Tewhey, R. et al. Cell 165, 1519–1529 (2016).

Ulirsch, J.C. et al. Cell 165, 1530–1545 (2016).

Our knowledge of the genome has been improving, but biochemical annotation and sequence conservation still cannot adequately predict the impact of genetic variation in noncoding regions. Two groups have now designed massively parallel reporter assays, each using pools of barcoded plasmids encoding variants and a minimal promoter, to scan for effects on gene expression that can be read out by sequencing. In lymphoblastoid and hepatocarcinoma cells, Tewhey et al. tested over 32,000 variants from expression quantitative trait loci and putative regulatory regions, finding over 800 variants that increase expression levels. In erythroid cells, Ulirsch et al. studied over 2,700 variants genetically linked to red blood cell traits, finding 32 functional variants and confirming the role of three using targeted genome editing.