利用基于单倍型的 HLA 基因型估算,量化错误标记的祖先所带来的分子错配的不确定性。

IF 2.8 3区 生物学 Q2 GENETICS & HEREDITY Frontiers in Genetics Pub Date : 2024-09-25 eCollection Date: 2024-01-01 DOI:10.3389/fgene.2024.1444554
Benedict M Matern, Eric Spierings, Selle Bandstra, Abeer Madbouly, Stefan Schaub, Eric T Weimer, Matthias Niemann
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引用次数: 0

摘要

引言现代组织相容性算法依赖于高分辨率 HLA 蛋白序列和结构的比较与分析,特别是在考虑基于表位的算法时,这种算法旨在模拟抗体或 T 细胞结合过程中的相互作用。在只有低/中分辨率 HLA 基因型或特定位点缺失的情况下,可以进行 HLA 基因型推算,通过提供个体的种族/民族/血统信息,推算结果可以更加准确。本研究评估了在各种祖先假设下,高分辨率基因型的归因对分子错配得分的影响:方法:我们比较了来自 "地面实况 "高分辨率基因型的分子配对得分和来自低分辨率基因型归因的基因型得分。分析的重点是模拟患者-捐献者数据集,并使用两个真实世界数据集进行确认,根据不同的祖先假设对偏差进行汇总:我们观察到,与单次归因相比,使用多次归因通常会导致分子匹配分数的误差降低,而且使用正确的祖先假设可以减少归因过程中引入的误差:我们得出结论:对于表位分析,只要注意表位分析的背景、祖先假设和(多重)归因策略,归因是一种有价值的低风险策略。
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Quantifying uncertainty of molecular mismatch introduced by mislabeled ancestry using haplotype-based HLA genotype imputation.

Introduction: Modern histocompatibility algorithms depend on the comparison and analysis of high-resolution HLA protein sequences and structures, especially when considering epitope-based algorithms, which aim to model the interactions involved in antibody or T cell binding. HLA genotype imputation can be performed in the cases where only low/intermediate-resolution HLA genotype is available or if specific loci are missing, and by providing an individuals' race/ethnicity/ancestry information, imputation results can be more accurate. This study assesses the effect of imputing high-resolution genotypes on molecular mismatch scores under a variety of ancestry assumptions.

Methods: We compared molecular matching scores from "ground-truth" high-resolution genotypes against scores from genotypes which are imputed from low-resolution genotypes. Analysis was focused on a simulated patient-donor dataset and confirmed using two real-world datasets, and deviations were aggregated based on various ancestry assumptions.

Results: We observed that using multiple imputation generally results in lower error in molecular matching scores compared to single imputation, and that using the correct ancestry assumptions can reduce error introduced during imputation.

Discussion: We conclude that for epitope analysis, imputation is a valuable and low-risk strategy, as long as care is taken regarding epitope analysis context, ancestry assumptions, and (multiple) imputation strategy.

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来源期刊
Frontiers in Genetics
Frontiers in Genetics Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
5.50
自引率
8.10%
发文量
3491
审稿时长
14 weeks
期刊介绍: Frontiers in Genetics publishes rigorously peer-reviewed research on genes and genomes relating to all the domains of life, from humans to plants to livestock and other model organisms. Led by an outstanding Editorial Board of the world’s leading experts, this multidisciplinary, open-access journal is at the forefront of communicating cutting-edge research to researchers, academics, clinicians, policy makers and the public. The study of inheritance and the impact of the genome on various biological processes is well documented. However, the majority of discoveries are still to come. A new era is seeing major developments in the function and variability of the genome, the use of genetic and genomic tools and the analysis of the genetic basis of various biological phenomena.
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