ERC FUNDED PROJECTS

A key question in modern science is to explain how the present-day universe of galaxies evolved from the initial conditions measured in the micro-wave background at recombination. Over the next 5 years I propose to undertake a major program of research to address this issue, by discovering and studying directly the progenitors of today's massive galaxies during the first ~2 billion years of cosmic history, and hence performing critical tests of current theories of galaxy formation. It is now clear that to sample representative volumes of the high-redshift universe requires ultra-deep near-infrared, mid-infrared and sub-mm surveys covering over ~1 sq. degree. Until now this has not been possible, but this field is about to be revolutionized by the introduction of a new generation of wide-field facilities in the next year. Specifically, 2009 will see the commissioning of the new near-infrared VISTA survey telescope in Chile, the new SCUBA2 sub-mm camera on the JCMT in Hawaii, the far-infrared Herschel Space Observatory, and the near-infrared camera WFC3 in the Hubble Space Telescope. Now, through my leadership of the deepest of the new generation of wide-field infrared and submm surveys to be undertaken with these revolutionary new facilities, I am unusually well-placed to take an integrated approach to the study of galaxy formation/evolution reaching back, for the first time, into the epoch of re-ionisation, at redshifts z ~ 7 - 10. Through this application I request the level of support required to exploit these new and unique data in what is one of the most important and topical areas at the forefront of modern astronomical research. Investment in this research program will also help ensure that European astronomers are strongly positioned to exploit the James Webb Space Telescope (JWST), the Atacama Large Millimetre Array (ALMA), and future large telescopes (e.g. E-ELT) to study the physics of galaxy formation over virtually all of cosmic history.

2 317 255 €

Start date: 2010-04-01, End date: 2016-03-31

Diffusive shock acceleration is widely acknowledged as the most likely source of cosmic rays and high energy particles. The basic macroscopic theory of how cosmic rays gain energy during multiple shock crossings is well known, but the microphysics of the interaction between cosmic rays (CR) and the MHD background fluid remained poorly understood before the recent discovery of a new non-resonant instability by which the CR precursor could greatly amplify the ambient magnetic field. The aims of the project are: 1) to develop the first self-consistent non-linear simulation of the CR/MHD interaction; to calculate the magnitude of the saturated magnetic field and the maximum energy to which CR are accelerated. We will characterise the structure of the amplified magnetic field and compare it with x-ray observations of the time-evolving outer shock of supernova remnants (SNR). We will investigate the effect of various orientations of the shock relative to the ambient magnetic field, the effect of non-diffusive transport on the energy spectrum and CR escape from the SNR, and how these match observation. 2) to extend the simulation to relativistic shocks as found in gamma-ray bursts (GRB) and active galactic nuclei (AGN); to establish whether the non-resonant instability operates effectively at relativistic shock velocities, whether it explains the large magnetic field found in GRB, and determine the maximum CR energy achieved by relativistic shocks. 3) to investigate high density shocks in GRB, x-ray flashes (XRF) and supernovae (SN) where radiative processes, pair production and other particle/photon and particle/particle interactions are important. We shall investigate CR acceleration on SN shock breakout and very young SNR as a possible source of very high energy CR.

900 024 €

Start date: 2010-05-01, End date: 2015-04-30

The central research theme of this proposal is the study of social change (skills, productivity, attitudes and beliefs) in Europe along cohort lines and as a function of changing age composition. Using demographic methods, age-specific and cohort-specific changes shall be quantitatively disentangled. The impact of migration flows as well as fertility differentials combined with intergenerational transmissions will be taken into account. It is expected that viewed together, these analyses will result in significant new insights and represent frontier research about likely social and economic challenges associated with ageing and demographic change in Europe and the appropriate policies for coping with them. Unlike projections of long-term economic growth or energy use, demographic forecasts tend to have comparatively low margins of error, even for forecasts half a century ahead. Traits that change systematically along age or cohort lines may therefore be projected with some degree of accuracy, which in turn can allow governments and individuals to better foresee and improve policies for predictable social change. The study will investigate two major topics, the first relating to human capital, skills, and work performance; the second relating to beliefs and attitudes in Europe. Understanding age variation in productivity and how to improve senior workers skills and capacities are paramount for ageing countries. Moreover, individual-level demographic behaviour can have aggregate level implications, including changing societal values and belief structures. The binding element is how such projections will improve one s capacity to foresee and hence develop more targeted policies that relate to ageing societies.

