SARS-CoV-2 within-host diversity and transmission.
SARS-CoV-2 within-host diversity and transmission.
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SARS-CoV-2宿主内多样性和传播。
DOI：
10.1126/science.abg0821
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发表时间：
2021-04-16
期刊：
影响因子：
--
通讯作者：
Golubchik T
中科院分区：
文献类型：
--
作者：
Lythgoe KA;Hall M;Ferretti L;de Cesare M;MacIntyre-Cockett G;Trebes A;Andersson M;Otecko N;Wise EL;Moore N;Lynch J;Kidd S;Cortes N;Mori M;Williams R;Vernet G;Justice A;Green A;Nicholls SM;Ansari MA;Abeler-Dörner L;Moore CE;Peto TEA;Eyre DW;Shaw R;Simmonds P;Buck D;Todd JA;Oxford Virus Sequencing Analysis Group (OVSG);Connor TR;Ashraf S;da Silva Filipe A;Shepherd J;Thomson EC;COVID-19 Genomics UK (COG-UK) Consortium;Bonsall D;Fraser C;Golubchik T
在严重急性呼吸综合征冠状病毒大流行一年后，我们正在经历一波又一波的新变种出现。其中一些变异具有令人担忧的功能影响，如增加的传播性或抗体治疗逃逸。Lythgoe等人对1000多名医院患者的分离株进行了深入测序，以了解病毒是如何在个体内变异的。总的来说，宿主内的病毒多样性似乎具有一致和可复制的模式。作者在大多数样本中只观察到一种或两种变异，但少数样本携带多种变异。尽管有证据表明强烈的净化选择，包括在负责病毒进入的刺突蛋白中，作者也看到了与家庭和其他可能的超级传播事件相关的传播集群的证据。在传播之后，大多数变异都消失了，但偶尔会有一些变异开始持续传播和更广泛的传播。来自英国的一千多个深度测序临床样本显示，SARS-CoV-2在大多数个体中具有有限的遗传多样性。在严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）大流行期间，以前所未有的规模进行的基因组测序有助于追踪该病毒的传播并识别新的变体。这项工作的大部分考虑了每个感染者的单一共识序列。在这里，我们在共识之下分析了构成感染的病毒种群的遗传变异，并研究了感染传播给新个体时宿主内突变的命运。宿主内多样性提供了帮助确认直接传播和识别令人关切的新变异的手段。我们对来自英国第一波感染的1313个SARS-CoV-2样本进行了测序。我们在传播和持续的病毒进化的背景下描述了宿主内的多样性和动态。宿主内多样性可以通过宿主内单核苷酸变异（iSNVs）的数量来描述，这些变异发生在给定的次要等位基因频率（MAF）阈值之上。我们发现，在低病毒载量的样本中，随机抽样效应导致maff的较大方差，导致在任何阈值下检测到更多的isnv。基于27对高病毒载量复制RNA样本的子集（50万个唯一映射的veSEQ reads，对应于~22的周期阈值），具有至少3% MAF的isnv具有高度可重复性。通过比较平均间隔6天（四分位数比为2 ~ 10）的41个个体的两个时间点的样本，我们观察到一个动态的iSNV产生和丧失过程。通过比较14对家庭接触者的isnv，我们估计了1至8种病毒的传播瓶颈大小。在同一家庭中，样本深度允许检测到iSNV，个体之间的共识差异可以通过配对个体中同一部位存在iSNV来解释，这与直接传播导致固定一致。接下来，我们重点研究了一组563个高置信度的iSNV位点，这些位点在至少一个高病毒载量样本（bbb50 000个唯一映射）中发生变异；排除了不太可能代表基因组多样性的低置信度isnv。在高病毒载量样本中，宿主内多样性有限（每个样本平均1.4 iSNVs）。有两个例外，每个有bbbb14个iSNVs，显示出与共感染或污染一致的变异频率。总体而言，我们估计数据集中1%至2%的样本被共感染和/或污染。此外，一个样本与另一种冠状病毒（OC43）共同感染，对多样性没有可检测到的影响。非同义iSNVs与同义iSNVs （dN/dS）的比值在整个基因组中与宿主内纯化选择一致[dN/dS = 0.55, 95%可信区间(95% CI) = 0.49至0.61]，对于Spike基因（dN/dS = 0.60, 95% CI = 0.45至0.82）。然而，我们在多个样本中观察到Spike变异体已显示出增加病毒传染性（L5F）或对抗体（G446V和A879V）的抗性。我们观察到高置信度iSNVs与系统发育的共识变化之间有很强的关联（153例），与传播后固定或新生突变达成共识一致。未达成共识的共有变异（261例）与系统发育无关。使用健壮的方法调用宿主内变异，我们发现了宿主内低多样性、净化选择和窄传播瓶颈的一致模式。在宿主内出现疫苗和治疗性逃逸突变可能相对罕见，至少在病毒载量高的早期感染期间是如此，但在高病毒载量样本中观察到的免疫逃逸变异强调需要继续保持警惕。具有高病毒载量的个体通常很少（如果有的话）在宿主内变异。狭窄的传播瓶颈意味着源个体中的主要变异通常被传播，而次要变异则丢失。偶尔，小变异被传播，导致共识改变，或多个变异被传播，导致混合感染。来源：FontAwesome，在CC BY 4.0下授权。对大流行病毒严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）进行广泛的全球采样和测序，使研究人员能够监测其传播并确定有关的新变体。变异传播的两个重要决定因素是它们在个体中出现的频率以及它们传播的可能性。为了表征宿主内的多样性和传播，我们对来自英国的1313份临床样本进行了深度测序。SARS-CoV-2感染的特点是病毒载量高时宿主内多样性水平低，传播瓶颈狭窄。大多数变异要么丢失，要么偶尔在传播点固定下来，共享多样性的持久性极小，这种模式在系统发育树上很容易观察到。我们的研究结果表明，增强传播和/或免疫逃逸的SARS-CoV-2变体可能不经常出现，但如果成功传播，可能会迅速传播。
A year into the severe acute respiratory syndrome coronavirus 2 pandemic, we are experiencing waves of new variants emerging. Some of these variants have worrying functional implications, such as increased transmissibility or antibody treatment escape. Lythgoe et al. have undertaken in-depth sequencing of more than 1000 hospital patients' isolates to find out how the virus is mutating within individuals. Overall, there seem to be consistent and reproducible patterns of within-host virus diversity. The authors observed only one or two variants in most samples, but a few carried many