Project acronym BactInd
Project Bacterial cooperation at the individual cell level
Researcher (PI) Rolf Kümmerli
Host Institution (HI) UNIVERSITAT ZURICH
Call Details Consolidator Grant (CoG), LS8, ERC-2015-CoG
Summary All levels of life entail cooperation and conflict. Genes cooperate to build up a functional genome, which can yet be undermined by selfish genetic elements. Humans and animals cooperate to build up societies, which can yet be subverted by cheats. There is a long-standing interest among biologists to comprehend the tug-of-war between cooperation and conflict. Recently, research on bacteria was successful in identifying key factors that can tip the balance in favour or against cooperation. Bacteria cooperate through the formation of protective biofilms, cell-to-cell communication, and the secretion of shareable public goods. However, the advantage of bacteria being fast replicating units, easily cultivatable in high numbers, is also their disadvantage: they are small and imperceptible, such that measures of cooperation typically rely on averaged responses across millions of cells. Thus, we still know very little about bacterial cooperation at the biological relevant scale: the individual cell level. Here, I present research using the secretion of public goods in the opportunistic human pathogen Pseudomonas aeruginosa, to tackle this issue. I will explore new dimensions of bacterial cooperation by asking whether bacteria engage in collective-decision making to find optimal group-level solutions; whether bacteria show division of labour to split up work efficiently; and whether bacteria can distinguish between trustworthy and cheating partners. The proposed research will make two significant contributions. First, it will reveal whether bacteria engage in complex forms of cooperation (collective decision-making, division of labour, partner recognition), which have traditionally been associated with higher organisms. Second, it will provide insights into the evolutionary stability of cooperation – key knowledge for designing therapies that interfere with virulence-inducing public goods in infections, and the design of stable public-good based remediation processes.
Summary
All levels of life entail cooperation and conflict. Genes cooperate to build up a functional genome, which can yet be undermined by selfish genetic elements. Humans and animals cooperate to build up societies, which can yet be subverted by cheats. There is a long-standing interest among biologists to comprehend the tug-of-war between cooperation and conflict. Recently, research on bacteria was successful in identifying key factors that can tip the balance in favour or against cooperation. Bacteria cooperate through the formation of protective biofilms, cell-to-cell communication, and the secretion of shareable public goods. However, the advantage of bacteria being fast replicating units, easily cultivatable in high numbers, is also their disadvantage: they are small and imperceptible, such that measures of cooperation typically rely on averaged responses across millions of cells. Thus, we still know very little about bacterial cooperation at the biological relevant scale: the individual cell level. Here, I present research using the secretion of public goods in the opportunistic human pathogen Pseudomonas aeruginosa, to tackle this issue. I will explore new dimensions of bacterial cooperation by asking whether bacteria engage in collective-decision making to find optimal group-level solutions; whether bacteria show division of labour to split up work efficiently; and whether bacteria can distinguish between trustworthy and cheating partners. The proposed research will make two significant contributions. First, it will reveal whether bacteria engage in complex forms of cooperation (collective decision-making, division of labour, partner recognition), which have traditionally been associated with higher organisms. Second, it will provide insights into the evolutionary stability of cooperation – key knowledge for designing therapies that interfere with virulence-inducing public goods in infections, and the design of stable public-good based remediation processes.
Max ERC Funding
1 994 981 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym BENDER
Project BiogENesis and Degradation of Endoplasmic Reticulum proteins
Researcher (PI) Friedrich Förster
Host Institution (HI) UNIVERSITEIT UTRECHT
Call Details Consolidator Grant (CoG), LS1, ERC-2016-COG
Summary The Endoplasmic Reticulum (ER) membrane in all eukaryotic cells has an intricate protein network that facilitates protein biogene-sis and homeostasis. The molecular complexity and sophisticated regulation of this machinery favours study-ing it in its native microenvironment by novel approaches. Cryo-electron tomography (CET) allows 3D im-aging of membrane-associated complexes in their native surrounding. Computational analysis of many sub-tomograms depicting the same type of macromolecule, a technology I pioneered, provides subnanometer resolution insights into different conformations of native complexes.
