Genome-wide phenotypic screens provide an unbiased way to identify genes involved in particular biological traits, and have been widely used in lower model organisms. However, cost and time have limited the utility of such screens to address biological and disease questions in mammals. Here we report a highly efficientpiggyBac(PB) transposon-based first-generation (F1) dominant screening system in mice that enables an individual investigator to conduct a genome-wide phenotypic screen within a year with fewer than 300 cages. ThePBscreening system uses visually trackable transposons to induce both gain- and loss-of-function mutations and generates genome-wide distributed new insertions in more than 55% of F1 progeny. Using this system, we successfully conducted a pilot F1 screen and identified 5 growth retardation mutations. One of these mutants, a Six1/4PB/+mutant, revealed a role in milk intake behavior. The mutant animals exhibit abnormalities in nipple recognition and milk ingestion, as well as developmental defects in cranial nerves V, IX, and X. ThisPBF1 screening system offers individual laboratories unprecedented opportunities to conduct affordable genome-wide phenotypic screens for deciphering the genetic basis of mammalian biology and disease pathogenesis.

SummaryThe mechanisms regulating human embryonic stem (ES) cell self-renewal and differentiation are not well defined in part due to the lack of tools for forward genetic analysis. We present a piggyBac transposon gain of function screen in human ES cells that identifies DENND2C, which genetically cooperates with NANOG to maintain self-renewal in the presence of retinoic acid. We show that DENND2C negatively regulates RHOA activity, which cooperates with NANOG to block differentiation. It has been recently shown that RHOA exists in the nucleus and is activated by DNA damage; however, its nuclear function remains unknown. We discovered that RHOA associates with DNA and that DENND2C affects nuclear RHOA localization, activity, and DNA association. Our study illustrates the power of piggyBac as a cost-effective, efficient, and easy to use tool for forward genetic screens in human ES cells and provides insight into the role of RHOA in the nucleus.

Background Although common variants in a large collection of patients are associated with increased risk for bipolar disorder (BD), studies have only been able to predict 25%‐45% of risks, suggesting that lots of variants that contribute to the risk for BD haven't been identified. Our study aims to identify novel BD risk genes. Methods We performed whole‐exome sequencing of 27 individuals from 6 BD multi‐affected Chinese families to identify candidate variants. Targeted sequencing of one of the novel risk genes, SERINC2, in additional sporadic 717 BD patients and 312 healthy controls (HC) validated the association. Magnetic resonance imaging (MRI) were performed to evaluate the effect of the variant to brain structures from 213 subjects (4 BD subjects from a multi‐affected family, 130 sporadic BD subjects and 79 HC control). Results BD pedigrees had an increased burden of uncommon variants in extracellular matrix (ECM) and calcium ion binding. By large‐scale sequencing we identified a novel recessive BD risk gene, SERINC2, which plays a role in synthesis of sphingolipid and phosphatidylserine (PS). MRI image results show the homozygous nonsense variant in SERINC2 affects the volume of white matter in cerebellum. Conclusions Our study identified SERINC2 as a risk gene of BD in the Chinese population.