生物与医学2022biorxiv.org
内切酶指纹表明 SARS-CoV-2 可能为合成起源？
Endonuclease fingerprint indicates a synthetic origin of SARS-CoV-2?
专业 · 约 90 分钟读完前置知识：病毒学与分子生物学基础、限制性内切酶/BAC 克隆、统计置换检验与多重比较
导读
这篇 bioRxiv 预印本尝试用内切酶“指纹”论证 SARS-CoV-2 可能具有合成来源：作者比较 SARS-CoV-2 与其他冠状病毒的 BsaI/BsmBI 等限制酶位点图谱，并用模拟/置换构建零分布，认为其位点模式异常。结论高度争议，尚属预印本，统计方法和推断链条受到评论者质疑。
HN 关注点：新冠病毒起源争议、实验室泄漏/合成假设，以及这篇预印本的统计方法是否足以支撑其结论。
HN 评论精选
这几条评论里：质疑 3 补充 1
补充提供作者本人对论文的科普摘要链接，便于补充阅读。
论文作者之一写的科普摘要：https://alexwasburne.substack.com/p/a-synthetic-origin-of-sars-cov-2
graeme查看英文原文
Popular science summary of paper from one of the authors: https://alexwasburne.substack.com/p/a-synthetic-origin-of-sars-cov-2
质疑质疑位点选择是否盲选、多重比较是否影响 p 值，以及模拟零分布是否真实可信。
“为了避免多重比较损失功效，我们把分析集中在 SARS-CoV-2 的 BsaI/BsmBI 位点，并将 SARS-CoV-2 的 BsaI/BsmBI 图谱与我们所分析的所有其他 CoV 的所有其他限制图谱进行比较。”关键是要知道作者是否在查看基因组之前盲选 BsaI 和 BsmBI。如果是在知道 SARS-CoV-2 基因组的情况下选，就不能避开多重比较问题，p 值不可靠。这取决于常用 type IIS 内切酶有多少；作者用 214 种生成 CoV 限制图谱的零假设分布，但说只有 6 种特别适合 BAC 克隆。图 3C 的片段长度“野生型分布”零分布是模拟（置换已知 CoV 基因组、在随机选择的限制位点切开）让我不安。初读时我以为它是真实病毒中片段长度的分布。通过置换合成虚拟基因组会产生真实的片段长度分布吗？
jpeloquin查看英文原文
"To avoid losing power with multiple comparisons, we focus our analysis on the BsaI/BsmBI sites in SARS-CoV-2 and compare the BsaI/BsmBI map in SARS-CoV-2 to all other restriction maps of all other CoVs used in our analysis." It's important to know whether or not the authors picked BsaI & BmBI blind, before looking at the genome. If they picked BsaI & BmBI with knowledge of the SARS-CoV-2 genome, that doesn't dodge the multiple comparisons problem and the p-values aren't reliable. I guess it depends on how many other commonly used type IIS endonucleases there are. The authors use 214 to generate their null hypothesis distribution for the CoV restriction maps but say only 6 are specifically amenable to BAC cloning. The "wild type distribution" null distribution for fragment length (Figure 3C) being a simulation (permutation of known CoV genomes, split at randomly selected restriction sites) bothers me. On the first read I thought it was a distribution of fragment lengths in real viruses. Does synthesizing virtual genomes by permutation produce a realistic distribution of fragment lengths?
质疑批评核心推断、忽视华南海鲜市场基因漂变证据，以及“理解起源有助于预防”的论证薄弱。
这项研究至少有几个可疑点：首先，核心主张是 5 个潜在限制性结合位点对 2 个意味着 SARS-CoV-2 非自然。这不一定成立。正如 SARS-CoV-2 对人类异常强的传染性和致病性，它也可能碰巧多出 3 个限制性结合位点。因此这与病毒特征的自然选择并不矛盾，只是野生与实验室病毒的比较。第二，关于华南海鲜市场起源的证据被轻视了。该论证指出基因漂变已被充分刻画，从华南海鲜市场培养出的两个密切相关的 SARS-CoV-2 变异体是病毒最初出现在那里的极强证据。两个论证都用详细遗传证据，但基于基因漂变的市场论证相当稳健，而这个替代理论只展示相似性，没有排除自然选择。第三，论文强调 COVID 大流行的强烈影响，并断言理解病毒起源必然有助于预防未来大流行。这并不显然成立。尤其如果病毒源于自然选择，没有明确明显的系统降低风险方式。仅生活在或旅行到蝙蝠等宿主种群所在地区就足以产生暴露，把人从农村清走并不简单。
m0llusk查看英文原文
There are at least a couple of suspicious points in this study: First and foremost the central claim is that 5 potential restriction binding sites versus 2 means that SARS-CoV2 is non natural. That does not necessarily follow. Just as SARS-CoV2 is unusually infectious and damaging to humans it could just happen to have an additional 3 restriction binding sites. So there is nothing inconsistent with natural selection of viral characteristics, only a comparison between wild and lab viruses. Second, the evidence for the wet market origin is trivialized. That argument points out that genetic drift is well characterized and the presence of two closely related SARS-CoV2 variants cultured from the wet market is extremely strong evidence that is where the virus initially appeared. Both arguments make use of detailed genetic evidence, but the wet market argument based on genetic drift is quite robust while this alternative theory merely presents similarities while not ruling out natural selection. Thirdly, this paper emphasizes the strong impact of the COVID pandemic and asserts that understanding the origins of the virus would necessarily aid in preventing future pandemics. This does not clearly follow. Especially if the virus had natural selection origins there is no clear and obvious way of systematically reducing risk. Simply living or traveling where host populations like bats live could be enough to generate exposures and it is not simple to clear people off of rural habitations. These second and third criticisms are not direct against the evidence and logic presented, but show a dangerous level of sloppiness in the research that makes this paper appear more like slanted analysis from someone with an agenda than a critical thinking scientist genuinely interested in the truth and therefore needing to consider alternatives and potential falsification of the hypothesis.
质疑质疑弄清具体起源对未来防控的实际价值，认为两种可能性都已已知，答案未必影响行动。
开头一句：“为了预防未来大流行，我们必须理解 SARS-CoV-2 是直接从动物溢出到人，还是间接通过实验室事故。”这是真的吗？我理解人们会好奇，但就我们需要做的事而言，这真的重要吗？我们知道病毒可以从动物溢出到人，也知道实验室环境中的病毒有可能因事故释放。就未来尽可能防止其发生而言，我不确定 COVID-19 到底发生了哪一种答案有多重要。再次，我明白人们为何关心。但只要我们已知两种都是现实可能性（我们确实知道），向前看这并不重要。
rossdavidh查看英文原文
The opening line: "To prevent future pandemics, it is important that we understand whether SARS-CoV-2 spilled over directly from animals to people, or indirectly in a laboratory accident." Is that true? I mean I understand why people would be curious, but does it really matter, in terms of what we need to do? We know that viruses _can_ spillover from animals to people, and we know that viruses in a laboratory setting _could_ plausibly get released in an accident. In terms of what we need to do to prevent (as far as possible) it happening in the future, I don't know that I believe that the answer to which one happened in the case of covid-19, is all that important. Again, I see why people would care. But as long as we know that both are realistic possibilities (and we do), it doesn't matter moving forward.
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