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Due to the emergence of new variants of the SARS-CoV-2 coronavirus, the question of how the viral genomes evolved, leading to the formation of highly infectious strains, becomes particularly important. Three major emergent strains, Alpha, Beta and Delta, characterized by a significant number of missense mutations, provide a natural test field. We accumulated and aligned 4.7 million SARS-CoV-2 genomes from the GISAID database and carried out a comprehensive set of analyses. This collection covers the period until the end of October 2021, i.e., the beginnings of the Omicron variant. First, we explored combinatorial complexity of the genomic variants emerging and their timing, indicating very strong, albeit hidden, selection forces. Our analyses show that the mutations that define variants of concern did not arise gradually but rather co-evolved rapidly, leading to the emergence of the full variant strain. To explore in more detail the evolutionary forces at work, we developed time trajectories of mutations at all 29,903 sites of the SARS-CoV-2 genome, week by week, and stratified them into trends related to (i) point substitutions, (ii) deletions and (iii) non-sequenceable regions. We focused on classifying the genetic forces active at different ranges of the mutational spectrum. We observed the agreement of the lowest-frequency mutation spectrum with the Griffiths–Tavaré theory, under the Infinite Sites Model and neutrality. If we widen the frequency range, we observe the site frequency spectra much more consistently with the Tung–Durrett model assuming clone competition and selection. The coefficients of the fitting model indicate the possibility of selection acting to promote gradual growth slowdown, as observed in the history of the variants of concern. These results add up to a model of genomic evolution, which partly fits into the classical drift barrier ideas. Certain observations, such as mutation “bands” persistent over the epidemic history, suggest contribution of genetic forces different from mutation, drift and selection, including recombination or other genome transformations. In addition, we show that a “toy” mathematical model can qualitatively reproduce how new variants (clones) stem from rare advantageous driver mutations, and then acquire neutral or disadvantageous passenger mutations which gradually reduce their fitness so they can be then outcompeted by new variants due to other driver mutations. 

Abstract Recent progress in microdissection and in DNA sequencing has facilitated the subsampling of multi-focal cancers in organs such as the liver in several hundred spots, helping to determine the pattern of mutations in each of these spots. This has led to the construction of genealogies of the primary, secondary, tertiary, and so forth, foci of the tumor. These studies have led to diverse conclusions concerning the Darwinian (selective) or neutral evolution in cancer. Mathematical models of the development of multi-focal tumors have been devised to support these claims. We offer a model for the development of a multi-focal tumor: it is a mathematically rigorous refinement of a model of Ling et al. (2015). Guided by numerical studies and simulations, we show that the rigorous model, in the form of an infinite-type branching process, displays distributions of tumor size which have heavy tails and moments that become infinite in finite time. To demonstrate these points, we obtain bounds on the tails of the distributions of the process and an infinite series expansion for the first moments. In addition to its inherent mathematical interest, the model is corroborated by recent literature on apparent super-exponential growth in cancer metastases.