Significance In this study, we discovered that the genome of SARS-CoV-2 to date can be classified in six major types characterized by 14 signature single nucleotide variations (SNVs). In particular, type VI, that was first reported in China and spread to different countries, has become the major type (more than 95% among data collected after mid-May 2020). The signature SNVs for this strain type, C241T (5′UTR), C3037T (nsp3 F924F), C14408T (nsp12 P4715L), and A23403G (S protein D614G), exhibit high pairwise allelic associations, and the haplotype 241T-3037T-14408T-23403G has the highest frequency. Understanding nucleotide variations in the SARS-CoV-2 genome will provide useful insight for the developmental history of the pandemic, and even the disease management, if the biological significance is understood. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of COVID 19, continues to evolve since its first emergence in December 2019. Using the complete sequences of 1,932 SARS-CoV-2 genomes, various clustering analyses consistently identified six types of the strains. Independent of the dendrogram construction, 13 signature variations in the form of single nucleotide variations (SNVs) in protein coding regions and one SNV in the 5′ untranslated region (UTR) were identified and provided a direct interpretation for the six types (types I to VI). The six types of the strains and their underlying signature SNVs were validated in two subsequent analyses of 6,228 and 38,248 SARS-CoV-2 genomes which became available later. To date, type VI, characterized by the four signature SNVs C241T (5′UTR), C3037T (nsp3 F924F), C14408T (nsp12 P4715L), and A23403G (Spike D614G), with strong allelic associations, has become the dominant type. Since C241T is in the 5′ UTR with uncertain significance and the characteristics can be captured by the other three strongly associated SNVs, we focus on the other three. The increasing frequency of the type VI haplotype 3037T-14408T-23403G in the majority of the submitted samples in various countries suggests a possible fitness gain conferred by the type VI signature SNVs. The fact that strains missing one or two of these signature SNVs fail to persist implies possible interactions among these SNVs. Later SNVs such as G28881A, G28882A, and G28883C have emerged with strong allelic associations, forming new subtypes. This study suggests that SNVs may become an important consideration in SARS-CoV-2 classification and surveillance.
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