Viruses utilize numerous mechanisms to avoid the host cell defense. One such 34 mechanism is the CpG dinucleotide reduction observed in many single-stranded RNA 35 fraction of the observed C>U changes represent multiple, independent events ( Figure S3 ). The reported C>U frequency is therefore most likely an underestimate. Over this 106 period of five months, we find a steady increase in C>U substitutions ( Figure 1B 5'-UU-3') in viral dinucleotide frequencies for the 5-month period ( Figure S4 ). Among all 121 dinucleotides, UpC showed the highest degree of decrease, while UpU exerted the 122 highest rates of increase. CpG, CpA, CpC, CpU and GpA also showed a negative net 123 gain but not as prominent as UpC, CpA or ApG. We find that the majority of dinucleotide 124 losses were due to C>U changes, in agreement with a recent study by Rice and et al. 2020 ). When analyzing the context of genomic sites undergoing C>U changes we 129 noticed an enrichment for 5'-UCG-3' motifs (Table S2) . To assess the contribution of 130 C>U changes in CpG loss, we examined the dynamics of [A/C/G/U]CG trinucleotides 131 over time ( Figure 1D ). The progressive change (~1% over a 5-month period) of 5'-UCG-132 3' to 5'-UUG-3' is most striking when supported by a larger number of genomes (days 133 70 to 115), whereas no such pattern is observed for the other trinucleotides ( Figure 1D ). 134
The association between cytosine deamination and CpG loss is further underlined by 135 the rapid, progressive increase in 5'-UCG-3' > 5'-UUG-3' changes compared to other 5'-136 
For all di-, tri-, and tetra-nucleotide motifs containing C in the reference genome, the noted. The ratio between these two measures was compared to the expected ratio, 215 defined as the number of C's with a C-to-U substitution divided by the total number of 216 C's in the genome. The probability was calculated using a binomial distribution. All 217 statistical tests were performed using Rstudio v. 1.1.414 (Booth et al. 2018) . 218 219 Folding potential 220
The reference sequence was divided into overlapping 500-nucleotides windows, each 221 shifted by 10 nucleotides. These sequences were folded using RNAfold (Lorenz et al. 1  6  11  16  21  26  31  36  41  46  51  56  61  66  71  76  81  86  91  96  101  106  111  116  121  126  131  136 We thank all laboratories which have contributed sequences to the GISAID database 270 and Zhadyra Yerkesh for giving her comments and helpful discussions. 
The data underlying this article are available in GISAID, at https://gisaid.org. The ID 283 numbers of genomes used are provided in Table S1 . 