Decoding epistatic genome/RNome interactions in eukaryotic fitness gain using Leishmania parasites as a unique model system

Introduction

Darwinian evolution plays a central yet poorly understood role in human disease. Iterations between genetic mutation and environmental selection drive cancer development, microbial infection, and therapeutic failure, thus increasing human mortality.

Molecular Mechanisms

The molecular mechanisms that harness the deleterious effects of genome instability to generate beneficial phenotypes in these pathogenic systems are unknown. Here we investigate this important unsolved question in the protozoan parasite Leishmania that causes devastating human infections.

Leishmania as a Model System

In the absence of transcriptional regulation, these early-branching eukaryotes exploit genome instability to regulate expression by gene dosage. Leishmania thus represents an ideal system to investigate how genome instability drives fitness gain in fast-evolving, eukaryotic cells, such as observed during cancer development.

Breakthrough Discoveries

Synergizing our expertise in genomics, evolution, systems, and RNA biology, we have recently made several breakthrough discoveries that link parasite fitness gain to epistatic interactions between co-amplifying genes of small, non-coding RNAs, which program epitranscriptomic and translational regulation.

Hypothesis

We hypothesize that these genome/RNome interactions generate the phenotypic landscape underlying Leishmania fitness gain.

Specific Aims

Our proposal investigates this ground-breaking concept through two Specific Aims:

1. Combine experimental parasite differentiation and evolution in vitro and in vivo to reveal molecular mechanisms underlying Leishmania predictive adaptation and fitness gain.
2. Investigate how RNA modification and non-coding RNAs contribute to adaptation by regulating mRNA stability and translational control.

Relevance of Findings

Our findings will be highly relevant to other fast-growing, eukaryotic systems that rely on genome instability, such as cancer or fungal pathogens.