I propose to leverage CET of cellular and cell-free systems to reveal the molecular details of ER protein bio-genesis and homeostasis. In detail, I will study: (a) The structure of the ER translocon, the dynamic gateway for import of nascent proteins into the ER and their maturation. The largest component is the oligosaccharyl transferase complex. (b) Cotranslational ER import, N-glycosylation, chaperone-mediated stabilization and folding as well as oligomerization of established model substrate such a major histocompatibility complex (MHC) class I and II complexes. (c) The degradation of misfolded ER-residing proteins by the cytosolic 26S proteasome using cytomegalovirus-induced depletion of MHC class I as a model system. (d) The structural changes of the ER-bound translation machinery upon ER stress through IRE1-mediated degradation of mRNA that is specific for ER-targeted proteins. (e) The improved ‘in silico purification’ of different states of native macromolecules by maximum likelihood subtomogram classification and its application to a-d.
This project will be the blueprint for a new approach to structural biology of membrane-associated processes. It will contribute to our mechanistic understanding of viral immune evasion and glycosylation disorders as well as numerous diseases involving chronic ER stress including diabetes and neurodegenerative diseases.
Summary
The Endoplasmic Reticulum (ER) membrane in all eukaryotic cells has an intricate protein network that facilitates protein biogene-sis and homeostasis. The molecular complexity and sophisticated regulation of this machinery favours study-ing it in its native microenvironment by novel approaches. Cryo-electron tomography (CET) allows 3D im-aging of membrane-associated complexes in their native surrounding. Computational analysis of many sub-tomograms depicting the same type of macromolecule, a technology I pioneered, provides subnanometer resolution insights into different conformations of native complexes.
I propose to leverage CET of cellular and cell-free systems to reveal the molecular details of ER protein bio-genesis and homeostasis. In detail, I will study: (a) The structure of the ER translocon, the dynamic gateway for import of nascent proteins into the ER and their maturation. The largest component is the oligosaccharyl transferase complex. (b) Cotranslational ER import, N-glycosylation, chaperone-mediated stabilization and folding as well as oligomerization of established model substrate such a major histocompatibility complex (MHC) class I and II complexes. (c) The degradation of misfolded ER-residing proteins by the cytosolic 26S proteasome using cytomegalovirus-induced depletion of MHC class I as a model system. (d) The structural changes of the ER-bound translation machinery upon ER stress through IRE1-mediated degradation of mRNA that is specific for ER-targeted proteins. (e) The improved ‘in silico purification’ of different states of native macromolecules by maximum likelihood subtomogram classification and its application to a-d.
This project will be the blueprint for a new approach to structural biology of membrane-associated processes. It will contribute to our mechanistic understanding of viral immune evasion and glycosylation disorders as well as numerous diseases involving chronic ER stress including diabetes and neurodegenerative diseases.
Max ERC Funding
2 496 611 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym CHROCODYLE
Project Chromosomal Condensin Dynamics: From Local Loading to Global Architecture
Researcher (PI) Stephan GRUBER
Host Institution (HI) UNIVERSITE DE LAUSANNE
Call Details Consolidator Grant (CoG), LS1, ERC-2016-COG
Summary Striking morphological transformations are a hallmark of any cell division cycle. During nuclear division chromatin is compacted into distinctive rod-shaped chromatids in preparation of chromosome segregation by the spindle apparatus. Multi-subunit SMC protein complexes and a large number of regulatory factors are at the heart of this elementary process. SMC complexes also play key roles during other aspects of genome function such as the control of gene expression and the repair of damaged DNA. They are thought to act as chromatin linkers with exquisite specificity for certain pairs of DNA fibres. However, the underlying molecular mechanisms are not understood. Active extrusion of DNA loops by the SMC complex has been proposed to be the mechanistic basis for the establishment of long-range, intra-chromatid DNA bridges.