981 415 €

Start date: 2009-10-01, End date: 2015-03-31

Following a long history of quantitative genetics in crop plants, it now becomes feasible to use naturally-occuring variation contained in Arabidopsis thaliana accessions (lines isolated from natural populations) as the source of quantitative genomics approaches, designed to map QTLs and resolve them at the gene level. Apart from being able to exploit in multiple genetic backgrounds allelic variation that cannot be easily generated by conventional mutagenesis, the (relatively few) success of the QTL studies has often been because of the use of quantitative phenotyping, as opposed to the qualitative gauges used in typical mutant screens. Among the various genetic mechanisms responsible for natural variation that have just started to be revealed, cis-acting regulation is potentially of large impact, despite remaining more difficult to recognize and confirm. The objective of this project is to apply genome-wide quantitative molecular genetics to both, a very integrative and classical quantitative trait (growth in interaction with the environment) and a molecular trait a priori more directly linked to the source of variation (gene expression under cis-regulation). We propose to use a combination of our unique high-troughput phenotyping robot, fine-mapping, complementation approaches and association genetics to pinpoint a significant number of QTLs and eQTLs to the gene level and identify causative polymorphisms and the molecular variation controlling natural diversity. Working at an unprecedented scale should finally allow to resolve enough quantitative loci and pay a significant contribution to drawing a general picture as to how and where in the pathways adaptation is shaping natural variation and improve our understanding of the transcriptional cis-regulatory code.

1 742 113 €

Start date: 2010-02-01, End date: 2016-01-31

Cells use circuits of interacting proteins to respond to their environment. In the past decades, molecular biology has provided detailed knowledge on the proteins in these circuits and their interactions. To fully understand circuit function requires, in addition to molecular knowledge, new concepts that explain how multiple components work together to perform systems level functions. Our lab has been a leader in defining such concepts, based on combined experimental and theoretical study of well characterized circuits in bacteria and human cells. In this proposal we aim to find novel principles on how circuits resist fluctuations and errors, and how they can be controlled by drugs: (1) Why do key regulatory systems use bifunctional enzymes that catalyze antagonistic reactions (e.g. both kinase and phosphatase)? We will test the role of bifunctional enzymes in making circuits robust to variations in protein levels. (2) Why are some genes regulated by a repressor and others by an activator? We will test this in the context of reduction of errors in transcription control. (3) Are there principles that describe how drugs combine to affect protein dynamics in human cells? We will use a novel dynamic proteomics approach developed in our lab to explore how protein dynamics can be controlled by drug combinations. This research will define principles that unite our understanding of seemingly distinct biological systems, and explain their particular design in terms of systems-level functions. This understanding will help form the basis for a future medicine that rationally controls the state of the cell based on a detailed blueprint of their circuit design, and quantitative principles for the effects of drugs on this circuitry.

