Precisely measuring the location and frequency of DNA double-strand breaks 
(DSBs) along the genome is instrumental to understanding genomic fragility, but 
current methods are limited in versatility, sensitivity or practicality. Here we 
present Breaks Labeling In Situ and Sequencing (BLISS), featuring the following: 
(1) direct labelling of DSBs in fixed cells or tissue sections on a solid 
surface; (2) low-input requirement by linear amplification of tagged DSBs by in 
vitro transcription; (3) quantification of DSBs through unique molecular 
identifiers; and (4) easy scalability and multiplexing. We apply BLISS to 
profile endogenous and exogenous DSBs in low-input samples of cancer cells, 
embryonic stem cells and liver tissue. We demonstrate the sensitivity of BLISS 
by assessing the genome-wide off-target activity of two CRISPR-associated 
RNA-guided endonucleases, Cas9 and Cpf1, observing that Cpf1 has higher 
specificity than Cas9. Our results establish BLISS as a versatile, sensitive and 
efficient method for genome-wide DSB mapping in many applications.