Single-nucleotide conservation state annotation of the SARS-CoV-2 genome

Abstract

Given the global impact and severity of COVID-19, there is a pressing need for a better understanding of the SARS-CoV-2 genome and mutations. Multi-strain sequence alignments of coronaviruses (CoV) provide important information for interpreting the genome and its variation. We apply a comparative genomics method, ConsHMM, to the multi-strain alignments of CoV to annotate every base of the SARS-CoV-2 genome with conservation states based on sequence alignment patterns among CoV. The learned conservation states show distinct enrichment patterns for genes, protein domains, and other regions of interest. Certain states are strongly enriched or depleted of SARS-CoV-2 mutations, and the state annotations are more predictive than existing genomic annotations in prioritizing bases without non-singleton mutations, which are likely enriched for important genomic bases. We expect the conservation states to be a resource for interpreting the SARS-CoV-2 genome and mutations.

SARS-CoV-2 gene content and COVID-19 mutation impact by comparing 44 Sarbecovirus genomes

“…This region overlaps the 3′-UTR pseudoknot RNA structure 45 involved in RNA synthesis, providing a likely explanation for its high nucleotide-level constraint. The alignment of ORF10 is strongly enriched for the combinatorial and spatial patterns characteristic of intergenic bases 46 , consistent with the non-coding status of ORF10. Moreover, ribosome footprints in the region occur in an overlapping upstream ORF or in a truncated ORF rather than uniquely in ORF10, consistent with incidental initiation events rather than functional translation (Fig.…”