Patterns of within-host genetic diversity in SARS-CoV-2.
Patterns of within-host genetic diversity in SARS-CoV-2.
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DOI：
10.7554/elife.66857
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发表时间：
2021-08-13
期刊：
影响因子：
7.7
通讯作者：
Wellcome Sanger Institute COVID-19 Surveillance Team
中科院分区：
文献类型：
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作者：
Tonkin-Hill G;Martincorena I;Amato R;Lawson ARJ;Gerstung M;Johnston I;Jackson DK;Park N;Lensing SV;Quail MA;Gonçalves S;Ariani C;Spencer Chapman M;Hamilton WL;Meredith LW;Hall G;Jahun AS;Chaudhry Y;Hosmillo M;Pinckert ML;Georgana I;Yakovleva A;Caller LG;Caddy SL;Feltwell T;Khokhar FA;Houldcroft CJ;Curran MD;Parmar S;COVID-19 Genomics UK (COG-UK) Consortium;Alderton A;Nelson R;Harrison EM;Sillitoe J;Bentley SD;Barrett JC;Torok ME;Goodfellow IG;Langford C;Kwiatkowski D;Wellcome Sanger Institute COVID-19 Surveillance Team
监测SARS-CoV-2的传播和重建传播链已成为世界许多国家政府关注的主要公共卫生问题。SARS-CoV-2的适度突变率和快速传播阻止了从一致的基因组序列重建传播链，但从理论上讲，宿主内的遗传多样性可以帮助识别密切接触者。在这里，我们描述了1181份SARS-CoV-2样本的宿主内多样性模式。95.1%的样本在可检测到的等位基因频率上显示出宿主内的突变。对突变谱的分析显示，在SARS-CoV-2大流行期间，强烈的链不对称暗示着正链的损伤或RNA编辑，而不是复制错误，主导了突变的积累。宿主内部和宿主间的多样性显示出强大的净化选择，特别是针对无义突变。反复出现的宿主内突变，其中许多与已知的系统发育同型一致，显示出一种光谱和纯化选择模式，比重组或收敛进化更能暗示突变热点。虽然等位基因频率表明大多数样本是由单一血统感染引起的，但我们确定了多个假定的联合感染实例。将这些结果整合到流行病学推断框架中，我们发现，虽然样本之间共享宿主内变异有助于传播链的重建，但突变热点和罕见的重复感染病例可能会扰乱这些分析。新冠肺炎疫情在全球范围内对健康产生了重大影响。科学界将大量注意力集中在寻找监测导致SARS-CoV-2大流行的病毒如何传播上。一种选择是对SARS-CoV-2样本进行基因测试，即所谓的测序，以确定病毒的遗传密码，并发现病毒样本之间的任何基因差异或突变。病毒在它们的宿主内发生变异，并可以发展成能够更容易在宿主之间传播的变种。基因测序可以揭示两个SARS-CoV-2样本在基因上的相似程度。但是，通过测序跟踪SARS-CoV-2病毒是如何从一个人传播到另一个人的可能是棘手的。即使是来自同一个人的SARS-CoV-2病毒样本，也可能在其遗传物质或宿主内变种上表现出差异。对宿主内变异的基因检测能否揭示推动SARS-CoV-2在人类身上进化的因素？为了弄清这一点，Tonkin-Hill，Martincorena等人。利用1181份样本对SARS-CoV-2宿主内变异株的遗传学进行了探讨。分析表明，95.1%的样本含有宿主内变体。在许多样本中频繁出现多个变异，这与SARS-CoV-2基因组中的突变热点一致。此外，宿主内的变异显示出与感染个体之间的模式相似的突变模式。样本之间共享的宿主内变体有助于重建传播链。然而，观察到的突变热点和对一个人体内多个菌株的检测可能会使这一点具有挑战性。这些发现可以用来帮助预测SARS-CoV-2在疫苗等干预措施下如何演变。他们还建议，当使用宿主内变异的信息来确定个体之间的传播时，需要谨慎。
Monitoring the spread of SARS-CoV-2 and reconstructing transmission chains has become a major public health focus for many governments around the world. The modest mutation rate and rapid transmission of SARS-CoV-2 prevents the reconstruction of transmission chains from consensus genome sequences, but within-host genetic diversity could theoretically help identify close contacts. Here we describe the patterns of within-host diversity in 1181 SARS-CoV-2 samples sequenced to high depth in duplicate. 95.1% of samples show within-host mutations at detectable allele frequencies. Analyses of the mutational spectra revealed strong strand asymmetries suggestive of damage or RNA editing of the plus strand, rather than replication errors, dominating the accumulation of mutations during the SARS-CoV-2 pandemic. Within- and between-host diversity show strong purifying selection, particularly against nonsense mutations. Recurrent within-host mutations, many of which coincide with known phylogenetic homoplasies, display a spectrum and patterns of purifying selection more suggestive of mutational hotspots than recombination or convergent evolution. While allele frequencies suggest that most samples result from infection by a single lineage, we identify multiple putative examples of co-infection. Integrating these results into an epidemiological inference framework, we find that while sharing of within-host variants between samples could help the reconstruction of transmission chains, mutational hotspots and rare cases of superinfection can confound these analyses. The COVID-19 pandemic has had major health impacts across the globe. The scientific community has focused much attention on finding ways to monitor how the virus responsible for the pandemic, SARS-CoV-2, spreads. One option is to perform genetic tests, known as sequencing, on SARS-CoV-2 samples to determine the genetic code of the virus and to find any differences or mutations in the genes between the viral samples. Viruses mutate within their hosts and can develop into variants that are able to more easily transmit between hosts. Genetic sequencing can reveal how genetically similar two SARS-CoV-2 samples are. But tracking how SARS-CoV-2 moves from one person to the next through sequencing can be tricky. Even a sample of SARS-CoV-2 viruses from the same individual can display differences in their genetic material or within-host variants. Could genetic testing of within-host variants shed light on factors driving SARS-CoV-2 to evolve in humans? To get to the bottom of this, Tonkin-Hill, Martincorena et al. probed the genetics of SARS-CoV-2 within-host variants using 1,181 samples. The analyses revealed that 95.1% of samples contained within-host variants. A number of variants occurred frequently in many samples, which were consistent with mutational hotspots in the SARS-CoV-2 genome. In addition, within-host variants displayed mutation patterns that were similar to patterns found between infected individuals. The shared within-host variants between samples can help to reconstruct transmission chains. However, the observed mutational hotspots and the detection of multiple strains within an individual can make this challenging. These findings could be used to help predict how SARS-CoV-2 evolves in response to interventions such as vaccines. They also suggest that caution is needed when using information on within-host variants to determine transmission between individuals.