Epidemiologically most successful SARS-CoV-2 variant: concurrent mutations in RNA-dependent RNA polymerase and spike protein

Abstract

The D614G mutation of the Spike protein is thought to be relevant for SARS-CoV-2 infection. Here we report biological and epidemiological aspects of this mutation. Using pseudotyped lentivectors, we were able to confirm that the G614 variant of the Spike protein is markedly more infectious than the ancestral D614 variant. We demonstrate by molecular modelling that the replacement of aspartate by glycine in position 614 facilitates the transition towards an open state of the Spike protein. To understand whether the increased infectivity of the D614 variant explains its epidemiological success, we analysed the evolution of 27,086 high-quality SARS-CoV-2 genome sequences from GISAID. We observed striking coevolution of D614G with the P323L mutation in the viral polymerase. Importantly, exclusive presence of G614 or L323 did not become epidemiologically relevant. In contrast, the combination of the two mutations gave rise to a viral G/L variant that has all but replaced the initial D/P variant. There was no significant correlation between reported COVID mortality in different countries and the prevalence of the Wuhan versus G/L variant. However, when comparing the speed of emergence and the ultimate predominance in individual countries, the G/L variant displays major epidemiological supremacy. Our results suggest that the P323L mutation, located in the interface domain of the RNA-dependent RNA polymerase (RdRp), is a necessary alteration that led to the epidemiological success of the present variant of SARS-CoV-2.

No association between the SARS-CoV-2 variants and mortality rates in the Eastern Mediterranean Region

“…Only seven countries were included in this analysis -Saudi Arabia, Oman, UAE, Bahrain, Palestine, Morocco, and Jordan, where none of the variants was significantly correlated with an increase in CFR ( Figure 5). Consistent with previous studies [22,23], we confirm that NSP12_P323L seems to have quickly co-evolved following S_D614G…”

Functional importance of the D614G mutation in the SARS-CoV-2 spike protein

“…Further, a small but significant positive correlation was reported between the prevalence of S(G614) in a given geographic area and case-fatality rate in that region [ 39 ]. Another group observed a similar trend, although not statistically significant in their dataset [ 40 ]. Moreover, computational models of evolutionary dynamics suggest that D614G is under strong selective pressure [ 31 ].…”

“…Further, quantitative estimates of the basic reproductive number R 0 from infection incidence data suggest that viruses bearing S(G614) are 31% more transmissible than D614, although this analysis did not consider the effect of concomitant changes at other loci in the circulating viral strains [ 41 ]. Various studies have identified co-segregation of changes in other viral genes along with the D614G mutation in spike, such as the P323L mutation in the viral polymerase RdRp which may attenuate replication to compensate for the increased transmissibility of D614G viruses [ 40 , 42 , 43 ].

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Мутации В Геномах SARS-COV-2 Биологических Образцов, Полученных В Конце Марта — Начале Апреля, От Пациентов Города Москвы

“…Many papers suggested that D614G mutation in the viral spike (S) protein SARS-CoV-2 can influence the ability of virus transmission. In recent work [1], it was shown D614G influences the rate of disease transmission only in combination with the P323L mutation in the viral polymerase. We have sequenced 28 full genomes of SARS-CoV-2, obtained from clinical material from patients of different ages.…”

“…По данным всемирной базе GISAID, мутация D614G в S-белке встречается в 76,53% последовательностей (по данным на 20 августа 2020); первый полногеномный сиквенс, в котором она была зарегистрирована -hCoV-19/England/NORW-E82AE/2020 [3]. В недавней работе [1]…”