Abstract
Genetic regulation of gene expression underlies variation in disease risk and other complex traits. The effect of expression quantitative trait loci (eQTLs) varies across cell types; however, the complexity of mammalian tissues makes studying cell-type eQTLs highly challenging. We developed a novel approach in the model nematode Caenorhabditis elegans that uses single-cell RNA sequencing to map eQTLs at cellular resolution in a single one-pot experiment. We mapped eQTLs across cell types in an extremely large population of genetically distinct C. elegans individuals. We found cell-type-specific trans eQTL hotspots that affect the expression of core pathways in the relevant cell types. Finally, we found 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.
Highlights
Gene expression differences have a strong genetic basis, and genome-wide studies have identified thousands of regions affecting gene expression, termed expression quantitative trait loci 1. eQTLs have been found to underlie genetic associations with complex traits and diseases molecular underpinnings of phenotypic variation., and genome-wide eQTL mapping holds great promise for uncovering the Studies in purified blood cell populations4– 6 and computational analyses in human tissues indicate that many eQTLs are cell-type specific
We recently developed a method, C. elegans extreme quantitative trait locus mapping, for genetic analysis of complex traits in extremely large populations of segregants forces the normally hermaphroditic C. elegans to reproduce via obligate outcrossing, allowing us to propagate a large crossing experiment for multiple generations
A large heterogeneous pool of cells from thousands of genetically distinct individuals is profiled using scRNA-seq, cell types are inferred by clustering scRNA-seq profiles and studying known cell-type markers, and genotype information is reconstructed using expressed genetic variants, enabling eQTL mapping in multiple cell types simultaneously
Summary
Gene expression differences have a strong genetic basis, and genome-wide studies have identified thousands of regions affecting gene expression, termed expression quantitative trait loci (eQTLs) 1. eQTLs have been found to underlie genetic associations with complex traits and diseases molecular underpinnings of phenotypic variation. In scRNA-seq, gene expression is profiled at the level of individual cells, and different cell populations are identified based on their gene expression profiles This approach allows simultaneous measurement of expression in multiple tissues and cell types in a “one-pot” experiment, reducing the number of samples that need to be processed and profiled separately. The size and complexity of mammalian tissues has so far limited the ability to use scRNA-seq for eQTL mapping, and studies have focused on purified cell populations and cell lines. One of the mainstays of modern genetic research, C. elegans has an invariant cell lineage that leads to each individual having the same number and identity of cells expression markers that uniquely identify them elegans exceptionally well-suited for using scRNA-seq to map eQTLs across cell types in the natural physiological context of a whole animal, down to cellular resolution.
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