ERC FUNDED PROJECTS

In our quest to fully understand the processes that shape the genomic variation of species, describing variation of the past is a fundamental objective. However, the origins and the extent of great ape variation, the genomic description of extinct primate species and the genomic footprints of introgression events all remain unknown. Even today, and in contraposition to human evolutionary biology, the almost null presence of ancient great ape samples has precluded a comprehensive exploration of such diversity. Here, I present two approaches that will expose great ape diversity throughout time and will allow me to compare the genomic impact of introgression events across lineages. First, I would like to take advantage of ancient ape samples that will provide us with a direct view of the genomes of extinct populations. Second, I would like to exploit current and recent diversity to indirectly access the parts of extinct ape genomes that became hybridized with current species in the past. For the latter, we will analyse hundreds of non-invasive samples taken from present-day great apes as well as historical specimens. Altogether, this information will enable me to decipher novel genomes that until now have been lost in time. In this way, I will be able to properly understand the origins and dynamics of genomic variants and to study how admixture has contributed to today´s adaptive landscape. By completing this proposal and performing analogies to the human lineage, fundamental insights will be revealed about (i) the spatial-temporal history of our closest species and (ii) the functional consequences of introgressed events. On top of that, these results will help to annotate functional consequences of novel mutations in the human genome. In so doing, a fundamental insight will be provided into the evolutionary history of these regions and into human mutations with multiple repercussions in the understanding of evolution and human biology.

1 896 875 €

Start date: 2020-06-01, End date: 2025-05-31

In this project, we will develop and use technology that combines synthetic genomics and live-cell imaging. These methods make it possible to study the intracellular biophysics at single-molecule detail in thousands of genetically different bacterial strains in parallel. Our approach is based on in situ genotyping of a barcoded strain library after phenotyping has been performed by live-cell imaging. Within the scope of the proposed project, the new technology will be used to solve mechanistic and structural questions of the bacterial cell cycle. To this end, we will explore two parallel but complementary applications. In the first application, we will determine the dynamic 3D structure of the E. coli chromosome at 1kb resolution throughout the cell cycle. The structure determination can be seen as a live-cell version of chromatin conformation capture, where we will follow the 3D distances of 10 000 pairs of chromosomal loci over the cell cycle at high resolution. In the second application, we will make a complete CRISPRi knockdown strain library where we can follow the replication forks of the E. coli chromosome and septum formation over the cell cycle in individual cells. Using this strategy, we will resolve how individual gene products contribute to the cell-to-cell accuracy in replication initiation and cell division. In particular, this approach allows us to address the challenging question of size sensing at replication initiation. How the cell can decide that it is large enough to initiate replication is still an open question despite decades of investigations. The general principles for high-end imaging of pool-synthesized cell libraries have nearly unlimited applications throughout cell biology. The specific applications explored in this project will take the understanding of the bacterial cell cycle to a new level and answer general questions about the chromosomal organization and cell size sensing.

2 411 410 €

Start date: 2020-09-01, End date: 2025-08-31

Cells are continuously exposed to insults that can break or chemically modify their DNA. To protect the DNA, cells have acquired an arsenal of repair mechanisms. Proper repair of DNA damage is essential for organismal viability and disease prevention. What is often overlooked is the fact that the eukaryotic nucleus contains many different chromatin domains that can each influence the dynamic response to DNA damage. Different chromatin environments are defined by specific molecular and biophysical properties, which could necessitate distinct chromatin responses to ensure safe DNA damage repair. The aim of this proposal is to understand how diverse chromatin domains, and in particular the dense heterochromatin environment, shape the dynamic chromatin response to DNA damage. I recently developed locus-specific DNA damage systems that allow for in-depth analysis of chromatin domain-specific repair responses in Drosophila tissue. I will employ these systems and develop new ones to directly observe heterochromatin-specific dynamics and repair responses. I will combine these systems and state-of-the art chromatin analysis with high-resolution live imaging to dissect the DNA damage-associated heterochromatin changes to determine their function in repair -kinetics, -dynamics and -pathway choice. Deciphering the chromatin dynamics that regulate DNA damage repair in heterochromatin will have broad conceptual implications for understanding the role of these dynamics in other essential nuclear processes, such as replication and transcription. More importantly, understanding how chromatin proteins promote repair will be important in determining how cancer-associated mutations in these chromatin proteins impact genetic instability in tumours in the long run.

1 499 404 €

Start date: 2019-12-01, End date: 2024-11-30

Branching morphogenesis, the process by which branched organs such as the lung, prostate, kidney or mammary gland are generated, is a paradigmatic example of complex developmental processes bridging multiple scales. The mechanisms through which given molecular signals and cellular behaviours give rise to a robust organ structure remains a fundamental and open question, for which theoretical methods are needed. Our experience in modelling cytoskeletal mechanics, stem cell dynamics and branching processes puts us in a unique position to tackle this fascinating problem, by combining systems biology and biophysical approaches at multiple scales. In particular, we will focus on: 1. Understanding how stochastic rules lead to robust morphogenetic outputs at the organ scale, and which constraints and optimal design principles they impose on physiological function. 2. Characterizing at the cellular scale the bi-directional feedbacks coordinating fate choices of stem/progenitor cells and niche signals during the extensive remodelling events that branching morphogenesis entails. 3. Developing at the subcellular and cellular scale an integrated mechanochemical theory of pattern formation in branched organs, to understand the coordination of mechanical forces and chemical signals defining their global structure. Towards these goals, we will combine analytical and numerical tools with data analysis methods, to reach a quantitative understanding of the emergent mechanisms driving branching morphogenesis. We will challenge our theoretical predictions with published datasets available for different organs, as well as design specific experimental tests in collaboration with experimental biology groups. This will allow us to compare and contrast different systems, and extract generic classes of design principles of organogenesis across length scales. With this, we expect to generate novel insights of broad relevance for the fields of systems, computational and developmental biology.

1 452 604 €

Start date: 2020-07-01, End date: 2025-06-30