2 261 440 €

Start date: 2010-03-01, End date: 2015-02-28

Our project is to understand the role of non coding (nc)RNA in the regulation of epigenetic landscape and gene expression. RNA interference pathway is absent in the budding yeast but recent works from our laboratory showed the existence of an original ncRNA-dependent pathway that controls gene expression in S. cerevisiae. We characterized a cryptic unstable ncRNA mediating the transcriptional silencing of the transposon Ty1 through histone methylation. Furthermore, unpublished data suggest the existence of subtelomeric ncRNAs that might control telomere metabolism and promoter-associated ncRNAs that mediate repressive epigenetic marks. We propose that a class of unstable ncRNA mediates genome expression and fluidity through histone modifications. Following 2 directions, our aim is to systematically identify these ncRNAs (A) and further characterize their regulatory mechanisms (B). (A) First, we aim to identify the regulatory ncRNAs by performing genome-wide approaches in strains accumulating these regulatory ncRNAs. We envisage developing protocols to analyze the cryptic transcriptome using deep sequencing technologies. (B) Second, we will further characterize the previously identified regulatory ncRNAs controlling repetitive regions (Ty1 transposon and telomeric repeats) but also gene expression. Through a range of experimental procedures from living cell biology (Fluorescence Immuno Hybridization), biochemical approaches (RNA-TRAP) and genetic, we will determine the dynamics of the regulatory ncRNA within the cell, the associated proteins that regulate their activities and the chromatin defects resulting from their expression. Our aim is to extensively describe the RNAi-like regulation in S. cerevisiae, that we anticipate to be broadly conserved in other eukaryotes.

1 735 524 €

Start date: 2009-12-01, End date: 2014-11-30

I propose to combine state-of-the-art observations of weak gravitational lensing and baryon acoustic oscillations to answer one fundamental question; is the accelerating expansion of our Universe caused by dark energy, or is it a manifestation of beyond-Einstein gravity theories, as might arise if the Universe has more dimensions? This frontier research will have a wide ranging impact as is it believed that understanding the dark energy phenomenon will revolutionize our understanding of Physics today. The observational task of detecting and analysing probes of dark energy is technically very challenging and may be subject to systematic limits. I detail how I will exploit synergies between the weak lensing and baryon acoustic oscillations techniques, showing that the physical systematics that effect each technique can be neatly resolved using complementary information from the alternative technique. With support from the ERC I will create an inter-disciplinary team well positioned to first solve many of the systematic problems associated with dark energy research and then apply those novel solutions to the dark energy analysis of three world-leading wide-field surveys that I currently co-investigate; CFHTLS, a recently completed 170 square degree ugriz survey, PanSTARRS-1, a soon to be started all-sky grizy survey and ADEPT, a space-based infra-red telescope for baryon acoustic oscillation studies proposed for NASA s Joint Dark Energy Mission. Using innovative 3D statistical analyses, optimised photometric redshifts and new combined lensing and galaxy clustering statistics, my ERC team will aim to control systematic errors to place joint constraints on the evolving nature of dark energy and test directly beyond-Einstein gravity.

1 258 797 €

Start date: 2010-04-01, End date: 2015-10-31

DNA sequence and epigenetic chromatin maps are important in understanding how genomes are regulated. However, these maps are linear and do not account for the three-dimensional context within which the genome functions in the cell. The spatial organisation of the genome in the nucleus is not random and is conserved in evolution, implying that it is under functional selection. This proposal aims to determine the functional significance of positioning specific genome regions at the edge of the nucleus in mammalian cells. The nuclear periphery has conventionally been considered as a zone of inactive chromatin and transcriptional repression. Several regulatory gene loci move away from the nuclear periphery as they are activated during differentiation. Novel approaches, developed by ourselves and others, that allow genomic regions to be relocated from the centre of the nucleus to the periphery, have directly shown that proximity to the nuclear edge can down-regulate human gene expression. We propose to dissect the pathways that mediate this spatially-defined transcriptional regulation, to determine what features make certain genes susceptible to it, to establish the functional consequences of preventing gene repositioning during differentiation, and to examine defects of the periphery found in premature ageing. A neglected hypothesis is that positioning of inactive chromatin against the nuclear periphery is a mechanism to minimize DNA damage on sequences in the nuclear centre. We will determine whether mutation rate is altered when loci are repositioned towards the nuclear periphery. By experimentally remodelling the spatial organisation of the genome, this proposal goes beyond the current descriptive phase of 3D nuclear organisation, into an understanding of its functional consequences on multiple aspects of genome function. It will also aid in understanding human diseases characterised by alterations of the nuclear periphery.

