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Abstract
Next-generation sequencing (NGS) is increasingly used in transplantation settings, but also as a method of choice for in-depth analysis of population-specific HLA genetic architecture and its linkage to various diseases. With respect to complex ethnic admixture characteristic for East Croatian population, we aimed to investigate class-I (HLA-A, -B, -C) and class-II (HLA-DRB1, -DQA1, -DQB1) HLA diversity at the highest, 4-field resolution level in 120 healthy, unrelated, blood donor volunteers. Genomic DNA was extracted and HLA genotypes of class I and DQA1 genes were defined in full-length, -DQB1 from intron 1 to 3′ UTR, and -DRB1 from intron 1 to intron 4 (Illumina MiSeq platform, Omixon Twin algorithms, IMGT/HLA release 3.30.0_5). Linkage disequilibrium statistics, Hardy-Weinberg departures, and haplotype frequencies were inferred by exact tests and iterative Expectation-Maximization algorithm using PyPop 0.7.0 and Arlequin v3.5.2.2 software. Our data provide first description of 4-field allele and haplotype frequencies in Croatian population, revealing 192 class-I and class-II alleles and extended haplotypic combinations not apparent from the existing 2-field HLA reports from Croatia. This established reference database complements current knowledge of HLA diversity and should prove useful in future population studies, transplantation settings, and disease-associated HLA screening.
Highlights
Next-generation sequencing (NGS) is increasingly used in transplantation settings, and as a method of choice for in-depth analysis of population-specific human leukocyte antigen (HLA) genetic architecture and its linkage to various diseases
We evaluated 120 donors (120 donors × 6 loci × 2 alleles = 1440 alleles), 9 of whom were excluded from further analysis due to low-performing samples on quality control check [low read count (≤2500 bp for class I and ≤5000 bp for class II genes) and/or low key exon coverage depth (≤30)]
This study represents the first report of HLA diversity in an east Croatian population of healthy blood donors, as studied by the generation sequencing of 6 HLA genes, providing extensive exon/intron coverage with minimum ambiguity
Summary
Next-generation sequencing (NGS) is increasingly used in transplantation settings, and as a method of choice for in-depth analysis of population-specific HLA genetic architecture and its linkage to various diseases. These historic and more recent 20th century migration events, encompassing emigration of Germans and Austrians from Slavonia, and the settlement of Balkan War veterans from Serbia, Croatian immigrants from Dalmatia, Herzegovina, and most recently from north Bosnia, have shaped the genetic diversity of East Croatian population. The implementation of NGS technologies in HLA research and routine clinical work, enables elucidation of full-length HLA gene sequences, permitting an in-depth characterisation of population HLA diversity In this context NGS can overcome limitations of traditional typing techniques, thereby sustaining optimal HLA matching of donor-recipient pairs for organ and haematopoietic stem cell transplantation (HSCT)[11], improved estimates of population structure and HLA associated disease risk[12,13,14], and better understanding of demographic history and geographic origin of a given population[15]. These previous studies were based on lower resolution (1st and 2nd field) HLA typing of selected HLA loci in individuals originating from various Croatian regions, providing partial insight into the HLA diversity of a general, but not East Croatia population
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