Here, I put forward a multi-pronged research programme that aims to elucidate fundamentally conserved features of SMC protein function and action using the prokaryotic SMC condensin complex in Bacillus subtilis as a tractable model system. We will conduct a combined structural, biochemical and cell biology approach (including crystallography, electron paramagnetic resonance, ChIP-Seq and ‘native’ HiC) to uncover how the SMC complex acts at the higher levels of organization of the bacterial chromosome to promote the efficient individualization of sister DNA molecules. We will reveal the molecular and structural bases for the association between the SMC complex and the bacterial chromosome at different stages of the loading reaction – each representing a crucial intermediate in a sophisticated chromosome organization process. For the first time, we will be able to map the paths of chromosomal DNA through an SMC complex.
Our in-depth mechanistic insights will likely have implications for the understanding of various pathological conditions and have the potential to contribute to the development of novel antibacterial compounds.
Summary
Striking morphological transformations are a hallmark of any cell division cycle. During nuclear division chromatin is compacted into distinctive rod-shaped chromatids in preparation of chromosome segregation by the spindle apparatus. Multi-subunit SMC protein complexes and a large number of regulatory factors are at the heart of this elementary process. SMC complexes also play key roles during other aspects of genome function such as the control of gene expression and the repair of damaged DNA. They are thought to act as chromatin linkers with exquisite specificity for certain pairs of DNA fibres. However, the underlying molecular mechanisms are not understood. Active extrusion of DNA loops by the SMC complex has been proposed to be the mechanistic basis for the establishment of long-range, intra-chromatid DNA bridges.
Here, I put forward a multi-pronged research programme that aims to elucidate fundamentally conserved features of SMC protein function and action using the prokaryotic SMC condensin complex in Bacillus subtilis as a tractable model system. We will conduct a combined structural, biochemical and cell biology approach (including crystallography, electron paramagnetic resonance, ChIP-Seq and ‘native’ HiC) to uncover how the SMC complex acts at the higher levels of organization of the bacterial chromosome to promote the efficient individualization of sister DNA molecules. We will reveal the molecular and structural bases for the association between the SMC complex and the bacterial chromosome at different stages of the loading reaction – each representing a crucial intermediate in a sophisticated chromosome organization process. For the first time, we will be able to map the paths of chromosomal DNA through an SMC complex.
Our in-depth mechanistic insights will likely have implications for the understanding of various pathological conditions and have the potential to contribute to the development of novel antibacterial compounds.
Max ERC Funding
1 999 599 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym CICHLIDX
Project An integrative approach towards the understanding of an adaptive radiation of East African cichlid fishes
Researcher (PI) Walter Salzburger
Host Institution (HI) UNIVERSITAT BASEL
Call Details Consolidator Grant (CoG), LS8, ERC-2013-CoG
Summary "More than 150 years after the publication of Charles Darwin’s The Origin of Species, the identification of the processes that govern the emergence of novel species remains a fundamental problem to biology. Why is it that some groups have diversified in a seemingly explosive manner, while others have lingered unvaried over millions of years? What are the external factors and environmental conditions that promote organismal diversity? And what is the molecular basis of adaptation and diversification? A key to these and related questions is the comparative study of exceptionally diverse yet relatively recent species assemblages such as Darwin’s finches, the Caribbean anole lizards, or the hundreds of endemic species of cichlid fishes in the East African Great Lakes, which are at the center of this proposal. More specifically, I intend to conduct the so far most thorough examination of a large adaptive radiation, combining in-depth eco-morphological assessments and whole genome sequencing of all members of a cichlid species flock. To this end, I plan to (i) sequence the genomes and transcriptomes of several specimens of each cichlid species from Lake Tanganyika to examine genetic and transcriptional diversity; (ii) apply stable-isotope and stomach-content analyses in combination with underwater transplant experiments and transect surveys to quantitate feeding performances, habitat preferences and natural-history parameters; (iii) use X-ray computed tomography to study phenotypic variation in 3D; and (iv) examine fossils from existing and forthcoming drilling cores to implement a time line of diversification in a cichlid adaptive radiation. This project, thus, offers the unique opportunity to test recent theory- and data-based predictions on speciation and adaptive radiation within an entire biological system – in this case the adaptive radiation of cichlid fishes in Lake Tanganyika."
