Allele imputation for the killer cell immunoglobulin-like receptor KIR3DL1/S1.
Allele imputation for the killer cell immunoglobulin-like receptor KIR3DL1/S1.
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DOI：
10.1371/journal.pcbi.1009059
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发表时间：
2022-03
影响因子：
4.3
通讯作者：
Norman PJ
中科院分区：
文献类型：
--
作者：
Harrison GF;Leaton LA;Harrison EA;Kichula KM;Viken MK;Shortt J;Gignoux CR;Lie BA;Vukcevic D;Leslie S;Norman PJ
KIR 3DL 1和KIR 3DS 1与HLA I类配体的高度多态性相互作用调节自然杀伤（NK）细胞和一些T细胞的效应子功能。这种遗传决定的多样性影响感染，免疫介导的疾病和某些癌症的严重程度，并影响免疫治疗（包括移植）的过程。KIR 3DL 1是抑制性受体，KIR 3DS 1是由KIR 3DL 1/S1基因编码的激活性受体，该基因具有200多种多样和不同的等位基因。用于医学应用的KIR 3DL 1/S1基因型的确定受到复杂序列和结构变异的阻碍，需要有针对性的方法来生成和分析高分辨率等位基因数据。为了克服这些障碍，我们开发并优化了一个模型，用于从全基因组SNP数据中以高分辨率插补KIR 3DL 1/S1等位基因。我们设计的模型代表了人类遗传多样性的一个重要组成部分。我们的全球插补模型在KIR 3DL 1/S1等位基因分型方面是有效的，准确率从非洲人的88%到东亚人的97%，对于>1%频率的等位基因，平均特异性为99%，灵敏度为95%。我们使用了HIBAG程序的既定算法，在一个名为“拉出自然杀伤细胞基因组学”（PONG）的修改中。因为HIBAG被设计成也从全基因组SNP数据中估算HLA等位基因，所以PONG允许在单个数据源上使用互补技术来分析KIR 3DL 1/S1与HLA-A和-B的组合多样性。因此，PONG的使用否定了在非常大规模的关联研究中对靶向测序数据的需要，其中这种方法可能不容易处理。自然杀伤（NK）细胞是细胞毒性淋巴细胞，识别和杀死感染或恶性细胞，并引导免疫反应。NK细胞的效应子功能通过其表面上的KIR 3DL 1/S1与人体中大多数其他细胞类型上发现的人白细胞抗原（HLA）的多态性相互作用来调节。KIR 3DL 1/S1在人群中具有高度多态性和分化性，影响多种免疫介导疾病及其治疗的易感性和病程。用于直接医学应用或研究的基因分型KIR 3DL 1/S1一直受到复杂序列和结构变异的阻碍，这需要有针对性的方法和广泛的领域专业知识来生成和验证高分辨率等位基因调用。因此，我们开发了Pulling Out Natural Killer Cell Genomics（PONG），从全基因组SNP数据中估算KIR 3DL 1/S1等位基因，并将其作为开源R包实现。我们使用代表人类遗传多样性的很大一部分的五个广泛人群组的数据评估了插补性能。我们可以估算KIR 3DL 1/S1等位基因的准确性范围从非洲人的88%到东亚人的97%。在全球范围内，频率>1%的KIR 3DL 1/S1等位基因的插补具有95%的平均灵敏度和99%的特异性。因此，PONG方法既能够实现高灵敏度的个体水平的调用，也使得KIR 3DL 1/S1的大规模医学遗传研究成为可能。
Highly polymorphic interaction of KIR3DL1 and KIR3DS1 with HLA class I ligands modulates the effector functions of natural killer (NK) cells and some T cells. This genetically determined diversity affects severity of infections, immune-mediated diseases, and some cancers, and impacts the course of immunotherapies, including transplantation. KIR3DL1 is an inhibitory receptor, and KIR3DS1 is an activating receptor encoded by the KIR3DL1/S1 gene that has more than 200 diverse and divergent alleles. Determination of KIR3DL1/S1 genotypes for medical application is hampered by complex sequence and structural variation, requiring targeted approaches to generate and analyze high-resolution allele data. To overcome these obstacles, we developed and optimized a model for imputing KIR3DL1/S1 alleles at high-resolution from whole-genome SNP data. We designed the model to represent a substantial component of human genetic diversity. Our Global imputation model is effective at genotyping KIR3DL1/S1 alleles with an accuracy ranging from 88% in Africans to 97% in East Asians, with mean specificity of 99% and sensitivity of 95% for alleles >1% frequency. We used the established algorithm of the HIBAG program, in a modification named Pulling Out Natural killer cell Genomics (PONG). Because HIBAG was designed to impute HLA alleles also from whole-genome SNP data, PONG allows combinatorial diversity of KIR3DL1/S1 with HLA-A and -B to be analyzed using complementary techniques on a single data source. The use of PONG thus negates the need for targeted sequencing data in very large-scale association studies where such methods might not be tractable. Natural killer (NK) cells are cytotoxic lymphocytes that identify and kill infected or malignant cells and guide immune responses. The effector functions of NK cells are modulated through polymorphic interactions of KIR3DL1/S1 on their surface with the human leukocyte antigens (HLA) that are found on most other cell types in the body. KIR3DL1/S1 is highly polymorphic and differentiated across human populations, affecting susceptibility and course of multiple immune-mediated diseases and their treatments. Genotyping KIR3DL1/S1 for direct medical application or research has been encumbered by the complex sequence and structural variation, which requires targeted approaches and extensive domain expertise to generate and validate high-resolution allele calls. We therefore developed Pulling Out Natural Killer Cell Genomics (PONG) to impute KIR3DL1/S1 alleles from whole genome SNP data, and which we implemented as an open-source R package. We assessed imputation performance using data from five broad population groups that represent a substantial portion of human genetic diversity. We can impute KIR3DL1/S1 alleles with an accuracy ranging from 88% in Africans to 97% in East Asians. Globally, imputation of KIR3DL1/S1 alleles having frequency >1% has a mean sensitivity of 95% and specificity of 99%. Thus, the PONG method both enables highly sensitive individual-level calling and makes large scale medical genetic studies of KIR3DL1/S1 possible.
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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：
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作者：
Diaz-Pena, Roberto;Ramon Vidal-Castineira, Jose;Lopez-Larrea, Carlos
通讯作者：
Lopez-Larrea, Carlos
影响因子：
7.3
作者：
Deng, Zhihui;Zhao, Jun;Norman, Paul J.
通讯作者：
Norman, Paul J.
影响因子：
4.3
作者：
Dilthey, Alexander;Leslie, Stephen;McVean, Gil
通讯作者：
McVean, Gil
影响因子：
10.9
作者：
Erbe, Amy K.;Wang, Wei;Sondel, Paul M.
通讯作者：
Sondel, Paul M.