Maximal resolution and full-length phasing for next-generation MHC-typing

新一代MHC分型的最大分辨率和全长相移 ARIMA基因组学 7.项目摘要/摘要 主要组织相容性复合体(MHC)基因座是基因组中最多态的基因座之一，并且 含有在人类免疫健康和疾病中发挥关键作用的基因。的多态性质 MHC基因座允许编码每个具有独特免疫细胞特征的个体，因此，匹配的人类白细胞抗原基因 捐赠者和接受者之间的合作是减少器官移植后免疫排斥反应的关键一步 移植。下一代测序技术的进步增加了DNA的普及 测序作为人类白细胞抗原基因座分型的一种手段，其临床意义。然而，目前的人类白细胞抗原配型技术 忽略潜在的重要DNA变异，以低分辨率逐个基因分型，无法进入单倍型阶段 最佳供受者所必需的MHC基因座上的非人类白细胞抗原基因和其他非编码等位基因 匹配。ARIMA基因组公司最近开发了一种创新的新方法来产生全长 高分辨率的MHC基因座单倍型，以我们专有的HaploSeq技术为基础 在人类基因组中构建跨越染色体的单倍型。我们的新技术“HaploSeq-Mx” 能够以~91%的分辨率和~99%的分辨率将整个3.5MB的HLA位点分相到单个单倍型块上 精确度只有2倍的测序深度。作为一种具有成本效益的下一代单倍型技术， HaploSeq-Mx已准备好支持高分辨率跨区域MHC分型的新标准。这个 ARIMA基因组公司拟议的研发工作的目标包括提高HaploSeq-Mx的靶向效率，以 进一步降低测序成本并将该方法推广到临床应用，开发计算 将HaploSeq-Mx的准确率进一步提高到99.5%的方法，并论证了 HaploSeq-Mx在一项造血干细胞移植(HSCT)研究中用于MHC分型 加州大学圣迭戈分校免疫遗传学和移植实验室(ITL)的临床合作者 高级实验室医学(CAME)，同时开发一种供受者匹配的新算法。 成功完成我们的研究目标将为正在进行的研究贡献宝贵的新知识 人类基因变异如何影响移植患者的结果，并将显著促进 我们的人类白细胞抗原配型技术在临床应用中的商业可行性。单序列-Mx 承诺极大地提高我们对人类遗传学在健康方面的理解，并为实现 个性化医疗。

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.