Subfunctionalisation of paralogous genes and evolution of differential codon usage preferences: The showcase of polypyrimidine tract binding proteins.

Gene paralogs are copies of an ancestral gene that appear after gene or full genome duplication. When two sister gene copies are maintained in the genome, redundancy may release certain evolutionary pressures, allowing one of them to access novel functions. Here, we focused our study on gene paralogs on the evolutionary history of the three polypyrimidine tract binding protein genes (PTBP) and their concurrent evolution of differential codon usage preferences (CUPrefs) in vertebrate species. PTBP1-3 show high identity at the amino acid level (up to 80%) but display strongly different nucleotide composition, divergent CUPrefs and, in humans and in many other vertebrates, distinct tissue-specific expression levels. Our phylogenetic inference results show that the duplication events leading to the three extant PTBP1-3 lineages predate the basal diversification within vertebrates, and genomic context analysis illustrates that local synteny has been well preserved over time for the three paralogs. We identify a distinct evolutionary pattern towards GC3-enriching substitutions in PTBP1, concurrent with enrichment in frequently used codons and with a tissue-wide expression. In contrast, PTBP2s are enriched in AT-ending, rare codons, and display tissue-restricted expression. As a result of this substitution trend, CUPrefs sharply differ between mammalian PTBP1s and the rest of PTBPs. Genomic context analysis suggests that GC3-rich nucleotide composition in PTBP1s is driven by local substitution processes, while the evidence in this direction is thinner for PTBP2-3. An actual lack of co-variation between the observed GC composition of PTBP2-3 and that of the surrounding non-coding genomic environment would raise an interrogation on the origin of CUPrefs, warranting further research on a putative tissue-specific translational selection. Finally, we communicate an intriguing trend for the use of the UUG-Leu codon, which matches the trends of AT-ending codons. Our results are compatible with a scenario in which a combination of directional mutation-selection processes would have differentially shaped CUPrefs of PTBPs in vertebrates: the observed GC-enrichment of PTBP1 in placental mammals may be linked to genomic location and to the strong and broad tissue-expression, while AT-enrichment of PTBP2 and PTBP3 would be associated with rare CUPrefs and thus, possibly to specialized spatio-temporal expression. Our interpretation is coherent with a gene subfunctionalisation process by differential expression regulation associated with the evolution of specific CUPrefs.

Enhanced neutralization escape to therapeutic monoclonal antibodies by SARS-CoV-2 omicron sub-lineages.

The landscape of SARS-CoV-2 variants dramatically diversified with the simultaneous appearance of multiple subvariants originating from BA.2, BA.4, and BA.5 Omicron sub-lineages. They harbor a specific set of mutations in the spike that can make them more evasive to therapeutic monoclonal antibodies. In this study, we compared the neutralizing potential of monoclonal antibodies against the Omicron BA.2.75.2, BQ.1, BQ.1.1, and XBB variants, with a pre-Omicron Delta variant as a reference. Sotrovimab retains some activity against BA.2.75.2, BQ.1, and XBB as it did against BA.2/BA.5, but is less active against BQ.1.1. Within the Evusheld/AZD7442 cocktail, Cilgavimab lost all activity against all subvariants studied, resulting in loss of Evusheld activity. Finally, Bebtelovimab, while still active against BA.2.75, also lost all neutralizing activity against BQ.1, BQ.1.1, and XBB variants.

COUSIN (COdon Usage Similarity INdex): A Normalized Measure of Codon Usage Preferences.

Codon Usage Preferences (CUPrefs) describe the unequal usage of synonymous codons at the gene, chromosome, or genome levels. Numerous indices have been developed to evaluate CUPrefs, either in absolute terms or with respect to a reference. We introduce the normalized index COUSIN (for COdon Usage Similarity INdex), that compares the CUPrefs of a query against those of a reference and normalizes the output over a Null Hypothesis of random codon usage. The added value of COUSIN is to be easily interpreted, both quantitatively and qualitatively. An eponymous software written in Python3 is available for local or online use (http://cousin.ird.fr). This software allows for an easy and complete analysis of CUPrefs via COUSIN, includes seven other indices, and provides additional features such as statistical analyses, clustering, and CUPrefs optimization for gene expression. We illustrate the flexibility of COUSIN and highlight its advantages by analyzing the complete coding sequences of eight divergent genomes. Strikingly, COUSIN captures a bimodal distribution in the CUPrefs of human and chicken genes hitherto unreported with such precision. COUSIN opens new perspectives to uncover CUPrefs specificities in genomes in a practical, informative, and user-friendly way.

Shaking the Tree: Multi-locus Sequence Typing Usurps Current Onchocercid (Filarial Nematode) Phylogeny.

During the past twenty years, a number of molecular analyses have been performed to determine the evolutionary relationships of Onchocercidae, a family of filarial nematodes encompassing several species of medical or veterinary importance. However, opportunities for broad taxonomic sampling have been scarce, and analyses were based mainly on 12S rDNA and coxI gene sequences. While being suitable for species differentiation, these mitochondrial genes cannot be used to infer phylogenetic hypotheses at higher taxonomic levels. In the present study, 48 species, representing seven of eight subfamilies within the Onchocercidae, were sampled and sequences of seven gene loci (nuclear and mitochondrial) analysed, resulting in the hitherto largest molecular phylogenetic investigation into this family. Although our data support the current hypothesis that the Oswaldofilariinae, Waltonellinae and Icosiellinae subfamilies separated early from the remaining onchocercids, Setariinae was recovered as a well separated clade. Dirofilaria, Loxodontofilaria and Onchocerca constituted a strongly supported clade despite belonging to different subfamilies (Onchocercinae and Dirofilariinae). Finally, the separation between Splendidofilariinae, Dirofilariinae and Onchocercinae will have to be reconsidered.