Discover the physiological and developmental functions of X chromosome dosage using new genetic and system models

Introduction

Sex chromosomes are critical for controlling the phenotypic differences between males and females. However, they also create an imbalance in the gene products of sex-linked genes, with males having only one copy and females having two copies. To counteract this imbalance, many species evolved a chromosome-wide mechanism known as dosage compensation, which helps equalise gene expression between the sexes.

Importance of Dosage Compensation

This process is vital, as failed dosage compensation can lead to sex-specific disorders and lethality in several species, including humans. Although researchers have made significant progress in understanding the mechanistic basis of dosage compensation, the core questions remain unanswered:

• Why is the lack of X-chromosome compensation lethal?
• What are the physiological consequences of its absence?

Research Objectives

The proposed research aims to identify the mechanisms underlying X monosomy-associated lethality by studying the genes, cells, and developmental processes sensitive to X chromosome doses. This question has been poorly investigated partly due to the difficulties of studying sex chromosome effects.

Methodology

To overcome this barrier, we will investigate flies, as these permit the remarkable possibility of generating mosaic animals where sex chromosomes can be genetically manipulated in defined organs, and consequently, functional and molecular analysis.

Here, I will combine classical fly genetics, two novel model systems, and cutting-edge genomic techniques to:

1. Identify the functions of X chromosome dosage in fly development.
2. Characterise the ancestral X chromosome compensatory system of all insects.
3. Discover the general shared functions of sex chromosome dosage in development using new insect model species.

Expected Impact

Thus, results from this research should have a major impact on our understanding of the importance of sex chromosome dosage in physiology and disease.