Low genetic diversity may be an Achilles heel of SARS-CoV-2.
Low genetic diversity may be an Achilles heel of SARS-CoV-2.
复制标题
DOI：
10.1073/pnas.2017726117
复制
发表时间：
2020-10-06
影响因子：
11.1
通讯作者：
Kearney MF
中科院分区：
文献类型：
--
作者：
Rausch JW;Capoferri AA;Katusiime MG;Patro SC;Kearney MF
世界各地的科学家正在竞相开发针对严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）的有效疫苗，SARS-CoV-2是COVID-19大流行的病原体。这项奋进的一个重要方面，也许是未得到充分重视的方面，是确保正在开发的疫苗赋予全球人口中所有病毒谱系的免疫力。为此，发表在PNAS上的一项开创性研究（1）分析了在大流行期间从84个国家获得的27，977个SARS-CoV-2序列，以跟踪和表征新型冠状病毒自其起源以来的演变。这项工作的作者得出的主要结论是，SARS-CoV-2的遗传多样性非常低，几乎完全是遗传漂变的产物，不应该期望阻碍广泛保护疫苗的开发。尽管基因组复制过程中引入的错误是所有病毒种群遗传变异的主要来源，但限制累积错误的适应性成本对冠状病毒尤其重要，因为冠状病毒的RNA基因组是已知最大的。由于这个原因，冠状病毒进化出非结构蛋白14（nsp 14），它在RNA合成过程中伴随病毒复制酶，并在新生链延伸之前从新生链中切除错误掺入的核糖核苷酸，从而防止错误成为永久性的。在SARS-CoV-1中发现之前，RNA病毒的这种纠错能力是未知的（2，3），它有助于复制错误率比其他RNA病毒低10倍以上（4，5）。这种活性也可能导致SARS-CoV-2的低遗传多样性，尽管据我们所知，nsp 14在新型冠状病毒中的功能还有待研究。对于许多病毒，表面糖蛋白不仅含有细胞受体特异性结合、膜融合和病毒进入宿主细胞所需的元件，而且含有作为有效适应性免疫应答的一部分产生的中和抗体识别的表位。因此，追踪SARS-CoV-2表面糖蛋白的遗传变异对于确定疫苗有效性或免疫逃逸的可能性至关重要。为了正确看待这种变化，图1显示了选定的人类致病性病毒（包括SARS-CoV-2）的表面糖蛋白之间的比较遗传多样性的图解说明，与相应预防性疫苗的可用性和有效性相关。虽然遗传多样性只是疫苗效力的众多决定因素之一，但在我们的分析中检查的病毒病原体中，这两个指标之间存在明显的负相关性。据推测，由于其相对较新的起源，由S基因编码的SARS-CoV-2表面糖蛋白spike的遗传多样性非常低，即使与其他人类冠状病毒相比也是如此。相反，甲型流感病毒表面糖蛋白的多样性是SARS-CoV-2的437倍。甲型流感的相对年龄（至少可追溯到世纪）肯定是造成这种差异的主要因素，编码甲型流感表面抗原血凝素（HA）和神经氨酸酶（NA）的基因组片段的重排也是如此（6）。事实上，含有HA-NA组合的甲型流感病毒变异体的突然出现导致了1918年（H1N1）、1957年（H2 N2）、1968年（H3 N2）和2009年（H1N1 pdm 09）的大流行。虽然冠状病毒的基因组不像流感病毒那样分段，但它们仍然能够进行高速率的重组。因此，未来...
Scientists worldwide are racing to develop effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic. An important and perhaps underappreciated aspect of this endeavor is ensuring that the vaccines being developed confer immunity to all viral lineages in the global population. Toward this end, a seminal study published in PNAS (1) analyzes 27,977 SARS-CoV-2 sequences from 84 countries obtained throughout the course of the pandemic to track and characterize the evolution of the novel coronavirus since its origination. The principle conclusion reached by the authors of this work is that SARS-CoV-2 genetic diversity is remarkably low, almost entirely the product of genetic drift, and should not be expected to impede development of a broadly protective vaccine. Although errors introduced during genome replication are a major source of genetic variation in all virus populations, limiting the fitness costs of accumulated errors is especially critical for coronaviruses, the RNA genomes of which are the largest known. For this reason, coronaviruses evolved nonstructural protein 14 (nsp14), which accompanies viral replicases during RNA synthesis and excises misincorporated ribonucleotides from nascent strands before they can be extended, thus preventing errors from becoming permanent. This error-correcting capacity was unknown among RNA viruses prior to its discovery in SARS-CoV-1 (2, 3), and it contributes to a replication error rate more than 10-fold lower than that of other RNA viruses (4, 5). This activity also likely contributes to the low genetic diversity of SARS-CoV-2, although to our knowledge nsp14 function in the novel coronavirus has yet to be investigated. For many viruses, surface glycoproteins contain not only elements required for specific binding of cellular receptors, membrane fusion, and virus entry into the host cell but also epitopes recognized by neutralizing antibodies produced as part of an effective adaptive immune response. Hence, tracking genetic variation in the SARS-CoV-2 surface glycoprotein is of paramount importance for determining the likelihood of vaccine effectiveness or immune escape. To put this variation in perspective, Fig. 1 shows a graphical illustration of comparative genetic diversity among surface glycoproteins of select human pathogenic viruses, including SARS-CoV-2, correlated with the availability and effectiveness of respective preventive vaccines. Although genetic diversity is only one of many determinants of vaccine efficacy, there is a clear inverse correlation between these two metrics among viral pathogens examined in our analysis. Presumably due to its relatively recent origins, genetic diversity in the SARS-CoV-2 surface glycoprotein, spike, encoded by the S gene, is exceedingly low, even in comparison to other human coronaviruses. Toward the opposite extreme, diversity among influenza A surface glycoproteins is 437-fold greater than that measured in SARS-CoV-2. The relative age of influenza A (dating at least back to the 16th century) is certainly a major factor in this disparity, as is reassortment of genome segments encoding influenza A surface antigens hemagglutinin (HA) and neuraminidase (NA)(6). Indeed, sudden emergence of influenza A virus variants containing HA–NA combinations not previously encountered by contemporaneous human populations caused the pandemics of 1918 (H1N1), 1957 (H2N2), 1968 (H3N2), and 2009 (H1N1pdm09). Although coronavirus genomes are not segmented like those of influenza viruses, they are nevertheless capable of high rates of recombination. Hence, future …
登录
查看更多内容
影响因子：
8.8
作者：
Marzi, Andrea;Chadinah, Spencer;Feldmann, Heinz
通讯作者：
Feldmann, Heinz
影响因子：
20.6
作者：
Tang, Xiaolu;Wu, Changcheng;Lu, Jian
通讯作者：
Lu, Jian
影响因子：
5.4
作者：
Law, John L. M.;Logan, Michael;Houghton, Michael
通讯作者：
Houghton, Michael
影响因子：
4.3
作者：
Zhang, Zhen-Hua;Wu, Chun-Chen;Lu, Meng-Ji
通讯作者：
Lu, Meng-Ji
影响因子：
64.5
作者：
Korber, Bette;Fischer, Will M.;Montefiori, David C.
通讯作者：
Montefiori, David C.