Summary
"More than 150 years after the publication of Charles Darwin’s The Origin of Species, the identification of the processes that govern the emergence of novel species remains a fundamental problem to biology. Why is it that some groups have diversified in a seemingly explosive manner, while others have lingered unvaried over millions of years? What are the external factors and environmental conditions that promote organismal diversity? And what is the molecular basis of adaptation and diversification? A key to these and related questions is the comparative study of exceptionally diverse yet relatively recent species assemblages such as Darwin’s finches, the Caribbean anole lizards, or the hundreds of endemic species of cichlid fishes in the East African Great Lakes, which are at the center of this proposal. More specifically, I intend to conduct the so far most thorough examination of a large adaptive radiation, combining in-depth eco-morphological assessments and whole genome sequencing of all members of a cichlid species flock. To this end, I plan to (i) sequence the genomes and transcriptomes of several specimens of each cichlid species from Lake Tanganyika to examine genetic and transcriptional diversity; (ii) apply stable-isotope and stomach-content analyses in combination with underwater transplant experiments and transect surveys to quantitate feeding performances, habitat preferences and natural-history parameters; (iii) use X-ray computed tomography to study phenotypic variation in 3D; and (iv) examine fossils from existing and forthcoming drilling cores to implement a time line of diversification in a cichlid adaptive radiation. This project, thus, offers the unique opportunity to test recent theory- and data-based predictions on speciation and adaptive radiation within an entire biological system – in this case the adaptive radiation of cichlid fishes in Lake Tanganyika."
Max ERC Funding
1 999 238 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym CRISPR2.0
Project Microbial genome defence pathways: from molecular mechanisms to next-generation molecular tools
Researcher (PI) Martin JINEK
Host Institution (HI) UNIVERSITAT ZURICH
Call Details Consolidator Grant (CoG), LS1, ERC-2018-COG
Summary The constant arms race between prokaryotic microbes and their molecular parasites such as viruses, plasmids and transposons has driven the evolution of complex genome defence mechanisms. The CRISPR-Cas defence systems provide adaptive RNA-guided immunity against invasive nucleic acid elements. CRISPR-associated effector nucleases such as Cas9, Cas12a and Cas13 have emerged as powerful tools for precision genome editing, gene expression control and nucleic acid detection. However, these technologies suffer from drawbacks that limit their efficacy and versatility, necessitating the search for additional exploitable molecular activities. Building on our recent structural and biochemical studies, the goal of this project is to investigate the molecular architectures and mechanisms of CRISPR-associated systems and other genome defence mechanisms, aiming not only to shed light on their biological roles but also inform their technological development. Specifically, the proposed studies will examine (i) the molecular basis of cyclic oligoadenylate signalling in type III CRISPR-Cas systems, (ii) the mechanism of transposon-associated type I CRISPR-Cas systems and their putative function in RNA-guided DNA transposition, and (iii) molecular activities associated with recently described non-CRISPR defence systems. Collectively, the proposed studies will advance our understanding of the molecular functions of genome defence mechanisms in shaping the evolution of prokaryotic genomes and make critical contributions to their development as novel genetic engineering tools.
Summary
The constant arms race between prokaryotic microbes and their molecular parasites such as viruses, plasmids and transposons has driven the evolution of complex genome defence mechanisms. The CRISPR-Cas defence systems provide adaptive RNA-guided immunity against invasive nucleic acid elements. CRISPR-associated effector nucleases such as Cas9, Cas12a and Cas13 have emerged as powerful tools for precision genome editing, gene expression control and nucleic acid detection. However, these technologies suffer from drawbacks that limit their efficacy and versatility, necessitating the search for additional exploitable molecular activities. Building on our recent structural and biochemical studies, the goal of this project is to investigate the molecular architectures and mechanisms of CRISPR-associated systems and other genome defence mechanisms, aiming not only to shed light on their biological roles but also inform their technological development. Specifically, the proposed studies will examine (i) the molecular basis of cyclic oligoadenylate signalling in type III CRISPR-Cas systems, (ii) the mechanism of transposon-associated type I CRISPR-Cas systems and their putative function in RNA-guided DNA transposition, and (iii) molecular activities associated with recently described non-CRISPR defence systems. Collectively, the proposed studies will advance our understanding of the molecular functions of genome defence mechanisms in shaping the evolution of prokaryotic genomes and make critical contributions to their development as novel genetic engineering tools.
