UC San Diego

Genome-wide association studies (GWAS) have suggested that the underlying genetic basis of complex traits and disease is driven by large numbers of non-coding variants with modest effects that likely act by modifying gene regulation. Towards understanding the regulatory impact of genetic variation, expression quantitative trait loci (eQTL) analyses have been performed across dozens of human tissues to link the influence of genetic variants on gene expression levels. While these eQTL studies have provided important biological insights, they are still limited by not considering the contexts in which these variants function, including the stage of development and cell type. Specifically, others have shown increased disease risk in adulthood has links to fetal origins, suggesting that characterizing gene expression in fetal-like cells could identify genetic variants that are associated with adult traits, but function primarily or solely during development. Additionally, as eQTL studies are typically performed across bulk tissues, unaccounted for cellular heterogeneity present in bulk gene expression measurements can affect genotype-gene expression associations. Thus, it is important to identify regulatory variants that alter gene expression in both primitive and adult cell types and to characterize cellular heterogeneity across tissues to comprehensively understand the genetic basis of complex traits and disease.

Here, I present two studies, which utilize gene expression data from fetal-like and adult tissues to characterize cellular heterogeneity at distinct stages of human development. I have examined the cellular heterogeneity in fetal-like induced pluripotent stem cell (iPSC)-derived cardiovascular progenitor cells (CVPCs) using single cell (sc)RNA-seq data to identify cell populations that emerge as a result of the cardiac differentiation. Further, I deconvoluted 180 iPSC-CVPCs and identified factors innate to iPSCs that impacted cardiac fate. Next, I showed that mouse scRNA-seq can be used as an alternative to human scRNA-seq for the deconvolution of adult GTEx bulk tissues and considering cell composition eQTL studies powered the discovery of novel eQTLs, some of which were cell-type-associated and colocalized with GWAS disease loci.