Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
BMC Bioinformatics. 2010 Oct 25;11:532. doi: 10.1186/1471-2105-11-532.
The occurrence of a genetic bottleneck in HIV sexual or mother-to-infant transmission has been well documented. This results in a majority of new infections being homogeneous, i.e., initiated by a single genetic strain. Early after infection, prior to the onset of the host immune response, the viral population grows exponentially. In this simple setting, an approach for estimating evolutionary and demographic parameters based on comparison of diversity measures is a feasible alternative to the existing Bayesian methods (e.g., BEAST), which are instead based on the simulation of genealogies.
We have devised a web tool that analyzes genetic diversity in acutely infected HIV-1 patients by comparing it to a model of neutral growth. More specifically, we consider a homogeneous infection (i.e., initiated by a unique genetic strain) prior to the onset of host-induced selection, where we can assume a random accumulation of mutations. Previously, we have shown that such a model successfully describes about 80% of sexual HIV-1 transmissions provided the samples are drawn early enough in the infection. Violation of the model is an indicator of either heterogeneous infections or the initiation of selection.
When the underlying assumptions of our model (homogeneous infection prior to selection and fast exponential growth) are met, we are under a very particular scenario for which we can use a forward approach (instead of backwards in time as provided by coalescent methods). This allows for more computationally efficient methods to derive the time since the most recent common ancestor. Furthermore, the tool performs statistical tests on the Hamming distance frequency distribution, and outputs summary statistics (mean of the best fitting Poisson distribution, goodness of fit p-value, etc). The tool runs within minutes and can readily accommodate the tens of thousands of sequences generated through new ultradeep pyrosequencing technologies. The tool is available on the LANL website.
艾滋病毒性传播或母婴传播中遗传瓶颈的发生已得到充分证实。这导致大多数新感染都是同质的，即由单一遗传株引发。在感染早期，宿主免疫反应尚未开始之前，病毒群体呈指数级增长。在这种简单的情况下，基于多样性度量比较来估计进化和人口统计学参数的方法是对现有贝叶斯方法（例如 BEAST）的可行替代方法，因为后者是基于谱系模拟的。
我们设计了一个网络工具，通过将其与中性生长模型进行比较，来分析急性感染 HIV-1 患者的遗传多样性。更具体地说，我们考虑在宿主诱导选择之前发生的同质感染（即由独特的遗传株引发），在这种情况下，我们可以假设突变的随机积累。此前，我们已经表明，只要样本在感染早期采集，这种模型就能成功地描述大约 80%的性传播 HIV-1 感染。模型的违反表明存在异质感染或选择的开始。
当我们模型的基本假设（选择前的同质感染和快速指数增长）得到满足时，我们就处于一种非常特殊的情况下，我们可以使用向前的方法（而不是如合并方法那样向后回溯时间）。这使得我们可以更有效地计算最近共同祖先的时间。此外，该工具对汉明距离频率分布进行统计检验，并输出汇总统计信息（最佳拟合泊松分布的平均值、拟合优度 p 值等）。该工具在几分钟内即可运行，并能轻松适应通过新的超深度焦磷酸测序技术生成的数万个序列。该工具可在 LANL 网站上使用。