Max ERC Funding
1 996 525 €
Duration
Start date: 2019-05-01, End date: 2024-04-30
Project acronym DIA
Project Deep Integration Agreements
Researcher (PI) Ralph Ossa
Host Institution (HI) UNIVERSITAT ZURICH
Call Details Consolidator Grant (CoG), SH1, ERC-2018-COG
Summary This project aims to improve our understanding of deep integration agreements, which have generated an extraordinary amount of controversy in recent years. Unlike ordinary trade agreements, deep integration agreements do not just focus on reducing tariff barriers but seek to achieve much broader economic integration. Prominent examples include the Transatlantic Trade and Investment Partnership (TTIP) negotiated between the EU and the US and the Comprehensive Economic and Trade Agreement (CETA) negotiated between the EU and Canada.
I proceed in three complementary parts, focusing on the most controversial deep integration issues. In a first part, I consider provisions regarding investor protection including the Investor-State Dispute Settlement System. My ambition is to provide a comprehensive theoretical treatment of international investment agreements, which sheds light on their fundamental purpose and assesses their real-world design. In a second part, I turn to efforts towards regulatory cooperation such as CETA’s Regulatory Cooperation Forum. Here, my goal is again to provide a broad theoretical analysis, which identifies the scope for regulatory cooperation and makes suggestions for their real-world design. In a third part, I study intellectual property rights protection, specifically the agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS). In particular, I propose to take a canonical model of intellectual property rights agreements to the data and quantitatively assess the efficiency and equity implications of TRIPS.
Summary
This project aims to improve our understanding of deep integration agreements, which have generated an extraordinary amount of controversy in recent years. Unlike ordinary trade agreements, deep integration agreements do not just focus on reducing tariff barriers but seek to achieve much broader economic integration. Prominent examples include the Transatlantic Trade and Investment Partnership (TTIP) negotiated between the EU and the US and the Comprehensive Economic and Trade Agreement (CETA) negotiated between the EU and Canada.
I proceed in three complementary parts, focusing on the most controversial deep integration issues. In a first part, I consider provisions regarding investor protection including the Investor-State Dispute Settlement System. My ambition is to provide a comprehensive theoretical treatment of international investment agreements, which sheds light on their fundamental purpose and assesses their real-world design. In a second part, I turn to efforts towards regulatory cooperation such as CETA’s Regulatory Cooperation Forum. Here, my goal is again to provide a broad theoretical analysis, which identifies the scope for regulatory cooperation and makes suggestions for their real-world design. In a third part, I study intellectual property rights protection, specifically the agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS). In particular, I propose to take a canonical model of intellectual property rights agreements to the data and quantitatively assess the efficiency and equity implications of TRIPS.
Max ERC Funding
1 433 281 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym DIVERSE-EXPECON
Project Discriminative preferences and fairness ideals in diverse societies: An ‘experimental economics’ approach
Researcher (PI) Sigrid SUETENS
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT BRABANT
Call Details Consolidator Grant (CoG), SH1, ERC-2016-COG
Summary In economics, a distinction is made between statistical and taste-based discrimination (henceforth, TBD). Statistical discrimination refers to discrimination in a context with strategic uncertainty. Someone who is uncertain about the future behaviour of a person with a different ethnicity may rely on information about the different ethnic group to which this person belongs to form beliefs about the behaviour of that person. This may lead to discrimination. TBD refers to discrimination in a context without strategic uncertainty. It implies suffering a disutility when interacting with ‘different’ others. This project systematically studies TBD in ethnically diverse societies.
Identifying TBD is important because overcoming it requires different policies than overcoming statistical discrimination: they should deal with changing preferences of people rather than providing information about specific interaction partners. But identifying TBD is tricky. First, it is impossible to identify using uncontrolled empirical data because these data are characterised by strategic uncertainty. Second, people are generally reluctant to identify themselves as a discriminator. In the project, I study TBS using novel economic experiments that circumvent these problems.
