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Since the first case of COVID-19 in December 2019 in Wuhan, China, SARS-CoV-2 has spread worldwide and within a year and a half has caused 3.56 million deaths globally. With dramatically increasing infection numbers, and the arrival of new variants with increased infectivity, tracking the evolution of its genome is crucial for effectively controlling the pandemic and informing vaccine platform development. Our study explores evolution of SARS-CoV-2 in a representative cohort of sequences covering the entire genome in the United States, through all of 2020 and early 2021. Strikingly, we detected many accumulating Single Nucleotide Variations (SNVs) encoding amino acid changes in the SARS-CoV-2 genome, with a pattern indicative of RNA editing enzymes as major mutators of SARS-CoV-2 genomes. We report three major variants through October of 2020. These revealed 14 key mutations that were found in various combinations among 14 distinct predominant signatures. These signatures likely represent evolutionary lineages of SARS-CoV-2 in the U.S. and reveal clues to its evolution such as a mutational burst in the summer of 2020 likely leading to a homegrown new variant, and a trend towards higher mutational load among viral isolates, but with occasional mutation loss. The last quartile of 2020 revealed a concerning accumulation of mostly novel low frequency replacement mutations in the Spike protein, and a hypermutable glutamine residue near the putative furin cleavage site. Finally, end of the year data and 2021 revealed the gradual increase to prevalence of known variants of concern, particularly B.1.1.7, that have acquired additional Spike mutations. Overall, our results suggest that predominant viral genomes are dynamically evolving over time, with periods of mutational bursts and unabated mutation accumulation. This high level of existing variation, even at low frequencies and especially in the Spike-encoding region may become problematic when super-spreader events, akin to serial Founder Events in evolution, drive these rare mutations to prominence. [ABSTRACT FROM AUTHOR]