Blue light induces neuronal-activity-regulated gene expression in the absence of optogenetic proteins, bioRxiv, 2019-03-09

Optogenetics is widely used to control diverse cellular functions with light, requiring experimenters to expose cells to bright light. Because extended exposure to visible light can be toxic to cells, it is important to characterize the effects of light stimulation on cellular function in the absence of exogenous optogenetic proteins. Here we exposed cultured mouse cortical neurons that did not express optogenetic proteins to several hours of flashing blue, red, or green light. We found that exposing neurons to as short as one hour of blue, but not red or green, light results in the induction of neuronal-activity-regulated genes without inducing neuronal activity. Our findings suggest blue light stimulation is ill-suited to long-term optogenetic experiments, especially those that measure transcription.Significance StatementOptogenetics is widely used to control cellular functions using light. In neuroscience, channelrhodopsins, exogenous light-sensitive channels, are used to achieve light-dependent control of neuronal firing. This optogenetic control of neuronal firing requires exposing neurons to high-powered light. We ask how this light exposure, in the absence of channelrhodopsin, affects the expression of neuronal-activity-regulated genes, i.e., the genes that are transcribed in response to neuronal stimuli. Surprisingly, we find that neurons without channelrhodopsin express neuronal-activity-regulated genes in response to as short as an hour of blue, but not red or green, light exposure. These findings suggest that experimenters wishing to achieve longer-term (an hour or more) optogenetic control over neuronal firing should avoid using systems that require blue light.

biorxiv neuroscience 200-500-users 2019

Whole exome sequencing and characterization of coding variation in 49,960 individuals in the UK Biobank, bioRxiv, 2019-03-09

SUMMARYThe UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world. Here we describe the first tranche of large-scale exome sequence data for 49,960 study participants, revealing approximately 4 million coding variants (of which ~98.4% have frequency < 1%). The data includes 231,631 predicted loss of function variants, a >10-fold increase compared to imputed sequence for the same participants. Nearly all genes (>97%) had ≥1 predicted loss of function carrier, and most genes (>69%) had ≥10 loss of function carriers. We illustrate the power of characterizing loss of function variation in this large population through association analyses across 1,741 phenotypes. In addition to replicating a range of established associations, we discover novel loss of function variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical significance in this population, finding that 2% of the population has a medically actionable variant. Additionally, we leverage the phenotypic data to characterize the relationship between rare BRCA1 and BRCA2 pathogenic variants and cancer risk. Exomes from the first 49,960 participants are now made accessible to the scientific community and highlight the promise offered by genomic sequencing in large-scale population-based studies.

biorxiv genomics 200-500-users 2019

 

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