The project consists of three main objectives. First, I investigate whether and how preferences of European natives in social interactions depend on others’ ethnicity. Are natives as altruistic, reciprocal, envious to immigrants as compared to other natives? Second, I study whether natives have different fairness ideals—what constitutes a fair distribution of resources from the perspective of an impartial spectator—when it comes to natives than when it comes to non-natives. Third, I analyse whether preferences and fairness ideals depend on exposure to diversity: do preferences and fairness ideals of natives change as contact with non-natives increases, and, if so, how?
Summary
In economics, a distinction is made between statistical and taste-based discrimination (henceforth, TBD). Statistical discrimination refers to discrimination in a context with strategic uncertainty. Someone who is uncertain about the future behaviour of a person with a different ethnicity may rely on information about the different ethnic group to which this person belongs to form beliefs about the behaviour of that person. This may lead to discrimination. TBD refers to discrimination in a context without strategic uncertainty. It implies suffering a disutility when interacting with ‘different’ others. This project systematically studies TBD in ethnically diverse societies.
Identifying TBD is important because overcoming it requires different policies than overcoming statistical discrimination: they should deal with changing preferences of people rather than providing information about specific interaction partners. But identifying TBD is tricky. First, it is impossible to identify using uncontrolled empirical data because these data are characterised by strategic uncertainty. Second, people are generally reluctant to identify themselves as a discriminator. In the project, I study TBS using novel economic experiments that circumvent these problems.
The project consists of three main objectives. First, I investigate whether and how preferences of European natives in social interactions depend on others’ ethnicity. Are natives as altruistic, reciprocal, envious to immigrants as compared to other natives? Second, I study whether natives have different fairness ideals—what constitutes a fair distribution of resources from the perspective of an impartial spectator—when it comes to natives than when it comes to non-natives. Third, I analyse whether preferences and fairness ideals depend on exposure to diversity: do preferences and fairness ideals of natives change as contact with non-natives increases, and, if so, how?
Max ERC Funding
1 499 046 €
Duration
Start date: 2018-01-01, End date: 2022-12-31
Project acronym DNAMEREP
Project The role of essential DNA metabolism genes in vertebrate chromosome replication
Researcher (PI) Vincenzo Costanzo
Host Institution (HI) IFOM FONDAZIONE ISTITUTO FIRC DI ONCOLOGIA MOLECOLARE
Call Details Consolidator Grant (CoG), LS1, ERC-2013-CoG
Summary "Faithful chromosomal DNA replication is essential to maintain genome stability. A number of DNA metabolism genes are involved at different levels in DNA replication. These factors are thought to facilitate the establishment of replication origins, assist the replication of chromatin regions with repetitive DNA, coordinate the repair of DNA molecules resulting from aberrant DNA replication events or protect replication forks in the presence of DNA lesions that impair their progression. Some DNA metabolism genes are present mainly in higher eukaryotes, suggesting the existence of more complex repair and replication mechanisms in organisms with complex genomes. The impact on cell survival of many DNA metabolism genes has so far precluded in depth molecular analysis. The use of cell free extracts able to recapitulate cell cycle events might help overcoming survival issues and facilitate these studies. The Xenopus laevis egg cell free extract represents an ideal system to study replication-associated functions of essential genes in vertebrate organisms. We will take advantage of this system together with innovative imaging and proteomic based experimental approaches that we are currently developing to characterize the molecular function of some essential DNA metabolism genes. In particular, we will characterize DNA metabolism genes involved in the assembly and distribution of replication origins in vertebrate cells, elucidate molecular mechanisms underlying the role of essential homologous recombination and fork protection proteins in chromosomal DNA replication, and finally identify and characterize factors required for faithful replication of specific vertebrate genomic regions.
The results of these studies will provide groundbreaking information on several aspects of vertebrate genome metabolism and will allow long-awaited understanding of the function of a number of vertebrate essential DNA metabolism genes involved in the duplication of large and complex genomes."