1 701 090 €

Start date: 2010-03-01, End date: 2016-02-29

Over the next decade, much effort on major astronomical facilities will be dedicated to large-scale surveys of the galaxy population. Their aim is two-fold: understanding the origin and evolution of galaxies and their central supermassive black holes, and clarifying the nature of dark matter, dark energy and the process that produced all cosmic structure. Achieving these goals will require powerful and flexible modelling tools that can simulate galaxy evolution in all viable cosmologies and under a wide variety of assumptions about the governing physical processes. Such capabilities do not currently exist. I propose to develop them through a major expansion of the functionality and scope of the Millennium Simulation archive. New simulations, new theoretical approaches and new web services will allow users to study galaxy formation across the full range of galaxy masses (from dwarf spheroidals to giant cDs). Remote users will be able to change parameters and modelling prescriptions at will, creating virtual surveys of universes with any chosen cosmology and galaxy formation model. Matching to multiwavelength surveys of real galaxies will make it possible to isolate the physical processes driving galaxy evolution, and to characterize the systematic errors that uncertain galaxy formation physics induce in precision estimates of cosmological parameters. Scientific problems where these new capabilities may be decisive in enabling progress include: the role of supermassive black holes in shaping galaxy formation; the origin of diversity in the forms of galaxies and in their nuclear activity; the effects of environment on galaxy structure; the formation history of our own Milky Way; the nature of the first galaxies and their effects on later and more easily observable generations of galaxies; the distribution and nature of dark matter; the origin of all cosmic structure; and the nature of dark energy.

1 830 000 €

Start date: 2010-01-01, End date: 2014-12-31

Comparative genomics revealed that ~5% of the human genome is conserved among mammals. This fraction is likely functional, and could harbor pathogenic mutations. We have shown (Nature 2002, Science 2003) that more than half of the constrained fraction of the genome consists of Conserved Non-Coding sequences (CNCs). Model organisms provided evidence for enhancer activity for a fraction of CNCs; in addition another fraction is part of large non-coding RNAs (lincRNA). However, the function of the majority of CNCs is unknown. Importantly, a few pathogenic mutations in CNCs have been associated with genetic disorders. We propose to i) perform functional analysis of CNCs, and ii) identify the spectrum of pathogenic CNC mutations in recognizable human phenotypes. The aims are: 1. Functional genomic connectivity of CNCs 1a. Use 4C in CNCs in various cell types and determine their physical genomic interactions. 1b. Perform targeted disruption of CNCs in cells and assess the functional outcomes. 2. Pathogenic variation of CNCs 2a. Assess the common variation in CNCs: i) common deletion/insertions in 350 samples by aCGH of all human CNCs; ii) common SNP/small indels using DNA selection and High Throughput Sequencing (HTS) of CNCs in 100 samples. 2b. Identify likely pathogenic mutations in developmental syndromes. Search for i) large deletions and duplications of CNCs using aCGH in 1500 samples with malformation syndromes, 1000 from spontaneous abortions, and 500 with X-linked mental retardation; and ii) point mutations in these samples by targeted HTS. The distinction between pathogenic and non-pathogenic variants is difficult, and we propose approaches to meet the challenge. 3. Genetic control (cis and trans eQTLs) of expression variation of CNC lincRNAs, using 200 samples.

