Discovering mechanisms of human genetic variation and controlling cell states at scale

Population-scale sequencing efforts have catalogued substantial genetic variation in humans such that variant discovery dramatically outpaces interpretation. We discuss how single-cell sequencing is poised to reveal genetic mechanisms at a rate that may soon approach that of variant discovery. The functional genomics toolkit is sufficiently modular to systematically profile almost any type of variation within increasingly diverse contexts and with molecularly comprehensive and unbiased readouts. As a result, we can construct deep phenotypic atlases of variant effects that span the entire regulatory cascade. The same conceptual approach to interpreting genetic variation should be applied to engineering therapeutic cell states. In this way, variant mechanism discovery and cell state engineering will become reciprocating and iterative processes towards genomic medicine.