Long intervals of stasis punctuated by bursts of positive selection in the seasonal evolution of influenza A virus
Long intervals of stasis punctuated by bursts of positive selection in the seasonal evolution of influenza A virus
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DOI：
10.1186/1745-6150-1-34
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发表时间：
2006-10-26
期刊：
影响因子：
5.5
通讯作者：
Lipman, David J.
中科院分区：
文献类型：
--
作者：
Wolf, Yuri I.;Viboud, Cecile;Lipman, David J.
背景：甲型流感病毒血凝素（HA）蛋白的大流行间进化通常被认为是正选择下快速进化变化的典范，其中氨基酸替代因其对抗原性的影响而固定，使病毒能够逃避免疫监测。结果：我们对最近获得的1995-2005年甲型流感病毒H3N2和H1N1亚型分离株HA序列的大量相对无偏倚样本进行了系统发育分析。出乎意料的是，研究发现H3N2 HA的进化包括一般中性序列的长间隔进化，没有明显的实质性抗原变化（“停滞”期），其特征是每个位点的同义替换多于非同义替换，缺乏氨基酸替换与表位区域的关联，以及共存病毒谱系的缓慢灭绝。这些长时间的停滞被短时间的快速进化打断，在积极选择下，新的优势谱系迅速取代了以前共存的谱系。与HA分子其余部分的替换相比，HA表位区域的氨基酸替换显著过剩，支持了在快速进化期间的正选择优势。相比之下，停滞期在HA分子上的替换分布更为均匀，在两种进化模式之间，表位区域的同义替换率与非同义替换率具有统计学上的显著差异。在H3N2 HA中也检测到许多平行氨基酸替换——在不同谱系中独立发生的相同氨基酸替换。这些平行突变在很大程度上与适应性快速变化的时期有关，这表明在抗原变化期间进化途径存在主要限制。停滞是H3N2进化的主要模式，这一发现表明，导致适应度增加的抗原变化通常是由于HA中几个氨基酸取代之间的上位性相互作用，可能还有其他病毒蛋白。由于适应度增加而成为优势的菌株来自于低频菌株，这要归功于最后一个氨基酸替换完成了产生显著抗原变化所需的一系列替换；没有一个子集的替换会导致显著的抗原性变化和相应的适应度增加。与H3N2相比，在相同的时间跨度内，没有检测到H1N1 HA在正选择下的明确进化间隔。因此，H1N1在某些季节的优势很可能是由于先前流行的H3N2谱系的相对适合度下降造成的，因为易感宿主的比例在停滞期减少。结论：我们表明，流感病毒的进化是一个快速的、积极的选择驱动的过程的共同观点，充其量是不完整的。更确切地说，流感大流行间的进化似乎是由间隔较长的停滞期组成的，其特征是中性序列进化，当进化变化是由积极选择驱动时，间隔较短的适应度快速增加被打断。这些观察结果对流感监测和疫苗制定具有指导意义；特别是，存在平行氨基酸替换可能作为新的优势菌株的预测因子。
Background: The interpandemic evolution of the influenza A virus hemagglutinin (HA) protein is commonly considered a paragon of rapid evolutionary change under positive selection in which amino acid replacements are fixed by virtue of their effect on antigenicity, enabling the virus to evade immune surveillance.Results: We performed phylogenetic analyses of the recently obtained large and relatively unbiased samples of the HA sequences from 1995-2005 isolates of the H3N2 and H1N1 subtypes of influenza A virus. Unexpectedly, it was found that the evolution of H3N2 HA includes long intervals of generally neutral sequence evolution without apparent substantial antigenic change ("stasis" periods) that are characterized by an excess of synonymous over nonsynonymous substitutions per site, lack of association of amino acid replacements with epitope regions, and slow extinction of coexisting virus lineages. These long periods of stasis are punctuated by shorter intervals of rapid evolution under positive selection during which new dominant lineages quickly displace previously coexisting ones. The preponderance of positive selection during intervals of rapid evolution is supported by the dramatic excess of amino acid replacements in the epitope regions of HA compared to replacements in the rest of the HA molecule. In contrast, the stasis intervals showed a much more uniform distribution of replacements over the HA molecule, with a statistically significant difference in the rate of synonymous over nonsynonymous substitution in the epitope regions between the two modes of evolution. A number of parallel amino acid replacements-the same amino acid substitution occurring independently in different lineages-were also detected in H3N2 HA. These parallel mutations were, largely, associated with periods of rapid fitness change, indicating that there are major limitations on evolutionary pathways during antigenic change. The finding that stasis is the prevailing modality of H3N2 evolution suggests that antigenic changes that lead to an increase in fitness typically result from epistatic interactions between several amino acid substitutions in the HA and, perhaps, other viral proteins. The strains that become dominant due to increased fitness emerge from low frequency strains thanks to the last amino acid replacement that completes the set of replacements required to produce a significant antigenic change; no subset of substitutions results in a biologically significant antigenic change and corresponding fitness increase. In contrast to H3N2, no clear intervals of evolution under positive selection were detected for the H1N1 HA during the same time span. Thus, the ascendancy of H1N1 in some seasons is, most likely, caused by the drop in the relative fitness of the previously prevailing H3N2 lineages as the fraction of susceptible hosts decreases during the stasis intervals.Conclusion: We show that the common view of the evolution of influenza virus as a rapid, positive selection-driven process is, at best, incomplete. Rather, the interpandemic evolution of influenza appears to consist of extended intervals of stasis, which are characterized by neutral sequence evolution, punctuated by shorter intervals of rapid fitness increase when evolutionary change is driven by positive selection. These observations have implications for influenza surveillance and vaccine formulation; in particular, the possibility exists that parallel amino acid replacements could serve as a predictor of new dominant strains.