Mallawaarachchi Sudaraka, Tonkin-Hill Gerry, Croucher Nicholas J, Turner Paul, Speed Doug, Corander Jukka, Balding David
Melbourne Integrative Genomics, School of Mathematics and Statistics, University of Melbourne, VIC 3010, Australia.
Parasites and Microbes, Wellcome Sanger Institute, Cambridge CB10 1SA, UK.
NAR Genom Bioinform. 2022 Feb 22;4(1):lqac011. doi: 10.1093/nargab/lqac011. eCollection 2022 Mar.
Whole-genome sequencing has facilitated genome-wide analyses of association, prediction and heritability in many organisms. However, such analyses in bacteria are still in their infancy, being limited by difficulties including genome plasticity and strong population structure. Here we propose a suite of methods including linear mixed models, elastic net and LD-score regression, adapted to bacterial traits using innovations such as frequency-based allele coding, both insertion/deletion and nucleotide testing and heritability partitioning. We compare and validate our methods against the current state-of-art using simulations, and analyse three phenotypes of the major human pathogen , including the first analyses of minimum inhibitory concentrations (MIC) for penicillin and ceftriaxone. We show that the MIC traits are highly heritable with high prediction accuracy, explained by many genetic associations under good population structure control. In ceftriaxone MIC, this is surprising because none of the isolates are resistant as per the inhibition zone criteria. We estimate that half of the heritability of penicillin MIC is explained by a known drug-resistance region, which also contributes a quarter of the ceftriaxone MIC heritability. For the within-host carriage duration phenotype, no associations were observed, but the moderate heritability and prediction accuracy indicate a moderately polygenic trait.
全基因组测序推动了对许多生物的全基因组关联、预测及遗传力分析。然而，细菌中的此类分析仍处于起步阶段，受到包括基因组可塑性和强烈群体结构等困难的限制。在此，我们提出了一套方法，包括线性混合模型、弹性网络和连锁不平衡分数回归，并通过基于频率的等位基因编码、插入/缺失和核苷酸检测以及遗传力划分等创新方法，使其适用于细菌性状。我们通过模拟将我们的方法与当前的先进技术进行比较和验证，并分析了主要人类病原体的三种表型，包括首次对青霉素和头孢曲松的最低抑菌浓度（MIC）进行分析。我们表明，在良好的群体结构控制下，MIC性状具有高度遗传性且预测准确性高，由许多遗传关联所解释。在头孢曲松MIC方面，这令人惊讶，因为根据抑菌圈标准，没有一个分离株具有抗性。我们估计，青霉素MIC遗传力的一半由一个已知的耐药区域解释，该区域也对头孢曲松MIC遗传力贡献了四分之一。对于宿主内携带持续时间表型，未观察到关联，但中等的遗传力和预测准确性表明这是一个中等多基因性状。
