ERC FUNDED PROJECTS

"Mutation and recombination are fundamental biological processes that determine adaptability of populations. The mutation rate reflects the equilibrium between the need to adapt, the burden of mutation load, the “cost of fidelity”, and random drift that determines a lower limit in achievable fidelity. Recombination fulfills an essential mechanistic role during meiosis, ensuring proper chromosomal segregation. Recombination affects the rate of creation and loss of favorable haplotypes, imposing 2nd-order selection pressure on modifiers of recombination. It is becoming apparent that recombination and mutation rates vary between individuals, and that these differences are in part inherited. Both processes are therefore “evolvable”, and amenable to genomic analysis. Identifying genetic determinants underlying these differences will provide insights in the regulation of mutation and recombination. The mutational load, and in particular the number of lethal equivalents per individual, remains poorly defined as epidemiological and molecular data yield estimates that differ by one order of magnitude. A relationship between recombination and fertility has been reported in women but awaits confirmation. Population structure (small effective population size; large harems), phenotypic data collection (systematic recording of > 50 traits on millions of cows), and large-scale SNP genotyping (for genomic selection), make cattle populations uniquely suited for genetic analysis. DAMONA proposes to exploit these unique resources, combined with recent advances in next generation sequencing and genotyping, to: (i) quantify and characterize inter-individual variation in male and female mutation and recombination rates, (ii) map, fine-map and identify causative genes underlying QTL for these four phenotypes, (iii) test the effect of loss-of-function variants on >50 traits including fertility, and (iv) study the effect of variation in recombination on fertility."

2 258 000 €

Start date: 2013-03-01, End date: 2018-02-28

98% of the human genome is non-protein coding raising the question of the role of the dark matter of the genome. It is now admitted that pervasive transcription generates thousands of noncoding transcripts that regulate gene expression and have broad impacts on development and disease. Among the long non coding (lnc)RNAs, antisense transcripts have been poorly studied despite their putative regulatory importance. Several functional examples include X-chromosome inactivation, maintenance of pluripotency and transcriptional regulation. However, no systematic study has yet addressed the comprehensive functional description of human antisense ncRNA, mainly because of technological issues and their low abundance. Indeed, in budding yeast S. cerevisiae, our group showed the existence of an entire class of antisense regulatory lncRNA extremely sensitive to RNA decay pathways, impinging their study so far. The roles for yeast antisense lncRNAs in shaping the epigenome raises important questions: What are the molecular and biochemical mechanisms by which antisense lncRNAs carry out their functions and are they functionally conserved in human cells? We propose that the dark side of the non-coding genome is another layer of gene regulation complexity that needs to be deciphered. With this proposal, we aim to draw the first exhaustive catalog of human antisense lncRNA in various cell types and tissues using up to date High throughput technologies and bioinformatics pipelines. Second, we propose to determine the functional role of antisense lncRNA on genome expression and stability in the context of cellular stress and cancer. We anticipate that powerful and modern genetic tools such DNA-mediated gene inactivation (ASO) and TALEN approaches will allow precise antisense genes manipulation never achieved so far. Our project is strongly supported by preliminary data indicating an unexpected large number of hidden antisense lncRNA in human cells controlled by RNA decay pathways.

1 998 884 €

Start date: 2014-12-01, End date: 2019-11-30

Regulation of gene expression lies at the heart of fundamental biological processes, such as the formation of different cell types inside an embryo or responses to environmental stimuli. Living cells ensure that the right genes are expressed at the right time and place by carefully controlling every RNA molecule inside a cell from its ‘birth’ by transcription to its final ‘death’ by degradation. While vast efforts strive to understand the first part of this process – transcription, studies of RNA degradation have been more limited. Current knowledge largely relies on small-scale investigation of key – but anecdotal – cases, while technical and experimental difficulties limit its large-scale analysis. Therefore, we still lack a systematic and predictive understanding of RNA degradation: technologies to globally measure it, the molecular mechanisms involved, its functional and physiological implications and models to decode and predict it. Transcriptional silencing makes early embryos an ideal system to study RNA degradation and uncover its basic concepts, as I propose here. Aim 1 will decipher how genomic information within native RNA sequences determines their degradation in embryos. Aim 2 will develop the technology to investigate RNA degradation at single-cell resolution, and uncover its regulation within arising embryonic cell populations. Aim 3 will reveal the molecular implementation of the regulatory code of RNA degradation and determine its physiological roles that underlie the massive degradation of maternal mRNAs – a key regulatory event and a main developmental transition in early embryos of all animals. This work will uncover new principles of RNA degradation in early development and elicit its mechanisms and functions using the zebrafish as an in vivo model system. The assays and models to be developed will be broadly applicable to study RNA degradation in diverse contexts, ranging from disease mechanisms to engineering of RNA- protein interactions.

1 500 000 €

Start date: 2020-03-01, End date: 2025-02-28

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