剑桥大学研究报告：疫情"暴发根源"不在中国，另有途径

剑桥大学网站在4月9日发表了关于新冠病毒的几个变种和传播路径的研究报告。研究报告指出，新冠病毒分为A、B、C三个变种，其中被称为"暴发根源"的A类病毒更多发现于美国和澳洲的受感染者，在武汉和东亚地区传播的主要是“Ｂ”类病毒，如果没有进一步的变异，它不会在该地区以外传播太多。

来自英国剑桥大学和德国的研究人员利用基因网络技术，重建了人体内COVID-19的早期“进化途径”。科学家们通过分析最初的160个来自于人类基因测序的完整病毒基因组，绘制了新冠状病毒通过其突变产生的原始族谱，从而产生了不同的病毒族谱。

剑桥大学的首席作者、遗传学家彼得·福斯特博士说： “这些技术主要是通过DNA来绘制史前人类的迁移轨迹。我们认为这是该种技术首次被用来追踪COVID-19冠状病毒的感染途径。”研究小组使用了从2019年12月24日至2020年3月4日期间从世界各地采集的病毒基因组数据。这项研究揭示了COVID-19的三个不同的“变种”，它们分别被标记为“A”、“B”和“C”。

福斯特和同事们发现，与在蝙蝠体内发现的COVID-19类型最接近的一种病毒——A型，即“原始病毒基因组”——在武汉存在，但令人惊讶的是，它并不是这座城市的主要病毒类型。据报道，在居住在武汉的美国人身上发现了A型病毒，在来自美国和澳大利亚的病人身上也发现了大量的A型病毒。在武汉和东亚地区传播的主要是“Ｂ”类病毒，如果没有进一步的变异，它不会在该地区以外传播太多。在法国、意大利、瑞典和英国等欧洲早期患者中发现是“C”类病毒。该研究在中国大陆的样本中没有发现“C”类病毒，但在新加坡、香港和韩国发现了此类病例。

研究结果发表在《美国国家科学院院刊》(PNAS)上。该研究使用的软件，以及1000多个冠状病毒基因组的分类和计数，可在www.fluxus-technology.com免费获得。

剑桥大学网站研究报告原文：Study charts the “incipient supernova” of COVID-19 through genetic mutations as it spread from China and Asia to Australia, Europe and North America. Researchers say their methods could be used to help identify undocumented infection sources.

Researchers from Cambridge, UK, and Germany have reconstructed the early “evolutionary paths” of COVID-19 in humans – as infection spread from Wuhan out to Europe and North America – using genetic network techniques.

By analysing the first 160 complete virus genomes to be sequenced from human patients, the scientists have mapped some of the original spread of the new coronavirus through its mutations, which creates different viral lineages.

“There are too many rapid mutations to neatly trace a COVID-19 family tree. We used a mathematical network algorithm to visualise all the plausible trees simultaneously,” said geneticist Dr Peter Forster, lead author from the University of Cambridge.

“These techniques are mostly known for mapping the movements of prehistoric human populations through DNA. We think this is one of the first times they have been used to trace the infection routes of a coronavirus like COVID-19.”

The team used data from virus genomes sampled from across the world between 24 December 2019 and 4 March 2020. The research revealed three distinct “variants” of COVID-19, consisting of clusters of closely related lineages, which they label ‘A’, ‘B’ and ‘C’.

Forster and colleagues found that the closest type of COVID-19 to the one discovered in bats – type ‘A’, the “original human virus genome” – was present in Wuhan, but surprisingly was not the city’s predominant virus type.

Mutated versions of ‘A’ were seen in Americans reported to have lived in Wuhan, and a large number of A-type viruses were found in patients from the US and Australia.

Wuhan’s major virus type, ‘B’, was prevalent in patients from across East Asia. However, the variant didn’t travel much beyond the region without further mutations – implying a "founder event" in Wuhan, or “resistance” against this type of COVID-19 outside East Asia, say researchers.

The ‘C’ variant is the major European type, found in early patients from France, Italy, Sweden and England. It is absent from the study’s Chinese mainland sample, but seen in Singapore, Hong Kong and South Korea.

The new analysis also suggests that one of the earliest introductions of the virus into Italy came via the first documented German infection on January 27, and that another early Italian infection route was related to a “Singapore cluster”.

Importantly, the researchers say that their genetic networking techniques accurately traced established infection routes: the mutations and viral lineages joined the dots between known cases.

As such, the scientists argue that these “phylogenetic” methods could be applied to the very latest coronavirus genome sequencing to help predict future global hot spots of disease transmission and surge.

“Phylogenetic network analysis has the potential to help identify undocumented COVID-19 infection sources, which can then be quarantined to contain further spread of the disease worldwide,” said Forster, a fellow of the McDonald Institute of Archaeological Research at Cambridge, as well as the University’s Institute of Continuing Education.

The findings are published today in the journal Proceedings of the National Academy of Sciences (PNAS). The software used in the study, as well as classifications for over 1,000 coronavirus genomes and counting, is available free at www.fluxus-technology.com.

Variant ‘A’, most closely related to the virus found in both bats and pangolins, is described as “the root of the outbreak” by researchers. Type ‘B’ is derived from ‘A’, separated by two mutations, then ‘C’ is in turn a “daughter” of ‘B’.

Researchers say the localisation of the ‘B’ variant to East Asia could result from a “founder effect”: a genetic bottleneck that occurs when, in the case of a virus, a new type is established from a small, isolated group of infections.

Forster argues that there is another explanation worth considering. “The Wuhan B-type virus could be immunologically or environmentally adapted to a large section of the East Asian population. It may need to mutate to overcome resistance outside East Asia. We seem to see a slower mutation rate in East Asia than elsewhere, in this initial phase.”

He added: “The viral network we have detailed is a snapshot of the early stages of an epidemic, before the evolutionary paths of COVID-19 become obscured by vast numbers of mutations. It’s like catching an incipient supernova in the act.”

Since today’s PNAS study was conducted, the research team has extended its analysis to 1,001 viral genomes. While yet to be peer-reviewed, Forster says the latest work suggests that the first infection and spread among humans of COVID-19 occurred between mid-September and early December.

The phylogenetic network methods used by researchers – allowing the visualisation of hundreds of evolutionary trees simultaneously in one simple graph – were pioneered in New Zealand in 1979, then developed by German mathematicians in the 1990s.

These techniques came to the attention of archaeologist Professor Colin Renfrew, a co-author of the new PNAS study, in 1998. Renfrew went on to establish one of the first archaeogenetics research groups in the world at the University of Cambridge.