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

下一代 MHC 分型的最大分辨率和全长定相

• 批准号: 9411580
• 负责人: Siddarth Selvaraj
• 金额: $ 4.95万
• 依托单位: ARIMA GENOMICS, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-12 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9411580
• 关键词: Algorithms; Alleles; Allogenic; Allografting; Biology; Blood specimen; Cells; Chromosomes; Clinical; Computational algorithm; DNA; DNA Probes; DNA sequencing; Data; Disease; Elements; Genes; Genetic Polymorphism; Genetic Variation; Genome; Genomics; Haplotypes; Health; Hematopoietic Stem Cell Transplantation; Human; Human Genetics; Human Genome; Hybrids; Immune; Immune System Diseases; Immunogenetics; Individual; Investigation; Joints; Knowledge; Laboratories; Lead; Length; Libraries; Linkage Disequilibrium; Major Histocompatibility Complex; Medicine; Methods; Modeling; Nature; Oligonucleotides; Organ Transplantation; Outcome; Patient-Focused Outcomes; Patients; Pattern; Phase; Play; Procedures; Reaction; Research; Resolution; Role; Sampling; Techniques; Technology; Transplantation; Untranslated RNA; Variant; adverse outcome; base; clinical application; clinically relevant; cohesion; cost; cost effective; density; experimental study; genotyping technology; human leukocyte antigen testing; immune health; improved; innovation; new technology; next generation; next generation sequencing; novel; novel strategies; personalized medicine; population based; prospective; research and development; restriction enzyme; sample collection

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.

用于下一代MHC分型的最大分辨率和全长定相 Arima Genomics 7.项目总结/摘要 主要组织相容性复合体（MHC）基因座是基因组中最具多态性的基因座之一， 携带在人类免疫健康和疾病中起关键作用的基因。的多态性 MHC基因座允许编码具有独特免疫细胞谱的每个个体，因此，匹配HLA基因 在捐赠者和接受者之间进行免疫接种是减轻器官移植后免疫排斥反应的关键步骤。 移植下一代测序技术的进步提高了DNA的普及程度 测序作为HLA基因座分型的手段，用于其临床相关性。目前的HLA分型技术 忽略潜在重要DNA变异，在低分辨率下逐个基因分型， MHC基因座中的非HLA基因和其他非编码等位基因，这些基因是最佳供体-受体 匹配. Arima Genomics最近开发了一种创新的新方法， 基于我们专有的HaploSeq技术， 在人类基因组中构建跨染色体单倍型。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 HLA基因座定相到单个单倍型块上， 精确度仅为2倍测序深度。作为一种具有成本效益的下一代单体型分析技术， HaploSeq-Mx有望成为高分辨率跨基因座MHC分型的新标准。的 Arima Genomics提出的研发目标包括提高HaploSeq-Mx的靶向效率， 进一步降低测序成本并将该方法推进到临床实用， 进一步将HaploSeq-Mx的准确性提高到> 99.5%的方法，并证明了 HaploSeq-Mx用于造血干细胞移植（HSCT）研究中的患者样品的MHC分型， UCSD中心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（CALM），同时开发一种新的算法供受体匹配。 成功完成我们的研究目标将为正在进行的调查提供宝贵的新知识 人类遗传变异如何影响移植患者的结果，并将大大推动 我们的HLA分型技术在临床应用中的商业可行性。HaploSeq-Mx 有望大大提高我们对人类健康遗传学的理解，并有助于实现 个性化医疗