In recent years, genetic screens performed using high throughput fluorescent microscopes have generated large data-sets that contributed many insights into cell biology. However, such approaches cannot tackle question of ultra-structure that are below the resolution limit of fluorescent microscopy. Electron microscopy (EM) overcomes this resolution limit and generates high-resolution, ultra-structure, imaging. However, this advantage comes at a cost, as EM requires long and expensive sample preparation limiting throughput. To overcome this obstacle, we suggest a robust method to perform high(er) content screening using correlative light and EM. Our approach is based on pooling together different yeast populations for EM sample preparation and subsequent identification if each cell’s genotype using fluorescent barcodes. Coupled with easy to use software for correlation, segmentation and computer image analysis, our method currently allows us to extract 15 different yeast populations from a single sample preparation. Such a methodology is not restricted to yeast and can be utilized in multiple ways to enable EM to become a powerful screening methodology.