variants. Although the evidence indicates strong purifying selection, including in the spike protein responsible for viral entry, the authors also saw evidence for transmission clusters associated with households and other possible superspreader events. After transmission, most variants fizzled out, but occasionally some initiated ongoing transmission and wider dissemination. Science, this issue p. eabg0821 More than a thousand deep-sequenced clinical samples from the UK reveal that SARS-CoV-2 has limited genetic diversity within most individuals. Genome sequencing at an unprecedented scale during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is helping to track spread of the virus and to identify new variants. Most of this work considers a single consensus sequence for each infected person. Here, we looked beneath the consensus to analyze genetic variation within viral populations making up an infection and studied the fate of within-host mutations when an infection is transmitted to a new individual. Within-host diversity offers the means to help confirm direct transmission and identify new variants of concern. We sequenced 1313 SARS-CoV-2 samples from the first wave of infection in the United Kingdom. We characterized within-host diversity and dynamics in the context of transmission and ongoing viral evolution. Within-host diversity can be described by the number of intrahost single nucleotide variants (iSNVs) occurring above a given minor allele frequency (MAF) threshold. We found that in lower-viral-load samples, stochastic sampling effects resulted in a higher variance in MAFs, leading to more iSNVs being detected at any threshold. Based on a subset of 27 pairs of high-viral-load replicate RNA samples (>50,000 uniquely mapped veSEQ reads, corresponding to a cycle threshold of ~22), iSNVs with a minimum 3% MAF were highly reproducible. Comparing samples from two time points from 41 individuals, taken on average 6 days apart (interquartile ratio 2 to 10), we observed a dynamic process of iSNV generation and loss. Comparing iSNVs among 14 household contact pairs, we estimated transmission bottleneck sizes of one to eight viruses. Consensus differences between individuals in the same household, where sample depth allowed iSNV detection, were explained by the presence of an iSNV at the same site in the paired individual, consistent with direct transmission leading to fixation. We next focused on a set of 563 high-confidence iSNV sites that were variant in at least one high-viral-load sample (>50,000 uniquely mapped); low-confidence iSNVs unlikely to represent genomic diversity were excluded. Within-host diversity was limited in high-viral-load samples (mean 1.4 iSNVs per sample). Two exceptions, each with >14 iSNVs, showed variant frequencies consistent with coinfection or contamination. Overall, we estimated that 1 to 2% of samples in our dataset were coinfected and/or contaminated. Additionally, one sample was coinfected with another coronavirus (OC43), with no detectable impact on diversity. The ratio of nonsynonymous to synonymous (dN/dS) iSNVs was consistent with within-host purifying selection when estimated across the whole genome [dN/dS = 0.55, 95% confidence interval (95% CI) = 0.49 to 0.61] and for the Spike gene (dN/dS = 0.60, 95% CI = 0.45 to 0.82). Nevertheless, we observed Spike variants in multiple samples that