The recent outbreak of SARS-CoV-2 underscores the need for understanding the evolutionary processes that drive the emergence and adaptation of zoonotic viruses in humans. Here, we show that recombination in betacoronaviruses, including human-infecting viruses like SARS-CoV and MERS-CoV, frequently encompasses the Receptor Binding Domain (RBD) in the Spike gene. We find that SARS-CoV and SARS-CoV-2 are involved in an ancestral recombination event affecting the RBD. As a result of this recombination event, SARS-CoV and SARS-CoV-2 share a similar genotype in RBD, including two insertions (positions 432-436 and 460-472), and alleles 427N and 436Y which belong to a helix that interacts with the human ACE2 receptor. We perform reconstruction of ancestral states and protein-binding affinity analyses in order to understand what role this ancestral recombination involving SARS-CoV and SARS-CoV-2 might have played in the emergence of the new pandemic virus. We also analyze the ACE2-binding affinity of lineage-specific mutations in the SARS-CoV-2 RBD.

Learning Objectives:

1. Discuss the major drivers of viral evolution

2. Identify hotspots of recombination in coronaviruses

3. Present in-silico predictions of virus binding affinity to the host receptor, and explain what these predictions show about the emergence of SARS-CoV-2