2 353 920 €

Start date: 2010-07-01, End date: 2015-06-30

Much has been said on how to reduce current anthropogenic emissions with the aid of a portfolio of existing technologies. However, stabilization of atmospheric concentrations of greenhouse gasses to a safe level requires that over time net emissions fall to zero. There is only one way that this can be achieved in a manner that is acceptable to the majority of the world's citizens: through some kind of technological revolution. To bring about such an innovation breakthrough extensive research and development (R&D) investments will be required. This will be specifically important for Europe, given its leading position in climate negotiations and in the light of the Lisbon Agenda. Technological breakthroughs will have an essential role in tackling the competitiveness issue that has gained great relevance lately in the policy debate. On top of this, technological transfers to Developing Countries could be the turning key to solve the logjam affecting international negotiations. The current proposal aims at producing an unprecedented analysis of energy-related innovation mechanisms; understanding the role of R&D investments and of inter countries and inter sector spillovers; disentangling the role of public and private R&D investments; incorporating in the analysis the uncertainty that inevitably affects the successfulness of R&D programs; simulating optimal responses using an integrated assessment model. The analysis will make use of empirical analysis of existing databases and will collect new data. Expert elicitation methods will be used in order to better assess technology-specific uncertain effectiveness of R&D programs. Simulation models will be used to produce quantitative grounded results. Summa of the analyses will be projections for optimal public and private energy R&D and energy technologies investment strategies as a product of a cost effectiveness analysis of a stringent climate stabilization target.

920 000 €

Start date: 2010-01-01, End date: 2013-09-30

Since the mid-nineteen century life expectancy in developed countries has doubled, increasing from levels around 40 years to above 80 years. This research project is motivated by the need to further explore how societies have achieved the current levels of longevity, in terms of life expectancy and modal age at death. To achieve this, age-patterns and time-trends in cause of death contribution to longevity are assessed. This historical analysis is carried out in fifty developed and developing countries/areas. It is expected that the cause of death contribution to the advancement of longevity is country/region specific. However, the hypothesis to be tested is that there are common cause-specific time-trends across countries which can be described by a model of cause of death contribution to longevity. Several purposes for such a model can be listed: it will allow us to study expected future mortality directions in developed nations that are currently still facing high levels of some particular causes of death, e.g. the Netherlands and United States. It could also help investigating the retrocession in mortality observed in some transitional countries/areas, particularly in Eastern Europe. Finally, the accelerated epidemiological transition in developing countries is compared to the slower trend in the developed world at earlier times, model results versus observed cause-contribution. The interest in the latter comparison is to foresee the increase in the prevalence of chronic disease in low-income countries predicted by the WHO and the World Bank. Furthermore, one in every three countries in the world has adequate cause-specific mortality data. The proposed model could facilitate estimating the current cause of death status in developing countries. This project addresses a significant question concerning the mechanisms (age and cause of death) that direct reductions in mortality.

300 380 €

Start date: 2010-05-01, End date: 2015-04-30

Over the last decade epigenetic gene regulation has become a major focus of scientific research as it was shown to play an important role in normal plant and animal development, but also in the ontogeny of human disease. A role of epigenetic processes in evolution, however, has found little general support to date. The goal of this project is to understand the complex interplay of epigenetic mechanisms in plant development and evolution. Many of the approaches we use rely on the recent advances in sequencing technologies, which allow the analysis of molecular characters at an unprecedented level and speed. To achieve our goal, we will focus on two epigenetic paradigms. In Program A, we will focus on dissecting the mechanisms of genomic imprinting at the MEDEA (MEA) locus in Arabidopsis, which we will investigate using genetic, molecular, and innovative biochemical approaches to gain a comprehensive picture of the complex interplay of various epigenetic pathways. In program B, we will analyze the role of epigenetic change in adaptation and evolution using (i) an experimental selection approach in Arabidopsis, where genome-wide analyses of epigenetic modifications have become possible, and (ii) a stable, heritable, epigenetic change occurring in Mimulus populations. In this system, an epigenetic switch of the pollinator syndrome leads to reproductive isolation and, therefore, has an effect on population structure and thus the evolutionary trajectory. These experimental systems each offer unique opportunities to shed light onto the underlying mechanisms controlling epigenetic states. In combination with the new methodologies used, these analyses promise to provide step change in our understanding of epigenetic processes at the level of genes, organisms, and populations.

