
• MHC class II sequence structures are conserved within DR haplotype supergroups, with diversity peaks near HLA-A, HLA-B+C, and HLA class II genes.
• Read recruitment to the MHC improved by 0.06%-0.49% in a short-read remapping experiment.

Conclusions:

• The assembled MHC haplotypes serve as valuable community references.
• These references form the basis for a structurally accurate genotyping graph of the MHC region.
• Improved MHC haplotype resolution enhances the accuracy of population-scale immunogenomic studies.