Bioinformatics Institute (BII), Agency for Science Technology and Research (A*STAR), 30 Biopolis Street, #07-01, Matrix 138671, Singapore.
Virol J. 2010 Nov 1;7:297. doi: 10.1186/1743-422X-7-297.
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.
最近的 2009 年（H1N1）流感 A 大流行迅速蔓延到世界上几乎所有的地区。在其进化过程中，病毒发生了许多突变，其中一些突变由于在致死病例中高频发生而被认为与病毒严重性增加有关。例如，“在经实验室确诊的大流行（H1N1）病例中，有 42.9%的个体感染了具有血凝素（HA）Q310 H 突变的病毒。”这样的表述给人留下的印象是 HA-Q310 H 是高度危险或重要的，而仔细考虑所有现有数据表明，情况并非如此。
我们使用全基因组系统进化树、三维结构建模和完整的流行病学数据将 HA-Q310 H、PB2-K340N、HA-D239N 和 HA-D239G 这四种突变进行比较，以分析其与临床结果的关系。HA-Q310 H 和 PB2-K340N 在系统进化分析中表现为孤立的分支，这指向了其起源于奠基者效应，这与它们在时间上的聚集出现以及缺乏可以解释表型变化的直接结构基础相一致。考虑到当时流行的病毒基因组背景、样本的共同来源（均来自圣保罗市）以及时间范围狭窄（所有死亡病例样本均在 1 个月内），HA-Q310 H 实际上是当时该地区普遍存在的一种常见突变，这可以很容易地解释为什么在少数分析的致死病例中它的出现频率更高，而无需必然与严重性相关联。进一步支持这一观点的是，我们强调了 3 例具有 HA-Q310 H 突变的轻症病例。
我们认为，对于任何当前和未来流感突变的严重性的说法，需要根据系统进化、结构和详细的流行病学数据进行批判性地考虑，以区分由于可能的奠基者效应而导致的发生率增加，而不是真正的表型变化。
