HLA-HD: An accurate HLA typing algorithm for next-generation sequencing data

ABSTRACT

The accurate typing of HLA alleles is critical for a variety of medical applications, such as genomic studies of multifactorial diseases, including immune system and inflammation-related disorders, and donor selection in organ transplantation and regenerative medicine. Here we developed a new algorithm for determining HLA alleles using next-generation sequencing (NGS) results. The method consists of constructing an extensive dictionary of HLA alleles, precise mapping of the NGS reads, and calculating a score based on weighted read counts to select the most suitable pair of alleles. The developed algorithm compares the score of all allele pairs, taking into account variation not only in the domain for antigen presentation (G-DOMAIN), but also outside this domain. Using this method, HLA alleles could be determined with 6-digit precision. We showed that our method was more accurate than other NGS-based methods and revealed limitations of the conventional HLA typing technologies. Furthermore, we identified a novel HLA-A-like-pseudogene when we assembled NGS reads that had caused arguable typing, and confirmed it by direct sequencing. The accuracy of the HLA-A allele typing was improved after the pseudogene sequence was included in the HLA allele dictionary.

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