A palindromic RNA sequence as a common breakpoint contributor to copy-choice recombination in SARS-COV-2.

ABSTRACT

Much remains unknown concerning the origin of the novel pandemic coronavirus that has raged across the globe since emerging in Wuhan of Hubei province, near the center of the People's Republic of China, in December of 2019. All current members of the family Coronaviridae have arisen by a combination of incremental adaptive mutations, against the backdrop of many recombinational events throughout the past, rendering each a unique mosaic of RNA sequences from diverse sources. The consensus among virologists is that the base sequence of the novel coronavirus, designated SARS-CoV-2, was derived from a common ancestor of a bat coronavirus, represented by the strain RaTG13, isolated in Yunnan province in 2013. Into that ancestral genetic background, several recombination events have since occurred from other divergent bat-derived coronaviruses, resulting in localized discordance between the two. One such event left SARS-CoV-2 with a receptor binding domain (RBD) capable of binding the human ACE-2 receptor lacking in RaTG13, and a second event uniquely added to SARS-CoV-2 a site specific for furin, capable of efficient endoproteolytic cleavage and activation of the spike glycoprotein responsible for virus entry and cell fusion. This paper demonstrates by bioinformatic analysis that such recombinational events are facilitated by short oligonucleotide "breakpoint sequences", similar to CAGAC, that direct recombination naturally to certain positions in the genome at the boundaries between blocks of RNA code and potentially RNA structure. This "breakpoint sequence hypothesis" provides a natural explanation for the biogenesis of SARS-CoV-2 over time and in the wild.