Evolution of Mechanisms for Sex Chromosome Dosage Compensation and Gene Regulation

There is a remarkable diversity of phenotypes among multicellular animals, including differences between males and females. A major driver of phenotypic variation stems from differences in gene regulation. The evolution of these regulatory mechanisms is a central, yet unresolved question in biology. Sex chromosome dosage compensation (SCDC) is an epigenetic process that equalizes sex chromosomal gene expression between males and females. EMERGE uses SCDC as a model to uncover how and why epigenetic mechanisms evolve and function across animals. We will employ a taxonomic gradient from (1) molecular studies in malaria mosquitos to (2) comparative mechanistic analyses across multiple insects, and finally to (3) a broad investigation across all animal clades. First, we will determine how a novel SCDC pathway in malaria mosquitos evolved to specifically regulate the X chromosome. To achieve this, we will use heterologous expressions, alongside in vitro biochemistry and proximity proteomics. Second, we will assess the physiological relevance of SCDC to determine why its absence is lethal in only certain contexts and species. We will test how proteome homeostasis, transcriptional noise, and critical genes influence essentiality. Third, we will explore the diversity of SCDC mechanisms across dozens of animal species with heteromorphic sex chromosomes, including unexplored phyla such as Cnidaria or Mollusca. Employing microscopy, transcriptomics, proteomics, and epigenome profiling, we will study SCDC patterns, conserved and lineage-specific adaptations, as well as regulatory mechanisms. Our findings are expected to reveal general principles of how chromatin controls gene expression, responds to dosage imbalances, and evolves across the animal tree of life. By comprehensively investigating both sexes, EMERGE will at the same time shed light on the regulatory and physiological differences between males and females, a heavily overlooked aspect in research and healthcare.