Project description:Animal African trypanosomosis, caused by blood protozoan parasites transmitted mainly by tsetse flies, represents a major constraint for millions of cattle in sub-Saharan Africa. Exposed cattle include West African taurine breeds called trypanotolerant according to their ability to control parasite development and to survive and grow in enzootic areas, and indicine breeds that are trypanosusceptible to the disease. Until now the genetic basis of trypanotolerance remains unclear. Here, we improved knowledge in the biological processes involved in trypanotolerance by identifying bovine genes differentially expressed during an experimental infection by Trypanosoma congolense and their biological functions. To this end, whole blood genome-wide transcriptome profiling by RNA sequencing was performed on five West African cattle breeds, three trypanotolerant taurine breeds (N'Dama, Lagune and Baoulé), one susceptible zebu (Zebu Fulani) and one African taurine x zebu admixed breed (Borgou), at four dates, one before and three during infection. As expected, infection had a major impact on cattle blood transcriptome whatever the breed. The functional analysis of differentially expressed genes over time in each breed confirmed an early activation of the innate immune response, followed by an activation of the humoral response and an inhibition of T cells functions at the chronic stage of infection. More importantly, we highlighted overlooked features, as a strong disturbance in host metabolism and cell production energy that differentiate trypantolerant and trypanosusceptible breeds. N'Dama breed showed the earliest regulation of immune response, associated with a strong activation of cellular energy production, this last feature being also shared with Lagune, and to a lesser extent with Baoulé. Susceptible Zebu Fulani breed was distinguished from other breeds by the strongest modification in lipid metabolism regulation. Lastly, basal differences in gene expression reflected the structuration of cattle genetic diversity, and could have consequences on the tolerant or susceptible phenotype. Overall, it would be of value to deeper investigate interactions between immune response and cell metabolism that likely impact disease outcome.
Project description:Prostate cancer (PrCa) manifests substantial variation in incidence rates among distinct populations. African American (AA) men are more likely to be diagnosed with and die from PrCa than European American (EA) men. Despite ongoing advancements in identifying polygenic risk variants from large genome-wide association study (GWAS) cohorts, the genetic mechanisms underlying the higher prevalence of PrCa in AA men remain unclear. A systematic approach that does not rely on extensive cohorts to identify causal regulatory variants contributing to PrCa development is still lacking. Here, by employing a sequence-based deep learning model of prostate regulatory enhancers, we identified ~2,000 essential SNPs (eSNPs) with increased alternative allele frequency in AA and which potentially affect the enhancer function leading to greater PrCa susceptibility. The identified eSNPs potentially mediate PrCa development through two complementary mechanisms: alternative alleles with increased enhancer activity are associated with immune system suppression, while those with decreased enhancer activity are linked to differentiation processes. Interestingly, the eSNPs disrupt the binding of key prostate transcription factors including FOX, AR and HOX families, collectively contributing to PrCa predisposition. Together these eSNPs can be used to assess polygenic risk score that is more effective than previous GWAS-based risk scores in distinguishing individuals with PrCa from the control.