Pelechano, V. et al. Nature 497, 127–131 (2013).

Full appreciation of a genome's functional repertoire requires looking at all the isoforms transcribed from each gene—a challenging endeavor. Pelechano et al. reasoned that to profile isoform diversity, the 5′ and 3′ ends of every transcript needed to be retained on the same sequence read. To accomplish this, they developed transcript isoform sequencing (TIF-seq). They attached a biotin tag to the 5′ end of full-length cDNA from Saccharomyces cerevisiae, circularized each molecule before fragmenting and then isolated the joint 5′-3′ end via the biotin tag. Deep sequencing revealed surprising isoform diversity: for every protein-encoding gene, they saw evidence of extensive alternative splicing, often affecting post-transcriptional regulation. And for the majority of genes, they detected variations in transcript boundaries.