High-Resolution Characterization of KIR Genes in a Large North American Cohort Reveals Novel Details of Structural and Sequence Diversity.
High-Resolution Characterization of KIR Genes in a Large North American Cohort Reveals Novel Details of Structural and Sequence Diversity.
复制标题
大型北美队列中 KIR 基因的高分辨率表征揭示了结构和序列多样性的新细节。
DOI：
10.3389/fimmu.2021.674778
复制
发表时间：
2021
影响因子：
7.3
通讯作者：
Hollenbach JA
中科院分区：
文献类型：
--
作者：
Amorim LM;Augusto DG;Nemat-Gorgani N;Montero-Martin G;Marin WM;Shams H;Dandekar R;Caillier S;Parham P;Fernández-Viña MA;Oksenberg JR;Norman PJ;Hollenbach JA
KIR（免疫细胞免疫球蛋白样受体）区域的特征在于基因之间的结构变异和高序列相似性，这给分析带来了技术困难。我们进行了迄今为止最全面的研究，在一个大的人口样本中的KIR遗传多样性，应用下一代测序在2,130个美国欧洲后裔的个人。使用我们专门设计的定制生物信息学管道分析数据，以解决确定KIR基因型的技术障碍。精确的基因拷贝数确定使我们能够识别一组不常见的基因含量KIR单倍型，占结构变异的5.2%。在这个队列中，KIR 2DL 4是拷贝数变化最大的框架基因（占所有个体的6.5%）。我们确定了大的多位点插入中的分阶段高分辨率等位基因，以及它们被删除的可能的创始人单倍型。此外，我们在5位数分辨率下观察到250个等位基因，其中90个频率≥ 1%。我们发现了与398（18.7%）个人中存在新等位基因一致的序列模式，并在KIR复合物中发现了多个孤儿dbSNP。我们还鉴定了一种新的KIR 2DL 1变体Pro 151 Arg，并通过分子动力学证明这种取代预计会影响与HLA-C的相互作用。没有以前的研究已经充分探讨了KIR的结构和序列变异的全方位，因为我们在这里。我们证明，配对高通量测序与国家的最先进的计算工具，在一个大的队列允许探索KIR变异的各个方面，包括确定人口水平的单倍型多样性，提高对KIR系统的理解，并为未来的研究提供了重要的参考。
The KIR (killer-cell immunoglobulin-like receptor) region is characterized by structural variation and high sequence similarity among genes, imposing technical difficulties for analysis. We undertook the most comprehensive study to date of KIR genetic diversity in a large population sample, applying next-generation sequencing in 2,130 United States European-descendant individuals. Data were analyzed using our custom bioinformatics pipeline specifically designed to address technical obstacles in determining KIR genotypes. Precise gene copy number determination allowed us to identify a set of uncommon gene-content KIR haplotypes accounting for 5.2% of structural variation. In this cohort, KIR2DL4 is the framework gene that most varies in copy number (6.5% of all individuals). We identified phased high-resolution alleles in large multi-locus insertions and also likely founder haplotypes from which they were deleted. Additionally, we observed 250 alleles at 5-digit resolution, of which 90 have frequencies ≥1%. We found sequence patterns that were consistent with the presence of novel alleles in 398 (18.7%) individuals and contextualized multiple orphan dbSNPs within the KIR complex. We also identified a novel KIR2DL1 variant, Pro151Arg, and demonstrated by molecular dynamics that this substitution is predicted to affect interaction with HLA-C. No previous studies have fully explored the full range of structural and sequence variation of KIR as we present here. We demonstrate that pairing high-throughput sequencing with state-of-art computational tools in a large cohort permits exploration of all aspects of KIR variation including determination of population-level haplotype diversity, improving understanding of the KIR system, and providing an important reference for future studies.
登录
查看更多内容
影响因子：
3.7
作者：
Augusto DG;Lobo-Alves SC;Melo MF;Pereira NF;Petzl-Erler ML
通讯作者：
Petzl-Erler ML
影响因子：
64.8
作者：
Fan, QR;Mosyak, L;Wiley, DC
通讯作者：
Wiley, DC
影响因子：
--
作者：
Crum, KA;Logue, SE;Middleton, D
通讯作者：
Middleton, D
影响因子：
3.7
作者：
Augusto DG
通讯作者：
Augusto DG
DOI：
10.1073/pnas.0906051106
发表时间：
2009-11-03
影响因子：
11.1
作者：
Gendzekhadze, Ketevan;Norman, Paul J.;Parham, Peter
通讯作者：
Parham, Peter