Combined electron- and super resolution fluorescence microscopy for multimodal high content genomic mapping.

Recent years have seen the development of advanced technologies enabling massive scale DNA sequencing with the ultimate aim of rapid de novo genome construction. Despite significant progress, all of the current 'next--‐generation' sequencing technologies suffer from two important drawbacks. Firstly, sample preparation is time--‐consuming and expensive, often requiring days. Secondly, sequence information is produced as a set of short, abstract fragments, which need to be assembled into a complete genome. This is a particularly error--‐ prone process, e.g. when trying to identify large-scale structural variations within the target genome which, although elusive, are particularly relevant for diagnostic and therapeutic use of genomic information in clinical settings. High-resolution 'genomic mapping' can address many of the aforementioned shortcomings. Site-specific labeling of large-or even full-sized genomic fragments with high spatial density can aid to significantly enhance the information content of the map. Here, the ability of (bio)‐functionalized metal nanoparticles to interact specifically with DNA will be used in conjunction with the unique imaging capabilities offered by integrated scanning electron-and super-resolution fluorescence microscopy to enable rapid genomic mapping with significantly enhanced information content. This will unlock the full information potential of complex or repetitive genomic loci and enable DNA mapping at unprecedented speed and reduced cost.