(A) Model for the synthesis of leader-containing genomic RNA. During negative-strand synthesis (indicated in gray) using positive-strand genomic RNA as a template (indicated in black), coronavirus polymerase switches template at the crossover region to acquire a leader sequence, generating negative-strand genomic RNA with the leader sequence. Alternatively, coronavirus polymerase may stay on the same positive-strand template to complete the synthesis of negative-strand genomic RNA containing a leader sequence. The synthesized negative-strand genomic RNA is then employed as a template to generate positive-strand genomic RNA with a leader sequence. The leader sequence is indicated with an open rectangle, and the polymerase crossover region is indicated with a dashed line. (B) Model for the synthesis of positive-strand leaderless genomic RNA using negative-strand leaderless genome as a template. Coronavirus polymerase employs positive-strand genomic RNA as a template to synthesize negative-strand genomic RNA. However, if template switching does not occur within the crossover region, the intergenic sequence on the positive-strand genomic RNA may serve as a terminator. Polymerase then falls off after copying the 3′-most nucleotide (cytosine) of the intergenic sequence UCUAAAC at position 70 on the positive-strand genomic RNA, which is also the 5′-most nucleotide of the crossover region on the positive-strand genomic RNA with respect to template switching during negative-strand synthesis, leading to the synthesis of leaderless negative-strand genomic RNA. The resulting leaderless negative-strand genomic RNA in turn serves as a template for the generation of leaderless positive-strand genomic RNA. (C) Model for the synthesis of positive-strand leaderless genomic RNA using negative-strand leader-containing genome as a template. After the synthesis of the leader-containing negative-strand genomic RNA, coronavirus polymerase recognizes the 3′-proximal intergenic sequence on the negative-strand leader-containing genomic template as a promoter and internally initiates the synthesis of positive-strand leaderless genomic RNA.