HISTOCOMPATIBILITY & IMMUNOGENETICS BY NGS

HLA genes encode major histocompatibility complex on cell surface. The antigens modulate adaptive immune system and innate immune system by interacting with T cell receptor and KIR receptors. The alleles define the histocompatibility in transplantation and they are also associated with certain diseases and drug response, e.g. insulin dependent diabetes mellitus, rheumatoid arthritis and multiple sclerosis. In addition, Class II antigens HLA-DQA1*01 and HLA-DR4 have been suggested as a potential risk factor in developing ME/CFS, which we study with the support of OMF. The HLA gene family has the most polymorphic genes in human genome. There are about 20,000 alleles identified at the 19 HLA genes and the number keeps increasing with the advances of NGS technology and the application on HLA typing. It is observed that the survival rate of organ transplantation would increase when the HLA genes of the donor and the recipient have allele-level matching. Therefore, not only SNP genotypes are required, building phased genomic sequences are necessary for clinical use.

To evaluate the capability of NGS for HLA typing, we worked with Stanford Blood Center in the 17th International HLA & Immunogenetics Workshop and Conference and collected HLA typing results of the same set of samples typed by multiple laboratories with their own set of reagent, hardwares and software. Standards for HLA typing were built and applied for typing reports generated by different vendors to make the typings comparable.  

 
 

To define epitopes leading to antibody production against HLA, we used an reverse engineering strategy to detect epitopes shared by groups of transplantation recipients with the same set of donor specific antibodies.  

Currently, we are working with Stanford Blood Center for genotyping of KIR genes, which have more homologous genes than HLA and have CNVs, which make typing more challenging. 

This project has been funded by grants from NIH and the Open Medicine Foundation

 

Dr. Chia-Jung Chang is in charge of this project.

PUBLICATIONS

  • Chang, C.-J., Chen, P.-L., Yang, W.-S. & Chao, K.-M. A fault-tolerant method for HLA typing with PacBio data. BMC bioinformatics 15, 296 (2014).
  • Chang, C.-J., Osoegawa, K., Milius, R. P., Maiers, M., Xiao, W., Fernandez-Vi{\v{n}}a, M. & Mack, S. J. Collection and storage of HLA NGS genotyping data for the 17th International HLA and Immunogenetics Workshop. Human immunology 79, 77-86 (2018).
  • Osoegawa, K., Vayntrub, T. A., Wenda, S., De Santis, D., Barsakis, K., Ivanova, M., Hsu, S., Barone, J., Holdsworth, R., Diviney, M. & others, Quality control project of NGS HLA genotyping for the 17th International HLA and Immunogenetics Workshop. Human immunology , (2019).
  • Chang, C.-J., Yamamoto, F. & Tyan, D. B. A Reverse-Engineering Strategy Utilizing the Integration of Single Antigen Beads and NGS HLA Genotypes to Detect Potential Antibody Inducing Epitopes. Human immunology , (2019).
  • Creary, L. E., Guerra, S. G., Chong, W., Brown, C. J., Turner, T. R., Robinson, J., Bultitude, W. P., Mayor, N. P., Marsh, S. G., Saito, K. & others, Next-generation HLA typing of 382 International Histocompatibility Working Group reference B-Lymphoblastoid cell lines: report from the 17th International HLA and Immunogenetics Workshop. Human immunology , (2019).
  • Yamamoto, F., Wang, L., Chang, C.-J. & Tyan, D. B. Mapping and definition of HLA class I and II serologic epitopes using an unbiased reverse engineering strategy. Human immunology , (2019).