Looking to the future of antibody genetics: resolving the roles of immunoglobulin diversity in gene regulation, function, and immunity.
Looking to the future of antibody genetics: resolving the roles of immunoglobulin diversity in gene regulation, function, and immunity.
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展望抗体遗传学的未来：解决免疫球蛋白多样性在基因调控、功能和免疫中的作用。
DOI：
10.1038/s41435-023-00238-3
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发表时间：
2024
影响因子：
5
通讯作者：
Smith,MelissaL
中科院分区：
文献类型：
--
作者：
Watson,CoreyT;Rodriguez,OscarL;Engelbrecht,Eric;Safonova,Yana;Marasco,WayneA;Smith,MelissaL
在我们最近的文章[1]中，我们将人免疫球蛋白重链（IGH）基因座的靶向长读单分子实时（SMRT）测序与来自不同遗传血统的健康供体队列中血细胞的表达适应性免疫受体库测序（AIRR-seq）相结合。通过这些数据，我们发现了IGH种系变异与循环抗体（Ab）库变异之间的直接联系，确立了遗传因素在设定个体Ab应答基线方面的基本作用。我们对IGH单倍型多样性进行了迄今为止最全面的调查，并克服了历史上挑战遗传学的技术障碍。在该地区进行调查。我们广泛地分类了新的IGH多态性，包括单核苷酸变异（SNV）、小插入缺失（indels）和大结构变异（SV），这些多态性与IGH可变（IGHV）、多样性（IGHD）和连接（IGHJ）基因在表达的重排重链转录本（“基因使用”）中观察到的频率相关。我们将这些变异称为基因使用数量性状位点（guQTL），并发现它们包括所有形式的IG种系变异，在某些情况下，解释了整个人群中给定基因使用的高达70%的变异。这包括由于遗传基因缺失而导致基因在个体谱系中完全缺失的例子。重要的是，我们表明，这些影响可以在幼稚（IgM）和抗原刺激（IgG）库中观察到，表明生殖系多态性对免疫应答期间可用于参与的循环受体的广泛影响的潜力。
In our recent article [1], we combined targeted long-read single-molecule real-time (SMRT) sequencing of the human immunoglobulin heavy chain (IGH) locus with expressed adaptive immune receptor repertoire sequencing (AIRR-seq) from blood cells in a cohort of healthy donors of diverse genetic ancestry. With these data, we uncovered direct links between IGH germline variation and variability in the circulating antibody (Ab) repertoire, establishing a fundamental role for heritable factors in setting the baseline for an individual’s Ab response.Leveraging the strengths of highly accurate, long-read sequencing, we conducted the most comprehensive survey of IGH haplotype diversity to date and overcame technical hurdles that have historically challenged genetic investigations in this region. We extensively cataloged novel IGH polymorphisms, including single nucleotide variants (SNVs), small insertiondeletions (indels), and large structural variants (SVs), that are associated with the frequency at which IGH variable (IGHV), diversity (IGHD), and joining (IGHJ) genes are observed among expressed rearranged heavy chain transcripts (“gene usage”). We termed these variants gene usage quantitative trait loci (guQTLs) and revealed that they were inclusive of all forms of IG germline variation, in some cases, explaining up to~ 70% of variation in usage of a given gene across the population. This includes examples in which genes were completely absent from individual repertoires due to inherited gene deletions. Critically, we showed that these effects could be observed across both naive (IgM) and antigen-stimulated (IgG) repertoires, indicating the potential for broad effects of germline polymorphism on circulating receptors that are available for engagement during an immune response.