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

There is remarkable genetic diversity throughout the human population, but variant interpretation lags far behind discovery. As a result, most genetic variation is not clinically actionable. Single-cell sequencing provides a high-throughput, disease- and pathway-agnostic means to profile variant effects with mechanistic detail across the entire regulatory cascade. Many single-cell genomics methods have been coupled to CRISPR-based gene disruption, but these techniques are rapidly expanding to accommodate increasingly diverse types of perturbations including missense variants, protein fusions, structural variants, genetic circuits, chemical perturbations, and increasingly their combinations. High-throughput, deep phenotyping of genetic variation will allow researchers to define causal mechanisms and nominate precision therapeutics for controlling cell states. 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. [ABSTRACT FROM AUTHOR]