2 496 641 €

Start date: 2010-04-01, End date: 2015-12-31

We apply for financial support for the new, fourth phase of the Optical Gravitational Lensing Experiment (OGLE-IV) - one of the largest scale sky surveys worldwide, operating continuously since 1992. During its operation the OGLE project contributed significantly to many fields of modern astrophysics including gravitational microlensing, extrasolar planets searches, stellar astrophysics, Galactic structure and many others. The main scientific goal of the OGLE-IV phase will be the second generation planetary microlensing survey. It should result in top rank discoveries of the Earth mass planets and should provide the full census of planets down to Earth masses orbiting their hosts at 1-5 AU orbits. This parameter space is only accessible to the microlensing technique. Complementary census of planets orbiting at the distances smaller that 1 AU is to be made by space missions using transit technique. OGLE-IV survey will also conduct research in many other top rank astrophysical topics like the search for Pluto size dwarf planets from the Kuiper Belt, search for free-floating black holes, microlensing in the Magellanic Clouds and Galactic disk. Hundreds of new discoveries in the variable star field are also guaranteed. Moreover, OGLE-IV will operate on-line services providing real time photometry of variable objects of many types. The OGLE-IV data will be placed in public domain and available to the astronomical community.

2 498 000 €

Start date: 2010-01-01, End date: 2014-12-31

Strong emission features dominate the IR spectra of the interstellar medium of the Milky Way, galaxies in the local Universe and out to redshifts of ~3. These features are generally attributed to IR fluorescence of large Polycyclic Aromatic Hydrocarbon (PAH) molecules pumped by UV photons. These species must be abundant, ubiquitous, and an important component of the ISM. However, despite extensive experimental and theoretical efforts, no specific PAH or even classes of PAHs have been unambiguously identified. Hence, we do not really know the intrinsic physical and chemical properties of these species and therefore cannot quantify their role in the Universe. I propose a highly interdisciplinary program combining observational, theoretical, and experimental studies to determine the IR emission characteristics of large PAH molecules, their origin and evolution, and their influence on the Universe around us. The proposed program will analyze interstellar PAH spectral maps obtained with Spitzer and ISO and relate the spatial variations in the spectral diversity to variations in the characteristics of the radiation field and the physical conditions of these regions that will be obtained with Herschel. This observational program will be aided by an innovative laboratory program that will measure the IR characteristics of large, astrophysically relevant PAH molecules in the gas phase and by a modelling program of the emission characteristics of these PAHs in space. In addition, the photochemistry of gaseous PAHs will be studied in the laboratory using novel techniques, allowing us to model the chemical evolution of PAHs and their reaction products in the interstellar medium. In this way, key astronomical questions involving interstellar PAHs can be addressed.

2 383 980 €

Start date: 2010-05-01, End date: 2015-04-30

Future, large galaxy surveys (such as BOSS, DES, LSST, EUCLID, ADEPT etc.) will cover of the order of 10000 square degrees on the sky, with the primary science goal to unravel the nature of the physics responsible for the current accelerated expansion of the universe. This acceleration likely involves new physics which could imply ether a modification of our understanding of particles and fields (if the acceleration is caused by a new negative pressure-component) or a change in our understanding of space and time (by modifying Einstein's General Relativity laws). The unprecedented and exquisite data provided by these surveys will make possible also other interesting science with implications for fundamental physics (e.g., inflation, neutrino properties) and astrophysics (e.g., biasing, galaxy formation). The success of future large-scale galaxy surveys evidently requires a correct interpretation of their data. The current proposal, which benefits from the interaction of Cosmology, astrophysics and particle physics, aims at building up a set of robust tools to maximize the physics extracted from large-scale structure data. Such an interplay is mandatory to ensure a suitable modeling of the observables and a meaningful comparison with the theoretical predictions. The PI is involved with surveys such as BOSS, ADEPT and LSST and for the past year has been leading a working group with the goal of bringing together particle physicists and cosmology to better understand dark energy. The methods developed in the proposal presented here are expected to be used by the international community involved in future surveys. This would imply a big step for Spanish groups joining or even leading future Cosmology or Astro-particle physics projects.

