Gene expression dosage as a driver of cellular and physiological traits

Introduction

The expression dosage of a gene is a fundamental determinant of its downstream function at the cellular and organismal level. Its genetic or environmental perturbations are a driving force of most common and rare diseases in humans. However, we have limited understanding of the specific shape of dosage-to-function curves for human genes, what factors and mechanisms drive their variation across genes, phenotypes, and cellular contexts, and how this contributes to the functional architecture of human traits.

Project Overview

This project addresses these questions using large human genetic data sets and cutting-edge experimental approaches. Using blood cell traits as our study system, we will characterize the relationship between gene dosage and cellular and physiological function on an unprecedented scale and depth. This addresses fundamental questions in systems biology and produces insights that can also benefit genomic medicine and drug development.

Work Packages

The Work Packages of this study will:

1. Establish the dosage-to-function relationship for hundreds of human genes, associating genetically driven gene dosage to blood cell traits in large human genetic data, and by an innovative CRISPR-based experimental approach that maps gene dosage changes to multiple cellular phenotypes.
2. Elucidate how the dosage-to-cellular-function relationships differ between cellular states, and use single-cell RNA sequencing to analyze how regulatory networks mediate context-specific dosage-to-function effects.
3. Characterize upstream genomic and environmental regulators of gene dosage.

Expected Outcomes

This project will build the first comprehensive, generalizable picture of gene dosage-to-function relationships in humans. Our analysis will link these insights to the functional architecture of human traits, providing unique generalizable insights into how disruption of gene dosage and regulatory networks underlies human traits at the cellular and physiological level.