Humans have evolved specialized traits and distinct disease vulnerabilities since divergence from nonhuman primates. However, the genetic and molecular basis for human evolution remains almost entirely unknown. Because it is difficult to predict how differences in genomic sequence and gene expression within the hominid lineage contribute to human-specific biology, there is a critical need for high-throughput, systematic approaches to interrogate functional genetic variation and gene networks.

Therefore, we are developing a quantitative genome-scale platform for (1) identifying the phenotypic consequences of human-specific deletions, and (2) identifying species-specific genetic dependencies in orthologous genes. To accomplish these goals, we are combining advances in human and great ape pluripotent stem cell-derived models with CRISPR interference (CRISPRi) and single-cell RNA-sequencing (scRNAseq). Together, these strategies enable systematic and unbiased analyses of the functional consequences of human genetic and molecular evolution. Decoding the genetic and molecular basis for recent human-specific changes can provide a mechanistic understanding of many human-specific adaptations and disease vulnerabilities through interrogation of sources of genetic variation not represented in typical studies of only humans.