have been shown to increase viral infectivity (L5F) or resistance to antibodies (G446V and A879V). We observed a strong association between high-confidence iSNVs and a consensus change on the phylogeny (153 cases), consistent with fixation after transmission or de novo mutations reaching consensus. Shared variants that never reached consensus (261 cases) were not phylogenetically associated. Using robust methods to call within-host variants, we uncovered a consistent pattern of low within-host diversity, purifying selection, and narrow transmission bottlenecks. Within-host emergence of vaccine and therapeutic escape mutations is likely to be relatively rare, at least during early infection, when viral loads are high, but the observation of immune-escape variants in high-viral-load samples underlines the need for continued vigilance. Individuals with high viral load typically have few, if any, within-host variants. Narrow transmission bottlenecks mean that the major variant in the source individual was typically transmitted and the minor variants lost. Occasionally, the minor variant was transmitted, leading to a consensus change, or multiple variants were transmitted, resulting in a mixed infection. Credit: FontAwesome, licensed under CC BY 4.0. Extensive global sampling and sequencing of the pandemic virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have enabled researchers to monitor its spread and to identify concerning new variants. Two important determinants of variant spread are how frequently they arise within individuals and how likely they are to be transmitted. To characterize within-host diversity and transmission, we deep-sequenced 1313 clinical samples from the United Kingdom. SARS-CoV-2 infections are characterized by low levels of within-host diversity when viral loads are high and by a narrow bottleneck at transmission. Most variants are either lost or occasionally fixed at the point of transmission, with minimal persistence of shared diversity, patterns that are readily observable on the phylogenetic tree. Our results suggest that transmission-enhancing and/or immune-escape SARS-CoV-2 variants are likely to arise infrequently but could spread rapidly if successfully transmitted.
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SARS-COV-2血统的估计可传播和影响B.1.1.7在英国。
DOI：
10.1126/science.abg3055
发表时间：
2021-04-09
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
Davies NG;Abbott S;Barnard RC;Jarvis CI;Kucharski AJ;Munday JD;Pearson CAB;Russell TW;Tully DC;Washburne AD;Wenseleers T;Gimma A;Waites W;Wong KLM;van Zandvoort K;Silverman JD;CMMID COVID-19 Working Group;COVID-19 Genomics UK (COG-UK) Consortium;Diaz-Ordaz K;Keogh R;Eggo RM;Funk S;Jit M;Atkins KE;Edmunds WJ
通讯作者：
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DOI：
10.1126/science.abe8499
发表时间：
2020-12-18
期刊：
Science (New York, N.Y.)
影响因子：
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通讯作者：
Baric RS
DOI：
10.1093/bioinformatics/bts565
发表时间：
2012-12-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
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作者：
Fu L;Niu B;Zhu Z;Wu S;Li W
通讯作者：
Li W
影响因子：
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Bonsall D;Ansari MA;Ip C;Trebes A;Brown A;Klenerman P;Buck D;STOP-HCV Consortium;Piazza P;Barnes E;Bowden R
通讯作者：
Bowden R
影响因子：
10.7
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通讯作者：
Vinh LS