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Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first occurred in Wuhan (China) in December of 2019. Since the outbreak, it has accumulated mutations on its coding sequences to optimize its adaptation to the human host. The identification of its genetic variants has become crucial in tracking and evaluating their spread across the globe. Methods: In this study, we compared 320,338 SARS-CoV-2 genomes isolated from all over the world to the first sequenced genome in Wuhan, China. To this end, we analysed over time the codon usage patterns of SARS-CoV-2 genes encoding for the membrane protein (M), envelope (E), spike surface glycoprotein (S), nucleoprotein (N), RNA-dependent RNA polymerase (RdRp) and ORF1ab. Results: We found that genes coding for the proteins N and S diverged more rapidly since the outbreak by accumulating mutations. Interestingly, all genes show a deoptimization of their codon usage with respect to the human host. Our findings suggest a general evolutionary trend of SARS-CoV-2, which evolves towards a sub-optimal codon usage bias to favour the host survival and its spread. Furthermore, we found that S protein and RdRp are more subject to an increasing purifying pressure over time, which implies that these proteins will reach a lower tendency to accept mutations. In contrast, proteins N and M tend to evolve more under the action of mutational bias, thus exploring a large region of their sequence space. Conclusions: Overall, our study shed more light on the evolution of SARS-CoV-2 genes and their adaptation to humans, helping to foresee their mutation patterns and the emergence of new variants.

Many studies about classification and the functional annotation of intrinsically disordered proteins (IDPs) are based on either the occurrence of long disordered regions or the fraction of disordered residues in the sequence. Taking into account both criteria we separate the human proteome, taken as a case study, into three variants of proteins: i) ordered proteins (ORDPs), ii) structured proteins with intrinsically disordered regions (IDPRs), and iii) intrinsically disordered proteins (IDPs). The focus of this work is on the different functional roles of IDPs and IDPRs, which up until now have been generally considered as a whole. Previous studies assigned a large set of functional roles to the general category of IDPs. We show here that IDPs and IDPRs have non-overlapping functional spectra, play different roles in human diseases, and deserve to be treated as distinct categories of proteins. IDPs enrich only a few classes, functions, and processes: nucleic acid binding proteins, chromatin binding proteins, transcription factors, and developmental processes. In contrast, IDPRs are spread over several functional protein classes and GO annotations which they partly share with ORDPs. As regards to diseases, we observe that IDPs enrich only cancer-related proteins, at variance with previous results reporting that IDPs are widespread also in cardiovascular and neurodegenerative pathologies. Overall, the operational separation of IDPRs from IDPs is relevant towards correct estimates of the occurrence of intrinsically disordered proteins in genome-wide studies and in the understanding of the functional spectra associated to different flavors of protein disorder.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which first occurred in Wuhan (China) in December of 2019, causes a severe acute respiratory illness with a high mortality rate, and has spread around the world. To gain an understanding of the evolution of the newly emerging SARS-CoV-2, we herein analyzed the codon usage pattern of SARS-CoV-2. For this purpose, we compared the codon usage of SARS-CoV-2 with that of other viruses belonging to the subfamily of Orthocoronavirinae. We found that SARS-CoV-2 has a high AU content that strongly influences its codon usage, which appears to be better adapted to the human host. We also studied the evolutionary pressures that influence the codon usage of five conserved coronavirus genes encoding the viral replicase, spike, envelope, membrane and nucleocapsid proteins. We found different patterns of both mutational bias and natural selection that affect the codon usage of these genes. Moreover, we show here that the two integral membrane proteins (matrix and envelope) tend to evolve slowly by accumulating nucleotide mutations on their corresponding genes. Conversely, genes encoding nucleocapsid (N), viral replicase and spike proteins (S), although they are regarded as are important targets for the development of vaccines and antiviral drugs, tend to evolve faster in comparison to the two genes mentioned above. Overall, our results suggest that the higher divergence observed for the latter three genes could represent a significant barrier in the development of antiviral therapeutics against SARS-CoV-2.