Summary
"Faithful chromosomal DNA replication is essential to maintain genome stability. A number of DNA metabolism genes are involved at different levels in DNA replication. These factors are thought to facilitate the establishment of replication origins, assist the replication of chromatin regions with repetitive DNA, coordinate the repair of DNA molecules resulting from aberrant DNA replication events or protect replication forks in the presence of DNA lesions that impair their progression. Some DNA metabolism genes are present mainly in higher eukaryotes, suggesting the existence of more complex repair and replication mechanisms in organisms with complex genomes. The impact on cell survival of many DNA metabolism genes has so far precluded in depth molecular analysis. The use of cell free extracts able to recapitulate cell cycle events might help overcoming survival issues and facilitate these studies. The Xenopus laevis egg cell free extract represents an ideal system to study replication-associated functions of essential genes in vertebrate organisms. We will take advantage of this system together with innovative imaging and proteomic based experimental approaches that we are currently developing to characterize the molecular function of some essential DNA metabolism genes. In particular, we will characterize DNA metabolism genes involved in the assembly and distribution of replication origins in vertebrate cells, elucidate molecular mechanisms underlying the role of essential homologous recombination and fork protection proteins in chromosomal DNA replication, and finally identify and characterize factors required for faithful replication of specific vertebrate genomic regions.
The results of these studies will provide groundbreaking information on several aspects of vertebrate genome metabolism and will allow long-awaited understanding of the function of a number of vertebrate essential DNA metabolism genes involved in the duplication of large and complex genomes."
Max ERC Funding
1 999 800 €
Duration
Start date: 2014-06-01, End date: 2019-05-31
Project acronym EdGe
Project The molecular genetic architecture of educational attainment and its significance for cognitive health
Researcher (PI) Philipp Daniel Koellinger
Host Institution (HI) STICHTING VU
Call Details Consolidator Grant (CoG), SH1, ERC-2014-CoG
Summary Since many social and economic outcomes are moderately heritable, it is in principle possible to discover genetic variants associated with them. Such discoveries could yield new insights into the causal pathways underlying human behaviour, the complex interplay of environmental and genetic factors, and the relationship between socio-economic traits and health.
This proposal builds on a recent genome-wide association study on educational attainment (EA) led by the applicant (Rietveld et al. 2013, Science), which identified for the first time specific genetic variants robustly associated with a socio-economic outcome. The project will leverage the unique resources of the Social Science Genetic Association Consortium (SSGAC), which is co-led by the applicant.
The proposed research will extend existing knowledge by: 1) discovering additional genetic variants and causal pathways associated with EA; 2) developing methods to use the available genetic association results in novel, more efficient ways; 3) shedding new light on characteristics related to EA such as economic preferences, cognitive function, and cognitive health; 4) showing how policies promoting EA interact with genetic predisposition; 5) using genetic information to better understand the causal effects of educational policy interventions, 6) developing better tools to identify individuals at risk for cognition-related diseases before the onset of symptoms; and 7) identifying causal pathways of genetic influence on cognitive health via neurobiological measures. The project aims to elucidate the complex causal pathways connecting genes, environment, individual characteristics, and health-related outcomes; make methodological contributions applicable in genetic epidemiology and the social sciences; and contribute towards designing more effective public policy, which could improve public health and lower health costs.
Summary
Since many social and economic outcomes are moderately heritable, it is in principle possible to discover genetic variants associated with them. Such discoveries could yield new insights into the causal pathways underlying human behaviour, the complex interplay of environmental and genetic factors, and the relationship between socio-economic traits and health.
This proposal builds on a recent genome-wide association study on educational attainment (EA) led by the applicant (Rietveld et al. 2013, Science), which identified for the first time specific genetic variants robustly associated with a socio-economic outcome. The project will leverage the unique resources of the Social Science Genetic Association Consortium (SSGAC), which is co-led by the applicant.
