fluorescence in-situ hybridization

Most DNA methods first grind cells up and extract their DNA, which tells you what sequences are there but throws away where they were inside the cell. Sometimes the location is the whole point — which chromosome a gene sits on, whether a piece of one chromosome has broken off and stuck to another. FISH answers the 'where' by lighting up a specific DNA or RNA sequence right inside the intact cell, under the microscope. 'In situ' is Latin for 'in its original place.'

You make a probe: a short piece of DNA whose sequence matches the target you care about, tagged with a fluorescent dye. The cells (often on a slide, with chromosomes spread out) are gently treated so their DNA strands separate, then the labeled probe is washed over them. The probe base-pairs with — hybridizes to — its matching sequence wherever that sequence physically sits in the cell. Under a fluorescence microscope, the target then appears as a glowing spot exactly at its location. Use several probes with different colors and you can label several targets at once, each its own color.

FISH is how you can literally see a gene on a chromosome. It is used in the clinic to count chromosomes (detecting an extra chromosome 21 in Down syndrome), to spot deletions or duplications, and to find the gene fusions and amplifications that drive certain cancers (for example, checking HER2 status in breast cancer). Its strength and its limit are the same: FISH tells you presence and location of a specific, pre-chosen sequence with beautiful spatial resolution, but it only ever looks for the targets you designed probes against — it is a spotlight, not a survey.