tetano
Editor, Senior Moderator
Mol Biol Evol
. 2023 Jun 21;msad142.
doi: 10.1093/molbev/msad142. Online ahead of print. A non-coding A-to-U Kozak site change related to the high transmissibility of Alpha, Delta, and Omicron VOCs
Jianing Yang[SUP] 1 [/SUP], Yingmin Cui[SUP] 2 [/SUP], Dalang Yu[SUP] 1 [/SUP], Guoqing Zhang[SUP] 1 [/SUP], Ruifang Cao[SUP] 1 [/SUP], Zhili Gu[SUP] 1 [/SUP], Guangyi Dai[SUP] 1 [/SUP], Xiaoxian Wu[SUP] 3 [/SUP], Yunchao Ling[SUP] 1 [/SUP], Chunyan Yi[SUP] 4 [/SUP], Xiaoyu Sun[SUP] 4 [/SUP], Bing Sun[SUP] 4 [/SUP], Xin Lin[SUP] 1 [/SUP], Yu Zhang[SUP] 3 [/SUP], Guo-Ping Zhao[SUP] 1 3 5 [/SUP], Yixue Li[SUP] 1 6 [/SUP], Yi-Hsuan Pan[SUP] 2 [/SUP], Haipeng Li[SUP] 1 [/SUP]
Affiliations
Three prevalent SARS-CoV-2 Variants of Concern (VOCs) emerged and caused epidemic waves. It is essential to uncover advantageous mutations that cause the high transmissibility of VOCs. However, viral mutations are tightly linked so traditional population genetic methods, including machine-learning based methods, cannot reliably detect mutations conferring a fitness advantage. In this study, we developed an approach based on the sequential occurrence order of mutations and the accelerated furcation rate in the pandemic-scale phylogenomic tree. We analyzed 3,777,753 high-quality SARS-CoV-2 genomic sequences and the epidemiology metadata using the Coronavirus GenBrowser. We found that two non-coding mutations at the same position (g.a28271-/u) may be crucial to the high transmissibility of Alpha, Delta, and Omicron VOCs although the non-coding mutations alone cannot increase viral transmissibility. Both mutations cause an A-to-U change at the core position -3 of the Kozak sequence of the N gene and significantly reduce the protein expression ratio of ORF9b to N. Using a convergent evolutionary analysis, we found that g.a28271-/u, S
.P681H/R, and N.R203K/M occur independently on three VOC lineages, suggesting that coordinated changes of S, N, and ORF9b proteins are crucial to high viral transmissibility. Our results provide new insights into high viral transmissibility co-modulated by advantageous non-coding and non-synonymous changes.
Keywords: Kozak sequence; SARS-CoV-2; VOCs; a28271-/u; non-coding mutation; transmissibility.
. 2023 Jun 21;msad142.
doi: 10.1093/molbev/msad142. Online ahead of print. A non-coding A-to-U Kozak site change related to the high transmissibility of Alpha, Delta, and Omicron VOCs
Jianing Yang[SUP] 1 [/SUP], Yingmin Cui[SUP] 2 [/SUP], Dalang Yu[SUP] 1 [/SUP], Guoqing Zhang[SUP] 1 [/SUP], Ruifang Cao[SUP] 1 [/SUP], Zhili Gu[SUP] 1 [/SUP], Guangyi Dai[SUP] 1 [/SUP], Xiaoxian Wu[SUP] 3 [/SUP], Yunchao Ling[SUP] 1 [/SUP], Chunyan Yi[SUP] 4 [/SUP], Xiaoyu Sun[SUP] 4 [/SUP], Bing Sun[SUP] 4 [/SUP], Xin Lin[SUP] 1 [/SUP], Yu Zhang[SUP] 3 [/SUP], Guo-Ping Zhao[SUP] 1 3 5 [/SUP], Yixue Li[SUP] 1 6 [/SUP], Yi-Hsuan Pan[SUP] 2 [/SUP], Haipeng Li[SUP] 1 [/SUP]
Affiliations
- PMID: 37341536
- DOI: 10.1093/molbev/msad142
Three prevalent SARS-CoV-2 Variants of Concern (VOCs) emerged and caused epidemic waves. It is essential to uncover advantageous mutations that cause the high transmissibility of VOCs. However, viral mutations are tightly linked so traditional population genetic methods, including machine-learning based methods, cannot reliably detect mutations conferring a fitness advantage. In this study, we developed an approach based on the sequential occurrence order of mutations and the accelerated furcation rate in the pandemic-scale phylogenomic tree. We analyzed 3,777,753 high-quality SARS-CoV-2 genomic sequences and the epidemiology metadata using the Coronavirus GenBrowser. We found that two non-coding mutations at the same position (g.a28271-/u) may be crucial to the high transmissibility of Alpha, Delta, and Omicron VOCs although the non-coding mutations alone cannot increase viral transmissibility. Both mutations cause an A-to-U change at the core position -3 of the Kozak sequence of the N gene and significantly reduce the protein expression ratio of ORF9b to N. Using a convergent evolutionary analysis, we found that g.a28271-/u, S
.P681H/R, and N.R203K/M occur independently on three VOC lineages, suggesting that coordinated changes of S, N, and ORF9b proteins are crucial to high viral transmissibility. Our results provide new insights into high viral transmissibility co-modulated by advantageous non-coding and non-synonymous changes.Keywords: Kozak sequence; SARS-CoV-2; VOCs; a28271-/u; non-coding mutation; transmissibility.