Anomalous biases of reverse mutations in SARS-CoV-2 variants

Abstract

Anomalous reverse mutation patterns in the Delta variants and the Omicron variants are investigated. A previous study on the Omicron BA.1, BA.1.1, and BA.2 has found almost all the variations of sequences containing only one reverse mutation and no other point mutations, suggesting lab origin of the Omicron variant. The histograms of mutations in the spike proteins of major variants are compared, where BA.1 is outstanding in its high reverse mutation rate and low variety of mutations. Among the reverse mutations of BA.1, H681P reversion while preserving K679 is least likely to emerge naturally either through homologous recombination, point mutation, or both of them put together when the sequence alignment and mutation spectrum are taken into account. The sequences including both K679 and P681 are registered by multiple submitters, which consolidates their existence. G614D reverse mutations, a reversion of the earliest and the most dominant point mutation in SARS-CoV-2, in the Delta variant are concentrated around the Great Lakes and G614D in the BA.2 lineage are concentrated on each side of the Hudson River. To elucidate the origin of these sequences that are improbable to emerge through community spread, inspections of laboratories are needed, where the geographical distribution of anomalous sequence detections can help to narrow down the potential sources.