Gap in the functional genomics toolbox and enable direct comparison across genes to assess their mechanistic convergence. A rapid, reproducible, and disease-relevant system in which multiple genes could be studied in parallel would fill an important Laboratories, strains, or individuals ( Kilpinen et al. Identifying convergent mechanismsĪcross diverse disease-associated genes first requires establishing a high-throughput and disease-relevant model system toīoth perturb numerous genes and systematically assess the functional consequences.Īlthough animal models and patient-derived induced pluripotent stem cell (iPSC) models are powerful tools for the study ofĭisease mechanisms, these systems are generally low throughput and require long generation times, and results can vary across On the other hand, if subsets of these genes converge in their mechanisms, then these points of convergence wouldīe logical targets for more broadly applicable therapeutics that apply to the entire subset. If, at anĮxtreme, each disease-associated gene follows a separate mechanistic route, then each will require the development of an independent This genetic heterogeneity provides a substantial challenge to the development of broadly useful therapeutics. When a single copy is mutated to a loss-of-function allele ( O'Roak et al. In autism spectrum disorder (ASD) alone, recent exome sequencing studies have identified over 100 genes that cause ASD Over 1100 of these genes have been causally linked to neurodevelopmental disorders ( Wright et al. Exome- and genome-wide sequencing studies have identified approximately 5500 single-geneĭisorders and traits caused by mutations in over 3800 genes ( Amberger et al. The tremendous progress in identifying disease-associated genes and variants has far outpaced the discovery of the functionsĪnd pathological mechanisms of these genes. Altogether, these results show the utility ofĪ novel and simple approach for the rapid functional elucidation of neurodevelopmental disease-associated genes. Shared clinical phenotypes among individuals with mutations in these genes. Finally, these functionally convergent ASD gene modules predicted Neural progenitor cell proliferation and neurite growth. Live-cell imaging after individual ASD-gene repression validated this functional module, confirming that these genes reduce
Neuron differentiation ( ADNP, ARID1B, ASH1L, CHD2, and DYRK1A) mechanistically converge, as they all dysregulate genes involved in cell-cycle control and progenitor cell proliferation. For a set of 13 autism spectrumĭisorder (ASD)–associated genes, we show that this approach generated important mechanistic insights, revealing two functionallyĬonvergent modules of ASD genes: one that delays neuron differentiation and one that accelerates it. Profiling in differentiating human neurons to rapidly assay the functions of multiple genes in a disease-relevant context,Īssess potentially convergent mechanisms, and prioritize genes for specific functional assays. Here, we have coupled multiplexed repression of neurodevelopmental disease–associated genes to single-cell transcriptional
Necessitates developing novel high-throughput functional genomics approaches to elucidate the molecular mechanisms of these The overwhelming success of exome- and genome-wide association studies in discovering thousands of disease-associated genes