The proposed research will extend existing knowledge by: 1) discovering additional genetic variants and causal pathways associated with EA; 2) developing methods to use the available genetic association results in novel, more efficient ways; 3) shedding new light on characteristics related to EA such as economic preferences, cognitive function, and cognitive health; 4) showing how policies promoting EA interact with genetic predisposition; 5) using genetic information to better understand the causal effects of educational policy interventions, 6) developing better tools to identify individuals at risk for cognition-related diseases before the onset of symptoms; and 7) identifying causal pathways of genetic influence on cognitive health via neurobiological measures. The project aims to elucidate the complex causal pathways connecting genes, environment, individual characteristics, and health-related outcomes; make methodological contributions applicable in genetic epidemiology and the social sciences; and contribute towards designing more effective public policy, which could improve public health and lower health costs.
Max ERC Funding
1 870 135 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym G-EDIT
Project Mechanisms of RNA-guided genome editing in eukaryotes
Researcher (PI) Mariusz Nowacki
Host Institution (HI) UNIVERSITAET BERN
Call Details Consolidator Grant (CoG), LS1, ERC-2015-CoG
Summary The goal of this project is to contribute to our understanding of RNA-mediated epigenetic mechanisms of genome regulation in eukaryotes. Ciliated protozoa offer a fantastic opportunity to investigate the complex process of trans-generational programming of chromosomal rearrangements, which is thought to serve as a form of immune defense against invasive DNA. Developmental processes in ciliates include extensive rearrangements of the germline DNA, including elimination of transposons and the precise excision of numerous single-copy elements derived from transposons. This process is considered to be maternally controlled because the maternal genome provides essential information in the form of RNA that determines the offspring's genome content and organization. This programmed DNA subtraction, the so-called ‘RNA scanning’ process, is mediated by trans-generational comparison between the germline and the maternal somatic genome. One of the most intriguing questions is how a complex population of small RNAs representing the entire germline genome can be compared to the entire rearranged maternal genome, resulting in the efficient selection of germline-specific RNAs, which are able to target DNA deletions in the developing genome. All this occurs in a very short time and involves a massively coordinated transport of all the components between three types of nuclei. This project focuses on characterizing the molecular machinery that can orchestrate the massive genome rearrangements in ciliates through nucleic acids and protein interactions. It also addresses the question how RNA targets DNA cleavage at the right place. In addition, this project aims to investigate the role of RNA in guiding chromosomal rearrangements in other eukaryotic systems, particularly in human cancer cells where genome editing often occurs on a large scale. This work may be the first step in providing novel insights into the process of programmed DNA rearrangements in higher eukaryotes.
Summary
The goal of this project is to contribute to our understanding of RNA-mediated epigenetic mechanisms of genome regulation in eukaryotes. Ciliated protozoa offer a fantastic opportunity to investigate the complex process of trans-generational programming of chromosomal rearrangements, which is thought to serve as a form of immune defense against invasive DNA. Developmental processes in ciliates include extensive rearrangements of the germline DNA, including elimination of transposons and the precise excision of numerous single-copy elements derived from transposons. This process is considered to be maternally controlled because the maternal genome provides essential information in the form of RNA that determines the offspring's genome content and organization. This programmed DNA subtraction, the so-called ‘RNA scanning’ process, is mediated by trans-generational comparison between the germline and the maternal somatic genome. One of the most intriguing questions is how a complex population of small RNAs representing the entire germline genome can be compared to the entire rearranged maternal genome, resulting in the efficient selection of germline-specific RNAs, which are able to target DNA deletions in the developing genome. All this occurs in a very short time and involves a massively coordinated transport of all the components between three types of nuclei. This project focuses on characterizing the molecular machinery that can orchestrate the massive genome rearrangements in ciliates through nucleic acids and protein interactions. It also addresses the question how RNA targets DNA cleavage at the right place. In addition, this project aims to investigate the role of RNA in guiding chromosomal rearrangements in other eukaryotic systems, particularly in human cancer cells where genome editing often occurs on a large scale. This work may be the first step in providing novel insights into the process of programmed DNA rearrangements in higher eukaryotes.
Max ERC Funding
1 953 000 €
Duration
Start date: 2016-05-01, End date: 2021-04-30
