All that glitters is not gold--founder effects complicate associations of flu mutations to disease severity.
All that glitters is not gold--founder effects complicate associations of flu mutations to disease severity.
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DOI：
10.1186/1743-422x-7-297
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发表时间：
2010-11-01
期刊：
影响因子：
4.8
通讯作者：
Maurer-Stroh S
中科院分区：
文献类型：
--
作者：
Lee RT;Santos CL;de Paiva TM;Cui L;Sirota FL;Eisenhaber F;Maurer-Stroh S
最近的2009年（H1N1）甲型流感大流行使该病毒迅速传播到世界各地。在其演变过程中，该病毒获得了许多突变，其中一些已在致命病例发生率高而严重程度增加的情况下进行了调查。例如，诸如“42.9%死于大流行（H1N1）实验室确诊病例的个体感染了血凝素（HA） Q310 H突变病毒”这样的陈述给人的印象是HA-Q310 H将是高度危险或重要的，而仔细考虑所有现有数据表明，情况不太可能是这样。我们使用全基因组系统发育树、三维结构建模以及从序列到临床结果的完整流行病学数据来比较突变HA-Q310 H、PB2-K340N、HA-D239N和HA-D239G。HA-Q310 H和PB2-K340N在系统发育分析中作为孤立的子树出现，这表明奠基者效应与它们的聚类时间外观一致，并且缺乏可以解释表型变化的直接结构基础。考虑到流行的病毒基因组背景、共同的样本来源（全部来自圣保罗市）和狭窄的时间窗口（所有死亡病例样本都在1个月内），很明显，HA-Q310 H实际上是当时该地区普遍常见的突变，这很容易解释其在少数分析的致命病例中发病率增加的原因，而不必与严重程度相关联。为了进一步支持这一点，我们强调了3例轻度HA-Q310 H突变病例。我们认为，任何当前和未来流感突变的严重程度都需要根据系统发育、结构和详细的流行病学数据进行批判性考虑，以区分由于可能的奠基者效应而不是真正的表型变化而增加的发生率。
The recent 2009 (H1N1) influenza A pandemic saw a rapid spread of the virus to essentially all parts of the world. In the course of its evolution, the virus acquired many mutations, some of which have been investigated in the context of increased severity due to high occurrences in fatal cases. For example, statements such as: "42.9% of individuals who died from laboratory-confirmed cases of the pandemic (H1N1) were infected with the hemagglutinin (HA) Q310 H mutant virus." give the impression that HA-Q310 H would be highly dangerous or important, while careful consideration of all available data suggests that this is unlikely to be the case. We compare the mutations HA-Q310 H, PB2-K340N, HA-D239N and HA-D239G using whole genome phylogenetic trees, structural modeling in their 3 D context and complete epidemiological data from sequences to clinical outcomes. HA-Q310 H and PB2-K340N appear as isolated subtrees in the phylogenetic analysis pointing to founder effects which is consistent with their clustered temporal appearance as well as the lack of an immediate structural basis that could explain a change of phenotypes. Considering the prevailing viral genomic background, shared origin of samples (all from the city of Sao Paulo) and narrow temporal window (all death case samples within 1 month), it becomes clear that HA-Q310 H was actually a generally common mutation in the region at that time which could readily explain its increased occurrence among the few analyzed fatal cases without requiring necessarily an association with severity. In further support of this, we highlight 3 mild cases with the HA-Q310 H mutation. We argue that claims of severity of any current and future flu mutation need to be critically considered in the light of phylogenetic, structural and detailed epidemiological data to distinguish increased occurrence due to possible founder effects rather than real phenotypic changes.