1 395 000 €

Start date: 2009-11-01, End date: 2015-10-31

The discovery of extra-solar planetary systems with properties so different from those of our own Solar System has overturned our theoretical understanding of how planets and planetary systems form. Indeed, planet formation models have to link observations of two classes of objects: Protoplanetary disk, whose structure and early evolution provide the initial conditions of planets formation, and actual detected planets. The observational knowledge of these two classes of objects will see in the near future dramatic improvements, with three major breakthroughs: 1) high angular resolution observations will tightly constrain the structure and early evolution of protoplanetary disks, 2) direct observation of extrasolar planets will allow to understand their internal structure as well as their formation process, and 3) detection of very low mass extrasolar planets will constrain the mass function of planets and planetary systems, down to the terrestrial planet regime The goal of this project is to develop a theoretical understanding of planet formation that quantitatively stands up to these observational confrontations. For this, we will build on the basis of first generation planet formation models developed at the time the PI was assistant at the Physikalisches Institute of the University of Berne. The PI, a PhD student, and a Postdoc will conduct three inter-related sub-projects linked to the three breakthroughs mentioned above: A) improving the disk part of planet formation models, B) determining the internal structure of forming planets, including the effects of accretion shocks and envelope pollution by infalling planetesimals, and calculating their early evolution, and C) building planetary system formation models, including both gas giant and low mass rocky planets.

1 395 323 €

Start date: 2010-02-01, End date: 2015-11-30

Living organisms change and evolve because of mutations in their DNA. Recent findings suggest that some DNA sequences are hypervariable and evolvable , while others are extremely robust and remain constant over evolutionary timescales. The long-term goal of our research is to combine theory and experiments to investigate the molecular mechanisms underlying genetic robustness and evolvability. Apart from the fundamental aspects, we also plan to explore practical facets, including swift evolution of pathogens and construction of hypervariable modules for synthetic biology. In this proposal we focus on one specific topic, namely the role of tandem repeats as hypervariable modules in genomes. Tandem repeats are short DNA sequences that are repeated head-to-tail. Such repeats have traditionally been considered as non-functional junk DNA and they are therefore mostly ignored. However, our ongoing research shows that tandem repeats often occur in coding and regulatory sequences. The repeats show mutation rates that are 10 to 10.000 fold higher than mutation rates in the rest of the genome. These frequent mutations alter the function and/or expression of genes, allowing organisms to swiftly adapt to novel environments. Hence, repeats may be a common mechanism for organisms to generate potentially beneficial variability in certain regions of the genome, while keeping other regions stable and robust (Rando and Verstrepen, Cell 128: 655; Verstrepen et al., Nature Genetics 37: 986; Verstrepen et al., Nature Microbiol. 2: 15). We propose a multidisciplinary systems approach to unravel the biological role of repeats. First, we will use bioinformatics to screen various model genomes and identify, categorize and analyze all tandem repeat loci in the model eukaryote Saccharomyces cerevisiae. Using this data, we will select a subset of repeats and apply experimental techniques to investigate the functional consequences of mutations in these repeats.

