Abstract
BackgroundThe adaptive immune response intrinsically depends on hypervariable human leukocyte antigen (HLA) genes. Concomitantly, correct HLA phenotyping is crucial for successful donor-patient matching in organ transplantation. The cost and technical limitations of current laboratory techniques, together with advances in next-generation sequencing (NGS) methodologies, have increased the need for precise computational typing methods.ResultsWe tested two widespread HLA typing methods using high quality full genome sequencing data from 150 individuals in 50 family trios from the Genome Denmark project. First, we computed descendant accuracies assessing the agreement in the inheritance of alleles from parents to offspring. Second, we compared the locus-specific homozygosity rates as well as the allele frequencies; and we compared those to the observed values in related populations. We provide guidelines for testing the accuracy of HLA typing methods by comparing family information, which is independent of the availability of curated alleles.ConclusionsAlthough current computational methods for HLA typing generally provide satisfactory results, our benchmark – using data with ultra-high sequencing depth – demonstrates the incompleteness of current reference databases, and highlights the importance of providing genomic databases addressing current sequencing standards, a problem yet to be resolved before benefiting fully from personalised medicine approaches HLA phenotyping is essential.
Highlights
The adaptive immune response intrinsically depends on hypervariable human leukocyte antigen (HLA) genes
The hallmark of the immune responses is the recognition of the offending antigen by the host cells through the major histocompatibility complex (MHC)
Methods for automatic typing of HLA regions are normally divided into assembly or alignment-based methods, according to whether the sequencing reads are either aligned to a reference, or the true alleles are predicted through probabilistic models [31]
Summary
The adaptive immune response intrinsically depends on hypervariable human leukocyte antigen (HLA) genes. The immune system maintains a complex equilibrium between identifying a variety of external pathogens and recognising the organism’s own tissue. This process is carried out by the adaptive immune system [1,2,3]. The hallmark of the immune responses is the recognition of the offending antigen by the host cells through the major histocompatibility complex (MHC). In humans, it is known as the human leukocyte antigen (HLA) system and is located within a 3.6 Mb region on chromosome 6 (6p21.3) [3,4,5]. This region contains roughly 220 genes, which can be divided in HLA-like coding genes and non-HLA coding
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