An ethnically diverse genomic reference resource for the human heavy and light chain immunoglobulin loci

项目总结 我们对免疫球蛋白(IG)胚系变异的理解存在一个根本的差距 (IgH)和轻链(Kappa，IGK；lambda，IGL)基因座影响人的发育 功能性抗体在健康和疾病中的反应。然而，人们越来越多地认识到这样一个事实 免疫球蛋白多态有助于抗体谱系的可变性，表明免疫球蛋白基因数据的整合 在基础和生物医学研究中可以帮助我们理解免疫球蛋白基因的调控，以及抗体 曲目动态，在不同的临床背景下的功能。取得进展的一个关键障碍是现有的 IG基因座的基因组资源是不完整的，并且不能很好地代表人类群体的多样性， 尤其是那些来自非欧洲祖先的人。不断积累的证据支持这样一种观点 IG区是人类基因组中结构最复杂和最多态的区域之一，富含 对于大结构变异(SVS)和单核苷酸变异(SNV)，导致极端的个体间 单倍型变异。这些复杂性长期以来使得使用标准的高密度脂蛋白基因座研究IG基因座变得困难。 吞吐量方法，对遗传病关联研究和最近的 适应性免疫受体谱系测序(AIRR-SEQ)数据分析。因此，人类的知识 IG种系多样性，特别是在基因组数据库中代表性不足的人群中的多样性及其贡献 疾病的发病率远远落后于其他经过充分研究的免疫基因。这突显了直接需要公开 来自不同种族的可用的、特征明确的IG单倍型参考和准确的变异目录 背景帮助设计和集成更准确的基因分型工具、分析管道和 他们的解释。为了满足这些需求，我们制定了这项更新建议，它将建造最多的 迄今为止全面的免疫球蛋白基因组数据集，对B细胞领域具有变革性的潜在影响 免疫学和免疫遗传学。所产生的资源将：(1)阐明IG多样性的程度 世界范围内；(2)建立一个框架，将基因数据与表达的抗体谱系变异联系起来，以告知 我们对V(D)J重组和抗体库动力学种子模型的理解；以及(Iii) 大幅增加关键数据库和研究计划，推动基因组学和免疫学的前沿 研究。这一更新项目将在基础IG基因组数据的基础上无缝构建和扩展 在我们最初的提案中产生并继续为人类建立急需的基因组资源 IG基因座，特别是在代表性不足的人群和与生物医学直接相关的队列中，这将 在未来几年为免疫学和更大的基因组学社区服务。

PROJECT SUMMARY There is a fundamental gap in our understanding of how germline variation in the immunoglobulin (IG) heavy (IGH) and light chain (kappa, IGK; lambda, IGL) loci in the human population impacts the development of the functional antibody (Ab) response in health and disease. However, there is growing appreciation for the fact that IG polymorphism contributes to variability in the Ab repertoire, indicating that the integration of IG genetic data in basic and biomedical research can inform our understanding of how IG gene regulation, as well as Ab repertoire dynamics, function in various clinical contexts. A critical barrier to progress has been that existing genomic resources for the IG loci are incomplete and poorly represent diversity across human populations, particularly those from non-European ancestries. Evidence continues to accumulate in support of the notion that the IG regions are among the most structurally complex and polymorphic regions of the human genome, enriched for large structural variants (SVs) and single nucleotide variants (SNVs), resulting in extreme interindividual haplotype variation. These complexities have long made the IG loci difficult to study using standard high- throughput methods, with direct negative impacts on genetic disease association studies and, more recently, the analysis of adaptive immune receptor repertoire sequencing (AIRR-seq) data. As a result, knowledge of human IG germline diversity, particularly in populations underrepresented in genomics databases, and its contribution to disease lags far behind that of other well-studied immune loci. This highlights a direct need for publicly available, well-characterized IG haplotype references and accurate variant catalogues from diverse ethnic backgrounds to facilitate the design and integration of more accurate genotyping tools, analysis pipelines, and their interpretation. To meet these needs, we have developed this renewal proposal, which will build the most comprehensive IG genomic dataset to date, with transformative potential impact for the fields of B cell immunology and immunogenetics. The resource generated will: (i) shed light on the extent of IG diversity worldwide; (ii) establish a framework for linking genetic data to expressed antibody repertoire variation to inform our understanding of V(D)J recombination and seed models of antibody repertoire dynamics; and (iii) substantially augment key databases and research initiatives pushing the frontiers of genomics and immunology research. This renewal project will seamlessly build and expand upon the foundational IG genomics data generated in our initial proposal and continue to establish desperately needed genomic resources for the human IG loci, particularly in underrepresented populations and cohorts of immediate biomedical relevance, which will serve the immunology and larger genomics communities for years to come.