1 753 527 €

Start date: 2009-12-01, End date: 2014-11-30

We aim to study transcriptomes with single-cell resolution, a long-standing goal in biology, to answer fundamental questions about gene regulation. The main objective concerns gene regulation during in vivo differentiation and in pluripotent cells by studying single-cells from murine preimplantation embryos, a model system with natural single-cell resolution, important biology and medical potential. This would also allow us to explore general regulatory principles of gene expression programs of individual cells. This research program will be accomplished by novel deep sequencing technology of mRNAs (mRNA-Seq) to obtain quantitative, unbiased and genome-wide gene and isoform expression measurements. We are therefore developing new experimental and computational methods for genome-wide analyses of transcriptomes at single-cell resolution. The biological significances of the proposed research are unique insights into early embryonic development. Deep sequencing of transcriptomes will also reveal post-transcriptional gene regulation important for pluripotent cells and identified pluripotency-specific gene and isoform expressions will be important for future stem cell based therapies. The inherit single-cell nature of the model system together with its important biology makes it a model systems exceptionally well suited for a systems biology approach aiming to characterize gene regulation at single-cell resolution. The novel methodology has tremendous potential to enable complete mRNA characterization of individual cells. The deep sequencing approach with state-of-the-art computational analyses is both more quantitative than previous methods and it will give readouts on alternative isoforms generated by alternative promoters, splicing and polyadenylation.

1 654 384 €

Start date: 2010-02-01, End date: 2015-01-31

Telomeres have long been known to play crucial roles in protecting chromosome ends from attrition and fusion and thus safeguarding genome stability, but their complete functional repertoire has yet to be fully understood. Among the fundamental roles of telomeres is their role in meiosis, the process by which parental genomes are recombined and halved, allowing the generation of genetic diversity via sexual reproduction. As cells progress from mitotic to meiotic cycles, telomere functions change radically as all telomeres gather to a small region of the nuclear periphery near the centrosome to form the telomere bouquet . While this bouquet is widely conserved, the challenges of manipulating meiosis in most eukaryotes has made bouquet function a matter of speculation until recently. We utilize the fission yeast Schizosaccharomyces pombe as a model to study telomeres, as this organism provides a powerful combination of genetic manipulability and striking conservation of chromosomal structure/function with human. Recently, we made the unexpected discovery that the bouquet controls the behavior of meiotic centrosomes and spindles. Furthermore, we find that the bouquet is required not only for proper spindle formation, but also for attachment of meiotic chromosomes to the spindle via their centromeres. Using molecular genetics, quantitative live analysis and biochemistry, we propose to define the mechanisms by which the gathered telomeres control spindle behavior. We will also investigate what aspect of the telomere confers proper centromere-spindle attachment and what goes wrong at centromeres in cells lacking the bouquet. These studies will illuminate mechanisms of communication between chromosomes and the spindle apparatus that should be widely conserved among eukaryotes.

1 451 943 €

Start date: 2010-06-01, End date: 2015-05-31

Most of nature s biodiversity, and many potentially useful metabolic capabilities, remain hidden among the vast numbers of uncharacterized environmental microbes. Because cultivation is still not possible for most of these microbes, cultivation-independent molecular techniques such as polymerase chain reaction (PCR), fluorescent in situ hybridization (FISH), or shotgun DNA sequencing have been used in order to study their function and ecology in their natural habitats. However, none of the above techniques have so far been sufficient for any systematic assignment of molecular functions to distinct microbial lineages. Thus, most of the molecular ecology of natural microbes remains elusive. Here, we propose a computational meta-analysis and synthesis of existing and newly generated molecular sequence data sampled directly from the environment combining DNA sequencing data (metagenomics), and proteome expression data (metaproteomics). This analysis will be coupled to computational modelling of genome content evolution at the community level. We will aim to assess how gene repertoires of microbial communities, and their taxonomic compositions, change across distinct environments, in response to changed conditions, and through time. We plan to address fundamental questions in microbial ecology, including the extent of cooperation among members of the communities, stability of community composition at evolutionary timescales, the importance of lateral gene transfers, the extent of functional adaptation/regulation in situ, and whether gene occurrence and expression patterns are diagnostic of community functions and ecological status.

1 129 800 €

Start date: 2010-02-01, End date: 2016-01-31