The 18th International HLA & Immunogenetics workshop project report: Creating fully representative MHC reference haplotypes

Abstract

A fundamental endeavor of the International Histocompatibility and Immunogenetics Workshop (IHIW) was assembling a collection of DNA samples homozygous through the MHC genomic region. This collection proved invaluable for assay development in the histocompatibility and immunogenetics field, for generating the human reference genome, and furthered our understanding of MHC diversity. Defined by their HLA-A, -B, -C and -DRB1 alleles, the combined frequency of the haplotypes from these individuals is ~20% in Europe. Thus, a significant proportion of MHC haplotypes, both common and rare throughout the world, and including many associated with disease, are not yet represented. In this workshop component, we are collecting the next generation of MHC-homozygous samples, to expand, diversify and modernize this critical community resource that has been foundational to the field. We asked laboratories worldwide to identify samples homozygous through all HLA class I and/or HLA class II genes, or through whole-genome SNP genotyping or sequencing, to have extensive homozygosity tracts within the MHC region. The focus is non-Europeans or those having HLA haplotypes less common in Europeans. Through this effort, we have obtained samples from 537 individuals representing 294 distinct haplotypes, as determined by their HLA class I and II alleles, and an additional 50 haplotypes distinct in HLA class I or II alleles. Although we have expanded the diversity, many populations remain underrepresented, particularly from Africa, and we encourage further participation. The data will serve as a resource for investigators seeking to characterize variation across the MHC genomic region for disease and population studies.

Keywords: HLA; IHIW; MHC; ancestry; assembly; ethnicity; homozygous; long‐read; reference haplotype; sequencing; short‐read.

Figure 1.. Geographic representation of the MHC region within the human genome reference sequences (hg38/GRCh38).

From left to right: hg38/GRCh38 haplotype ID, IHWG Cell ID, HLA-A~C~B~DRB1 haplotype, frequency of haplotype in major population groups, population having highest frequency. † - standard reference of hg38 (hap1-7 are the alt_refs), ‡ - additional haplotype from Houwaart et al.. The haplotype frequencies were obtained from allelefrequencies.net; shown for each major ancestry group is the highest frequency within that group. Population having highest frequency at the right is obtained from studies having >1,000 subjects. The completed haplotypes are available with GenBank ID numbers OK649231-6.

Figure 2:. Geographic origins and representation of HLA homozygous DNA samples analyzed.

A. Shows the country of origin for the samples included in the study. Colours indicate the number of samples from a given country (grey 0, light blue 1–4, dark blue 5–9, orange10–19, red >20). B. Shows an estimation of the global representation of the HLA-A~C~B~DRB1 haplotypes included in the study. Countries are coloured yellow if 5% or more of individuals are estimated to carry at least one of the haplotypes. The haplotype frequencies were obtained from allelefrequencies.net.