Project acronym 2-HIT
Project Genetic interaction networks: From C. elegans to human disease
Researcher (PI) Ben Lehner
Host Institution (HI) FUNDACIO CENTRE DE REGULACIO GENOMICA
Call Details Starting Grant (StG), LS2, ERC-2007-StG
Summary Most hereditary diseases in humans are genetically complex, resulting from combinations of mutations in multiple genes. However synthetic interactions between genes are very difficult to identify in population studies because of a lack of statistical power and we fundamentally do not understand how mutations interact to produce phenotypes. C. elegans is a unique animal in which genetic interactions can be rapidly identified in vivo using RNA interference, and we recently used this system to construct the first genetic interaction network for any animal, focused on signal transduction genes. The first objective of this proposal is to extend this work and map a comprehensive genetic interaction network for this model metazoan. This project will provide the first insights into the global properties of animal genetic interaction networks, and a comprehensive view of the functional relationships between genes in an animal. The second objective of the proposal is to use C. elegans to develop and validate experimentally integrated gene networks that connect genes to phenotypes and predict genetic interactions on a genome-wide scale. The methods that we develop and validate in C. elegans will then be applied to predict phenotypes and interactions for human genes. The final objective is to dissect the molecular mechanisms underlying genetic interactions, and to understand how these interactions evolve. The combined aim of these three objectives is to generate a framework for understanding and predicting how mutations interact to produce phenotypes, including in human disease.
Summary
Most hereditary diseases in humans are genetically complex, resulting from combinations of mutations in multiple genes. However synthetic interactions between genes are very difficult to identify in population studies because of a lack of statistical power and we fundamentally do not understand how mutations interact to produce phenotypes. C. elegans is a unique animal in which genetic interactions can be rapidly identified in vivo using RNA interference, and we recently used this system to construct the first genetic interaction network for any animal, focused on signal transduction genes. The first objective of this proposal is to extend this work and map a comprehensive genetic interaction network for this model metazoan. This project will provide the first insights into the global properties of animal genetic interaction networks, and a comprehensive view of the functional relationships between genes in an animal. The second objective of the proposal is to use C. elegans to develop and validate experimentally integrated gene networks that connect genes to phenotypes and predict genetic interactions on a genome-wide scale. The methods that we develop and validate in C. elegans will then be applied to predict phenotypes and interactions for human genes. The final objective is to dissect the molecular mechanisms underlying genetic interactions, and to understand how these interactions evolve. The combined aim of these three objectives is to generate a framework for understanding and predicting how mutations interact to produce phenotypes, including in human disease.
Max ERC Funding
1 100 000 €
Duration
Start date: 2008-09-01, End date: 2014-04-30
Project acronym EPIRNAS
Project Small RNA Mediated Epigenetics in Vertebrates
Researcher (PI) René Ketting
Host Institution (HI) INSTITUT FUR MOLEKULARE BIOLOGIE GGMBH
Call Details Starting Grant (StG), LS2, ERC-2007-StG
Summary Since the discovery of RNAi small RNA molecules have been under intense study. They have been shown to impact many different processes, ranging from development to organ function and carcinogenesis. Recently, it has become clear that many distinct small RNA families exist. However, all act through a member of the well-conserved Argonaute family of proteins. I try to understand how specificity of the different Argonaute proteins is achieved, and I am particularly interested in Argonautes that may contribute to the epigenetic marking of genomic DNA in animals. My focus is on Argonaute function in the vertebrate germline, a tissue that is an especially intriguing system with regard to the resetting and establishment of epigenetic marks. As model system I use the zebrafish. Piwi proteins are Argonaute proteins that in vertebrates are specifically expressed in germ cells, and have been implicated in modifying chromatin structures. We demonstrated that zebrafish piwi is expressed in both the male and the female gonad and that loss of piwi results in loss of germ cells due to apoptosis. We have characterized small RNAs that bind to piwi (piRNAs) in both ovary and testis, and found that they play a role in the silencing of transposable elements. Furthermore, we have shown that the biogenesis of piRNAs differs markedly from that of other small RNAs like miRNAs. The experiments I propose address how Piwi proteins and piRNAs act in germ cells to ensure a functional germline and a stable propagation of intact chromatin over generations. First, I will address the biogenesis of piRNAs. Second, I will identify novel components of the Piwi pathway. Third, I will address the mode(s) of action of piRNAs. On all fronts a combination of genetics, molecular biology and biochemistry will be used.
Summary
Since the discovery of RNAi small RNA molecules have been under intense study. They have been shown to impact many different processes, ranging from development to organ function and carcinogenesis. Recently, it has become clear that many distinct small RNA families exist. However, all act through a member of the well-conserved Argonaute family of proteins. I try to understand how specificity of the different Argonaute proteins is achieved, and I am particularly interested in Argonautes that may contribute to the epigenetic marking of genomic DNA in animals. My focus is on Argonaute function in the vertebrate germline, a tissue that is an especially intriguing system with regard to the resetting and establishment of epigenetic marks. As model system I use the zebrafish. Piwi proteins are Argonaute proteins that in vertebrates are specifically expressed in germ cells, and have been implicated in modifying chromatin structures. We demonstrated that zebrafish piwi is expressed in both the male and the female gonad and that loss of piwi results in loss of germ cells due to apoptosis. We have characterized small RNAs that bind to piwi (piRNAs) in both ovary and testis, and found that they play a role in the silencing of transposable elements. Furthermore, we have shown that the biogenesis of piRNAs differs markedly from that of other small RNAs like miRNAs. The experiments I propose address how Piwi proteins and piRNAs act in germ cells to ensure a functional germline and a stable propagation of intact chromatin over generations. First, I will address the biogenesis of piRNAs. Second, I will identify novel components of the Piwi pathway. Third, I will address the mode(s) of action of piRNAs. On all fronts a combination of genetics, molecular biology and biochemistry will be used.
