Mitov Venelin, Stadler Tanja
Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland.
Swiss Institute of Bioinformatics, Switzerland.
Mol Biol Evol. 2018 Mar 1;35(3):756-772. doi: 10.1093/molbev/msx328.
Pathogen traits, such as the virulence of an infection, can vary significantly between patients. A major challenge is to measure the extent to which genetic differences between infecting strains explain the observed variation of the trait. This is quantified by the trait's broad-sense heritability, H2. A recent discrepancy between estimates of the heritability of HIV-virulence has opened a debate on the estimators' accuracy. Here, we show that the discrepancy originates from model limitations and important lifecycle differences between sexually reproducing organisms and transmittable pathogens. In particular, current quantitative genetics methods, such as donor-recipient regression of surveyed serodiscordant couples and the phylogenetic mixed model (PMM), are prone to underestimate H2, because they neglect or do not fit to the loss of resemblance between transmission partners caused by within-host evolution. In a phylogenetic analysis of 8,483 HIV patients from the United Kingdom, we show that the phenotypic correlation between transmission partners decays with the amount of within-host evolution of the virus. We reproduce this pattern in toy-model simulations and show that a phylogenetic Ornstein-Uhlenbeck model (POUMM) outperforms the PMM in capturing this correlation pattern and in quantifying H2. In particular, we show that POUMM outperforms PMM even in simulations without selection-as it captures the mentioned correlation pattern-which has not been appreciated until now. By cross-validating the POUMM estimates with ANOVA on closest phylogenetic pairs, we obtain H2 ≈ 0.2, meaning ∼20% of the variation in HIV-virulence is explained by the virus genome both for European and African data.
病原体特征，如感染的毒力，在患者之间可能有显著差异。一个主要挑战是衡量感染菌株之间的基因差异在多大程度上解释了观察到的特征变异。这通过特征的广义遗传力H2来量化。最近关于HIV毒力遗传力估计值之间的差异引发了对估计器准确性的争论。在这里，我们表明这种差异源于模型的局限性以及有性生殖生物和可传播病原体之间重要的生命周期差异。特别是，当前的数量遗传学方法，如对调查的血清学不一致夫妇进行供体-受体回归和系统发育混合模型（PMM），容易低估H2，因为它们忽略或无法拟合宿主内进化导致的传播伙伴之间相似性的丧失。在对来自英国的8483名HIV患者的系统发育分析中，我们表明传播伙伴之间的表型相关性随着病毒在宿主内进化的程度而衰减。我们在玩具模型模拟中重现了这种模式，并表明系统发育奥恩斯坦-乌伦贝克模型（POUMM）在捕捉这种相关模式和量化H2方面优于PMM。特别是，我们表明即使在没有选择的模拟中，POUMM也优于PMM——因为它捕捉到了上述相关模式——而这一点直到现在才被认识到。通过对最接近的系统发育对进行方差分析交叉验证POUMM估计值，我们得到H2≈0.2，这意味着对于欧洲和非洲的数据，HIV毒力变异的约20%由病毒基因组解释。
