Maximal resolution and full-length phasing for next-generation MHC-typing Arima Genomics 7. Project Summary/Abstract The Major Histocompatibility complex (MHC) locus is among the most polymorphic loci in the genome, and harbors genes that play critical roles in human immune health and disease. The polymorphic nature of the MHC locus allows for encoding every individual with a unique immune cell profile, hence, matching HLA genes among donors and recipients has been a critical step in mitigating immune rejections following organ transplants. Advances in next-generation sequencing technologies have increased the popularity of DNA sequencing as a means of typing the HLA locus for its clinical relevance. Yet current HLA typing technologies ignore potentially important DNA variants, type gene-by-gene at low resolution, and fail to haplotype phase non-HLA genes and other non-coding alleles in the MHC locus that are necessary for optimal donor-recipient matching. Arima Genomics has recently developed an innovative new approach to generate full-length haplotypes of the MHC locus at high-resolution, building on our proprietary HaploSeq technology for constructing chromosome-spanning haplotypes in the human genome. Our new technology, HaploSeq-Mx is capable of phasing the entire 3.5Mb HLA locus onto a single haplotype block at ~91% resolution and ~99% accuracy with just 2x sequencing depth. As a cost-effective, next-generation haplotyping technology, HaploSeq-Mx is poised to underpin a new standard in high-resolution locus-spanning MHC typing. The objectives of Arima Genomics' proposed R&D efforts involve improving HaploSeq-Mx's targeting efficiency to further reduce sequencing costs and advance the method to clinical utility, developing computational approaches to improve the accuracy of HaploSeq-Mx even further to >99.5%, and demonstrating feasibility of HaploSeq-Mx for MHC typing patient samples in a hematopoietic stem cell transplantation (HSCT) study with clinical collaborators at the Immunogenetics and Transplantation Laboratory (ITL) at the UCSD Center for Advanced Laboratory Medicine (CALM), while developing a new algorithm for donor-recipient matching. Successful completion of our research aims will contribute invaluable new knowledge to ongoing investigations of how human genetic variation influences patient outcomes in transplants, and will substantially advance the capabilities of our HLA typing technology toward commercial viability in clinical applications. HaploSeq-Mx promises to greatly enhance our understanding of human genetics in health and contribute to the realization of personalized medicine.
Maximal resolution and full-length phasing for next-generation MHC-typing Arima Genomics 8. Project Narrative Determining the haplotype of the MHC locus, or MHC-typing, is a critical step in identifying potential matches between donors and recipients for allogeneic transplants, but current methods evaluate only 5 HLA genes, missing information from hundreds of other genes as well as non-coding elements in this locus. Consequently, this can lead to potential adverse outcomes due to suboptimal MHC matching. Arima Genomics recently extended our innovative HaploSeq technology as a novel, cost-effective approach to accurately haplotype the entire human MHC locus at high resolution to phase HLA genes, non-HLA genes and non-coding elements in a single haplotype. This new HaploSeq-Mx method will enable high-fidelity matching of donor and recipient for hematopoietic stem cell transplants and other allograft procedures, and will contribute to a greater understanding of the human genome's role in transplant outcomes.