The NONO protein has been characterized as an important transcriptional regulator in diverse cellular contexts. Here we show that loss of NONO function is a likely cause of human intellectual disability and that NONO-deficient mice have cognitive and affective deficits. Correspondingly, we find specific defects at inhibitory synapses, where NONO regulates synaptic transcription and gephyrin scaffold structure. Our data identify NONO as a possible neurodevelopmental disease gene and highlight the key role of the DBHS protein family in functional organization of GABAergic synapses.

Various lines of evidence suggest a mechanistic role for altered cAMP-CREB (cAMP response element - binding protein) signaling in depressive and affective disorders. However, the establishment and validation of human inter-individual differences in this and other major signaling pathways has proven difficult. Here, we describe a novel lentiviral methodology to investigate signaling variation over long periods of time directly in human primary fibroblasts. On a cellular level, this method showed surprisingly large inter-individual differences in three major signaling pathways in human subjects that nevertheless correlated with cellular measures of genome-wide transcription and drug toxicity. We next validated this method by establishing a likely role for cAMP-mediated signaling in a human neuroendocrine response to light - the light-dependent suppression of the circadian hormone melatonin - that shows wide inter-individual differences of unknown origin in vivo. Finally, we show an overall greater magnitude of cellular CREB signaling in individuals with bipolar disorder, suggesting a possible role for this signaling pathway in susceptibility to mental disease. Overall, our results suggest that genetic differences in major signaling pathways can be reliably detected with sensitive viral-based reporter profiling, and that these differences can be conserved across tissues and be predictive of physiology and disease susceptibility.

Meiotic recombination rates vary across the genome, often involving localized crossover hotspots and coldspots. Studying the molecular basis and mechanisms underlying this variation has been challenging due to the high cost and effort required to construct individualized genome-wide maps of recombination crossovers. Here we introduce a new method, called ReMIX, to detect crossovers from gamete DNA of a single individual using Illumina sequencing of 10X Genomics linked-read libraries. ReMIX reconstructs haplotypes and identifies the valuable rare molecules spanning crossover breakpoints, allowing quantification of the genomic location and intensity of meiotic recombination. Using a single mouse and stickleback fish, we demonstrate how ReMIX faithfully recovers recombination hotspots and landscapes that have previously been built using hundreds of offspring. ReMIX provides a high-resolution, high-throughput, and low-cost approach to quantify recombination variation across the genome, providing an exciting opportunity to study recombination among multiple individuals in diverse organisms.

Meiotic recombination is a major molecular mechanism generating genomic diversity. Recombination rates vary across the genome, often involving localized crossover "hotspots" and "coldspots". Studying the molecular basis and mechanism underlying this variation within and among individuals has been challenging due to the high cost and effort required to construct individualized genome-wide maps of recombination crossovers. In this study we introduce a new method to detect recombination crossovers across the genome from sperm DNA using Illumina sequencing of linked-read libraries produced using 10X Genomics technology. We leverage the long range information provided by the linked short reads to phase and assign haplotype states to each DNA molecule. When applied to DNA from gametes of a diploid organism, the majority of linked-read molecules can be used to faithfully reconstruct an individual's two haplotypes present at each location in the genome. A valuable rare fraction of molecules that span meiotic crossovers between the two chromosome haplotypes can then be isolated from the broader population of nonrecombinant molecules. Our pipeline, called ReMIX, allows us to characterize the genomic location and intensity of meiotic crossovers in a single individual and faithfully detects previously described recombination hotspots discovered by studies using mapping panels in mice. With a median crossover resolution of the mouse and stickleback being 15kb and 23kb respectively, ReMIX provides a powerful, high-throughput, low-cost approach to quantify recombination variation across the genome opening up numerous opportunities to study recombination variation with high genomic resolution in multiple individuals. ReMIX source code is available at at https://github.com/adreau/ReMIX.