Genetic landscape of T cells identifies synthetic lethality for T-ALL

We conducted a ENU forward genetic screen in zebrafish; identifying 42 genes differentially regulating rag1-expressing T cells fitness relative to growth hormone-expressing somatotrophic epithelials. Our forward genetic screens in zebrafish for recessive mutations affecting early T cell development revealed several major genetic pathways. Genes encoding proteins required for DNA repair & replication, cell cycle regulation, pre-mRNA processing, protein processing in the ER, ribosome biogenesis and hematopoiesis were enriched in the collection of mutants identified. To examine the molecular consequences of these mutations, bulk RNAseq was conducted on mutant and sibling wildtype embryos at 5 day post-fertilisation. Overall design: RNA-Seq was performed on mutant and wt sibling from each zebrafish line (n = 2 – 6). Mutant and sibling wildtype embryos at 5 day post-fertilisation Please note that [1] each processed data files were generated from multiple samples (as indicated in the description field in the corresponding samples) and is linked to the corresponding (sibling) *WT1 sample records (exception for IG447_WT5, IY071_Mut1_2 lines). [2] As each zebrafish line is maintained by outcrossing to wt fish in order to sustain breeding fecundity, fish are likely to be a mixture of different wt strains (as indicated in the sample strain information), but not all will be equal proportions. Thus wt siblings were included in the analysis to try and correct for this. Researchers should proceed with care if performing any kind of polymorphism analysis as this will likely vary between fish lines.