We have generated the, to our knowledge, largest combination of genotypic and phenotypic information about the impact of codon usage preferences in human cells at several levels, spanning genomic, transcriptomic, proteomic and cell viability and growth data, immediately upon transfection and after experimental evolution and lineage competition. Only this dataset will allow us understand the implications of gene codon usage preferences on the connection between genotype and phenotype, on differential gene evolvability and on differential protein robustness.
Finally we have built on the information and knowledge generated in vitro at the cellular level to extend our research to organism-based level. We will have thus replaced this approach as far as possible for all questions and hypotheses that do not imply the local immune response and the virus-host interaction during chronic infection. We will generate by this approach invaluable, clinically relevant information about the differential progression, potential for malignisation and response to repeated infections depending on codon usage preferences of the viral oncogenes.
By exploring the transcription and translation outcomes from a broad diversity of synonymous sequences, we have been able to show that codon usage preferences strongly impact gene expression in human cells by the introduction of non-predicted splicing events, differentially promoting translation reinitiation upon termination and leaky scanning, it all leading to an increased diversity of transcription and translation products, resulting in an increased phenotypic diversity.
Our results will help disentangle the evolutionary forces underlying the largely divergent clinical, phenotypic presentation of the infections. Our ultimate aim is to understand why most papillomaviruses cause asymptomatic infections, some of them cause bening, wart-like lesions, and only a few are associated to human cancers.
