Rapid detection of inter-clade recombination in SARS-CoV-2 with Bolotie

Abstract

The ability to detect recombination in pathogen genomes is crucial to the accuracy of phylogenetic analysis and consequently to forecasting the spread of infectious diseases and to developing therapeutics and public health policies. However, previous methods for detecting recombination and reassortment events cannot handle the computational requirements of analyzing tens of thousands of genomes, a scenario that has now emerged in the effort to track the spread of the SARS-CoV-2 virus. Furthermore, the low divergence of near-identical genomes sequenced in short periods of time presents a statistical challenge not addressed by available methods. In this work we present Bolotie, an efficient method designed to detect recombination and reassortment events between clades of viral genomes. We applied our method to a large collection of SARS-CoV-2 genomes and discovered hundreds of isolates that are likely of a recombinant origin. In cases where raw sequencing data was available, we were able to rule out the possibility that these samples represented co-infections by analyzing the underlying sequence reads. Our findings further show that several recombinants appear to have persisted in the population.

SARS-CoV-2 variant B.1.1.7 is susceptible to neutralizing antibodies elicited by ancestral Spike vaccines

“…The serial waves of variant prevalence in these two countries suggest complex dynamics that may come into play as the SARS-CoV-2 continues to evolve. Furthermore, co-circulation of major variants in a geographically local region may enable recombination (36) bringing together mutations that enhance fitness either through infectivity or immunological resistance.…”

The emergence of inter-clade hybrid SARS-CoV-2 lineages revealed by 2D nucleotide variation mapping

“…Viral homologous recombination, discovered in several other RNA viruses, has the potential to create a novel strain with enhanced virulence 8–11 . For the SARS-CoV-2 virus, several accounts of recombination events have been reported 12–14 .…”

Recombination and low-diversity confound homoplasy-based methods to detect the effect of SARS-CoV-2 mutations on viral transmissibility

“…Most problematically for the van Dorp et al analysis, spurious placements of recombinant sequences can disrupt otherwise homogeneous clades, corrupting the sister-clade variant distributions that their statistic requires. One particularly clear example of this is a recombinant sampled in California that was identified using both clade-based approaches 22,23 as well as using our strategy ( Fig. 2C) 24 , and that gives rise to a D614 variant embedded within the G clade ( Fig 1A).…”

“…2C) 24 , and that gives rise to a D614 variant embedded within the G clade ( Fig 1A). While recombinant sequences clearly arise naturally in coronaviruses, they may also occur as in vitro artifacts resulting from strand switching during PCR amplification 20,25 , or as sequence assembly miscalls of minor variants 23 . Regardless of their origin (in nature, test tube, or software), recombinants violate methodological assumptions, and complicate phylogenetic inference and interpretation of trees; thus, it is important to be aware that recombination can be found among SARS CoV-2 sequences.…”