Whole-organism mapping of the genetics of gene expression at cellular resolution

Genetic variants affecting gene expression, termed expression quantitative trait loci (eQTLs), underlie phenotypic variation in complex traits and disease risk. Studies in purified blood cell populations and computational analyses in human tissues suggest that many eQTLs are cell-type specific. Single-cell RNA sequencing (scRNA-seq) has shown promise for eQTL mapping in blood cells and cell lines. However, the complexity of mammalian tissues makes studying cell-type eQTLs with scRNA-seq highly challenging. Here, we report a novel approach in the model nematode Caenorhabditis elegans that uses scRNA-seq to map eQTLs at cellular resolution in a single one-pot experiment. We studied an extremely large population of hundreds of thousands of genetically distinct individuals and mapped both cis and trans eQTLs across the different cell types of C. elegans. We find cell-type-specific trans-eQTL hotspots and show that they affect the expression of core pathways in the relevant cell types. Finally, we find single-cell-specific eQTL effects in the nervous system, including an eQTL with opposite effects in two individual neurons. Our results show that eQTL effects can be specific down to the level of single cells.