The rapid evolution of SARS-CoV-2 during the pandemic, driven by a plethora of mutations, many of which enable the virus to evade host resistance, has likely altered its genome’s compositional structure (i.e. the arrangement of compositional domains of varying lengths and nucleotide frequencies within the genome). To explore this hypothesis, we summarize the evolutionary effects of these mutations by computing the Sequence Compositional Complexity (SCC) in random datasets of fully sequenced genomes. Phylogenetic ridge regression of SCC against time reveals a striking downward evolutionary trend, as well as an increasing rate of change, suggesting the ongoing adaptation of the virus’s genome structure to the human host. Other genomic features, such as strand asymmetry, the effective number of K-mers, and the depletion of CpG dinucleotides, each linked to the virus’s adaptation to its human host, also exhibit decreasing phylogenetic trends over the course of the pandemic, along with strong phylogenetic correlations to SCC. Overall, our findings suggest an accelerated, genome-wide evolutionary trend toward a more symmetric and homogeneous genome compositional structure in SARS-CoV-2.

This project was funded by grants from the Spanish Minister of Science, Innovation and Universities (former Spanish Minister of Economy and Competitiveness) to J.L.O. (Project AGL2017-88702-C2-2-R), P.C. and P.B.G. (Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación, Grant. No. PID2020-116711GB-I00), A.M. (Project PID2019-105969GB-I00), and a grant from Generalitat Valenciana to A.M. (Project Prometeo/2018/A/133) and co-financed by the European Regional Development Fund (ERDF). The most time-demanding computations were done on Linux servers in 1) the Laboratory of Bioinformatics, Dept. of Genetics & Institute of Biotechnology, Center of Biomedical Research, 18100, Granada, Spain; and 2) the Dept. of Applied Physics II and Institute Carlos I for Theoretical and Computational Physics, University of Málaga, 29071, Málaga, Spain.

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