Assembly and re-alignment of HLA genomic region and its implication for fine-mapping suicidality in African descent population

项目摘要/摘要 技术正在迅速扩展我们对人类遗传密码和人类基因变化的知识 易患疾病；然而，少数群体(例如，非裔美国人)很少被包括在 基因组研究的发现分支。作为一个特定的基因组区域，主要组织相容性复合体 (MHC)包含人类白细胞抗原(HLA)基因和变异对 它们在呈递外来抗原和启动适应性免疫反应中的作用。然而，之前的MHC 基因组资源和相关的疾病基因发现大多是丰富的非西班牙裔白人个体。 即使使用最常用的短程猎枪，这一领域也很难破译 测序。这阻碍了免疫学基础上的功能性人类白细胞抗原变异的鉴定过程 不同人群的相关心理健康状况。新的测序技术(阅读已久)和 需要人口规模的非洲样本来弥补这一知识差距。最近我们取得了一些进展 访问所有美国(AOU)控制层数据(例如，长读和短读全基因组测序，WGS)和 英国生物库(UKB)WGS数据，由24,000名非洲裔参与者组成。我们的总体目标是 确定人类白细胞抗原长单倍型，并创建最详细的MHC区域参考图谱 并利用这一新知识精细绘制自杀表型的人类白细胞抗原基因座图。在……里面 第一个目标，我们假设一种同时具有短读和长读测序数据的混合组装方法 提供了相位模糊问题的解决方案。我们将产生非洲特有的人类白细胞抗原单倍型 组装，然后调用，分配，和阶段的所有非洲/黑人样本在AOU和 UKB。在第二个目标中，我们假设自杀中存在直接和间接的人类白细胞抗原遗传效应。 思想和行为(STB)。除了发现人类白细胞抗原变异和与STB及其相关基因 AOU中的相关炎症标志物，我们将进一步复制UKB中的顶级关联并对HLA进行注释 通过整合组学方法构建功能单元。更全面地描述非洲人群中的人类白细胞抗原变异 是一项重大而重要的创新，它对自杀基因组学的影响从未被做过 之前在这样的决议下。预计会生成针对云计算定制的分析管道和MHC资源 为了支持AOU研究员工作台中的大型项目，该工作台在精度上结合了HLA效果 医药。除了我们预期的精细定位变异和基因的研究目标外， STB，识别非洲人后裔独有的HL A等位基因也有以下切实的好处 改善移植和严重精神疾病的临床护理。

PROJECT SUMMARY/ABSTRACT Technology is rapidly expanding our knowledge of the human genetic code and the alterations which predispose to disease; however, minority populations (e.g., African Americans) are rarely included in the discovery arms of genomic studies. As a particular genomic region, the major histocompatibility complex (MHC) that encompasses the human leukocyte antigen (HLA) genes and variations are critically important for their role in presenting foreign antigens and initiating adaptive immune responses. However, previous MHC genomic resource and relevant disease gene findings were mostly enriched for non-Hispanic White individuals. This area has been intractably difficult to decipher even with the most commonly used short-read shotgun sequencing. This impedes the process for identification of functional HLA variants underlying immunologically relevant mental health conditions in diverse populations. New sequencing technology (long-read) and population-scale African samples are needed to address this knowledge gap. Recently we have gained access to All of US (AoU) controlled tier data (e.g., long- and short-read whole-genome sequencing, WGS) and UK Biobank (UKB) WGS data, consisting of >24,000 participants of African descent. Our overall goal is to identify HLA long haplotypes and create the most detailed reference map of the MHC region for individuals of African descent, and to leverage this new knowledge for fine-mapping HLA locus for suicidality phenotypes. In the first aim, we hypothesize that a hybrid assembly approach with both short- and long-read sequencing data provides a solution to the phasing ambiguity problem. We will generate African-specific HLA haplotype assembly, then call, impute, and phase HLA variants and haplotypes for all African/Black samples in AoU and UKB. In the second aim, we assume both direct and indirect HLA genetic effects are present in suicidal thoughts and behaviors (STB). In addition to discover HLA variations and genes associated with STB and its related inflammatory markers in AoU, we will further replicate top associations in UKB and annotate HLA functional units by integrative omics approaches. More fully characterizing HLA variation in African populations is both a significant and important innovation, and its implication for suicide genomics has never been done before at such a resolution. The cloud-tailored analytical pipeline and MHC resources generated is expected to support large projects in the AoU Researcher workbench that incorporates HLA effects in precision medicine. In addition to our intended research goal of fine-mapping variants and genes which contribute to STB, identifying HLA alleles that are exclusive to individuals of African descent also has the tangible benefit of improving clinical care for transplantation and serious mental illness.