This work has led to five major original research articles, three of which are already published and two in final stages of submission. We also produced two review articles to disseminate our conceptual advances, along with five collaborative publications extending the impact of our tools and findings to other areas of biology. Dissemination and outreach were central to this project. Findings were presented at over 35 national and international conferences by all members of the team, reaching diverse scientific communities including developmental biology, genetics, cancer biology, and sex differences in health. We also engaged extensively with the public throughout the grant period via science outreach initiatives, particularly targeting middle and high school students.
The genetic and conceptual tools developed in this project offer a powerful foundation for researchers investigating sex differences in both model organisms and human biology. By combining classical Drosophila genetics, innovative genome engineering, and high-resolution functional genomics, we uncovered five major findings over the 5-year duration of the project:
1. Refuting the “Toxic Y” Hypothesis & Establishing the Role of Phenotypic Sex in Longevity
Using novel genetic tools, we showed the Y chromosome does not shorten male lifespan, challenging the long-standing "toxic Y" hypothesis. Instead, phenotypic sex, controlled by a master regulator, determines lifespan and other physiological traits—independently of chromosomal sex. This suggests conserved lifespan regulation by sex-determining pathways across species.
2. Discovery of a Citrate-Dependent Pathway Linking Metabolism to Stem Cell Differentiation
In male germ cells, we uncovered a new axis where citrate uptake fuels Acetyl-CoA production, enabling N-terminal acetylation by NatB, which protects key proteins from degradation and supports sperm differentiation. This reveals a conserved link between metabolism and proteome stability.
3. Demonstrating the Universality and Function of Cellular Sex Identity
Contrary to the mosaic model, we showed that every somatic cell has a defined sexual identity driven by a binary genetic switch. This intrinsic sex identity regulates organ size, reproduction, and species-specific traits—marking the first organism-level demonstration of its physiological significance.
4. Redefining the Role of X Chromosome Dosage Compensation
A targeted screen of over 150 perturbations revealed that dosage compensation is essential in specific adult stem cells, notably in the respiratory system, but dispensable in many other tissues. This challenges the notion that X monosomy lethality results from cumulative gene mis-regulation and highlights polyploidy as a protective mechanism.
5. Identifying a Neural Basis for Sex Differences in Tumour Susceptibility
We showed that gut tumour vulnerability is governed by the intrinsic sexual identity of a central brain circuit, rather than by hormones or tumour cell sex. This fruitless-positive circuit regulates tumour-promoting ILP3 secretion from the visceral muscle via brain–gut projections—demonstrating, for the first time, a neural–tumour axis shaped by neuronal sex.
Together, these results not only reshape long-held views of sex determination and sexual dimorphism but also provide conceptual and technical advances that can be exploited across biological disciplines.
