Developmental GTEx Laboratory, Data Analysis and Coordination Center

ABSTRACT
Understanding the transcriptional programs governing cell identity and function is key to many outstanding
questions in biology and biomedicine. Most variants associated with common diseases and traits lie in non-
coding, regulatory regions of the genome, and to interpret their function, we need to identify the genes they affect
and how those are expressed in the different cells of a tissue within individuals, and quantify how their expression
varies across individuals. How these mechanisms are regulated during human development remains poorly
understood, and most studies to date have relied on human cell lines or model organisms as proxies. GTEx did
not profile tissues from postnatal stages of human development. Regulatory elements and gene networks are
highly cell type–specific, and may only be active during precise developmental stages, during which they may
also contribute to disease susceptibility. Thus, there is a critical need for measuring the transcriptional and
regulatory landscape of tissues and cell types during human development.
We will serve as the LDACC for the creation of the developmental GTEx (dGTEx) resource. (1) We will
work with the BPC to establish a biobank of 30 tissues from each of 120 human postnatal postmortem donors,
consented for broad research use and data sharing. (2) We will select 4 tissues of importance for common
diseases, and in which there is tissue remodelling during development - brain, gut, lung and heart. We will profile
these tissues with multiple single cell assays including snRNA-seq, multiomic RNA/ATAC, and spatial
transcriptomics to create deep molecular maps for variant characterization. (3) We will perform baseline
molecular profiling of genome sequence and bulk transcriptome for all samples, and integrate the resource with
GTEx. We will use these collective data to identify e/sQTLs; create maps of element-gene relationships across
tissues; chart differentiation hierarchies within tissues and across age ranges; nominate cell types in which a set
of variants manifest; and map cellular and spatial relationships among cells, cellular programs, and tissue
features.
This project brings together a team with expertise in human genetics, production science (GTEx,
ENCODE), computational biology, single cell technologies, and common disease genetics. We will create a data
and biospecimen resource for the scientific community that will underpin studies to understand cellular and tissue
changes during human development, genome regulation, and common disease variant interpretation.

Grant Number: 5U24HG012090-05
NIH Institute/Center: NIH
Principal Investigator: KRISTIN ARDLIE