Delta-1 variant of SARS-COV-2 acquires spike V1264L and drives the pandemic in Indonesia, Singapore and Malaysia (preprint)

ABSTRACT

Since April 2021, delta variant of SARS-COV-2 has gradually overtaken all other variants and become a dominant pandemic driver around the world. It has evolved and yielded four subvariants delta1, delta2, delta3 and delta4. While trying to understand how these subvariants drive the pandemic in Southeast Asia, I noticed that many d1 genomes from Indonesia encode an extra spike substitution, V1264L. Coincidentally, this confers an acidic dileucine motif because residues 1157-1262 are acidic and residue 1265 is leucine. Such a motif may affect subcellular trafficking of the resulting spike protein. Alarmingly, this V1264L-encoding delta1 subvariant (referred to as delta1L) has become the dominant pandemic driver in Indonesia, Singapore, Malaysia and East Timor. Moreover, it has acquired additional spike substitutions L1234L in Singapore and D215Y/N in Malaysia. On the average, the resulting sublineages carry 46-48 mutations per genome, making them some of the most mutated variants identified so far. Moreover, a d1 sublineage from the United Kingdom has acquired V1264L along with spike Y145H and A222V, a signature substitution of a SARS-COV-2 clade that was a major pandemic driver in Europe during the summer of 2020. A222V improves an extensive hydrophobic interaction network at the N-terminal domain of spike protein and may make this sublineage more virulent than delta1 and delta1L. Some delta2 subvariant genomes identified in the United States of America and other countries also encode V1264L. Thus, V1264L is a recurrent spike substitution frequently acquired by d subvariants during convergent evolution. This recurrence also suggests that V1264L is one key mechanism by which d variant adopts to expand its ‘evolutionary cage.’