Assigning functions to every gene in a living organism is the next challenge for functional genomics. In fact, 85–90% of the 19,000 genes of the nematode Caenorhabditis elegans genome do not produce any visible phenotype when inactivated, which hampers determining their function, especially when they do not belong to previously characterized gene families. We used ¹ H high-resolution magic angle spinning NMR spectroscopy ( ¹ H HRMAS-NMR) to reveal the latent phenotype associated to superoxide dismutase ( sod -1) and catalase ( ctl -1) C. elegans mutations, both involved in the elimination of radical oxidative species. These two silent mutations are significantly discriminated from the wild-type strain and from each other. We identify a metabotype significantly associated with these mutations involving a general reduction of fatty acyl resonances from triglycerides, unsaturated lipids being known targets of free radicals. This work opens up perspectives for the use of ¹ H HRMAS-NMR as a molecular phenotyping device for model organisms. Because it is amenable to high throughput and is shown to be highly informative, this approach may rapidly lead to a functional and integrated metabonomic mapping of the C. elegans genome at the systems biology level.

Schizophrenia is a severe mental illness characterized by delusional beliefs, hallucinations, disordered speech, and deficits in cognitive, emotional, and social behavior. This cross-cultural disorder has a lifetime prevalence of approximately 1%¹ and significant mortality. The disease imposes a substantial burden on individuals, families, and societies, ranking twelfth globally in years lived with disability.² Onset is typically in early adulthood with a frequently chronic trajectory. Schizophrenia’s defining pathophysiology is poorly understood, and current treatments have limited efficacy. High heritability (approximately 0.8)³ has driven the search for genetic variants, the identification of which will contribute to unravelling disease mechanisms and provide essential biological understanding needed for improved evidence-based therapeutics and personalized treatments.

Although zebrafish is used to model human diseases through mutational and morpholino-based knockdown approaches, there are currently no robust transgenic knockdown tools. Here we investigate the knockdown efficiency of three synthetic miRNA-expressing backbones and show that these constructs can downregulate a sensor transgene with different degrees of potency. Using this approach, we reproduce spinal muscular atrophy (SMA) in zebrafish by targeting the smn1 gene. We also generate different transgenic lines, with severity and age of onset correlated to the level of smn1 inhibition, recapitulating for the first time the different forms of SMA in zebrafish. These lines are proof-of-concept that miRNA-based approaches can be used to generate potent heritable gene knockdown in zebrafish.