Max ERC Funding
970 000 €
Duration
Start date: 2008-08-01, End date: 2014-07-31
Project acronym PHYGENOM
Project Models of genome evolution, phylogenomics and the tree of life
Researcher (PI) David Posada
Host Institution (HI) UNIVERSIDAD DE VIGO
Call Details Starting Grant (StG), LS2, ERC-2007-StG
Summary Understanding the evolution of all living organisms is one of the fundamental challenges in biology. The phylogenetic analysis of whole genomes has already proven very useful to decipher not only their history, but also their organization and function. Indeed, the accuracy of these inferences is intimately related to the quality of the models assumed. Despite important advances, models of genome evolution are still in its infancy, and more realistic models are needed to provide more precise and reliable inferences from genome data. In addition, a number of phylogenomic algorithms have been proposed to estimate phylogenies from complete genomes based on different genomic features. Although the application of these methods has already led to critical conclusions regarding the tree of life, the relative performance of these algorithms has not been properly evaluated yet. The first objective of this grant is to develop more realistic models of genome evolution, integrating changes in gene content and changes in gene sequences, and allowing for model variation along different branches of the phylogeny. In order to avoid model overparameterization, a statistical framework for the selection of best-fit models of genome evolution for the data at hand will also be implemented. Genome data simulated under these models will be used to compare the performance of different phylogenomic algorithms. Optimized phylogenomic strategies will then be applied to available genomes in order to decipher unresolved portions of the tree of life. Finally, all the bioinformatic tools developed under this grant will be made freely available to the scientific community.
Summary
Understanding the evolution of all living organisms is one of the fundamental challenges in biology. The phylogenetic analysis of whole genomes has already proven very useful to decipher not only their history, but also their organization and function. Indeed, the accuracy of these inferences is intimately related to the quality of the models assumed. Despite important advances, models of genome evolution are still in its infancy, and more realistic models are needed to provide more precise and reliable inferences from genome data. In addition, a number of phylogenomic algorithms have been proposed to estimate phylogenies from complete genomes based on different genomic features. Although the application of these methods has already led to critical conclusions regarding the tree of life, the relative performance of these algorithms has not been properly evaluated yet. The first objective of this grant is to develop more realistic models of genome evolution, integrating changes in gene content and changes in gene sequences, and allowing for model variation along different branches of the phylogeny. In order to avoid model overparameterization, a statistical framework for the selection of best-fit models of genome evolution for the data at hand will also be implemented. Genome data simulated under these models will be used to compare the performance of different phylogenomic algorithms. Optimized phylogenomic strategies will then be applied to available genomes in order to decipher unresolved portions of the tree of life. Finally, all the bioinformatic tools developed under this grant will be made freely available to the scientific community.
Max ERC Funding
994 800 €
Duration
Start date: 2008-10-01, End date: 2013-09-30
Project acronym RANK
Project The Formation and Visualisation of the Social and Political Order of Princes in late Medieval Europe. A Comparative Study between the Empire and England
Researcher (PI) Jörg Henning Peltzer
Host Institution (HI) RUPRECHT-KARLS-UNIVERSITAET HEIDELBERG
Call Details Starting Grant (StG), SH5, ERC-2007-StG
Summary This project examines the formation and differentiation of princely elites in pre-modern European rank societies. The project concentrates on the late Middle Ages (1200–1500), a key period in these processes, with geographic focus on the Empire and England. In both polities new princely elites emerged during this period. Yet, they did so in the context of the establishment of two different monarchical principles, the elective kingship in the Empire and the hereditary kingship in England. In the Empire, the electoral princes became a distinctive group and constituted themselves as the pillars of the imperium. In England, the title of duke appears to have been introduced to distinguish members of the royal family from other magnates. In examining these complex social and political processes in both polities the project contributes to establish a typology of different ways of constructing societies in pre-modern Europe using an interdisciplinary, comparative approach. The project combines history, architectural and art history, archaeology and semiotics to analyse princely actions, princely architecture and heraldry. In so doing we will endeavour to determine the strategies developed and deployed by princes in late medieval Europe to represent and improve their rank and thus their significance. The comparison sheds light on several key issues such as whether the emperorship, unique in Europe, enabled the development of a king-like position for (electoral) princes, and how in different political contexts the position of the magnates in relation to each other and the king was communicated and perpetuated. This project breaks new ground on several frontiers. Interconnecting different disciplines, it crosses existing subject boundaries and thus opens up new ways of fruitful cooperation. By comparing the Empire with England the project also transgresses the traditional boundaries of national history, thus helping to establish a European perspective in medieval studies.
Summary
This project examines the formation and differentiation of princely elites in pre-modern European rank societies. The project concentrates on the late Middle Ages (1200–1500), a key period in these processes, with geographic focus on the Empire and England. In both polities new princely elites emerged during this period. Yet, they did so in the context of the establishment of two different monarchical principles, the elective kingship in the Empire and the hereditary kingship in England. In the Empire, the electoral princes became a distinctive group and constituted themselves as the pillars of the imperium. In England, the title of duke appears to have been introduced to distinguish members of the royal family from other magnates. In examining these complex social and political processes in both polities the project contributes to establish a typology of different ways of constructing societies in pre-modern Europe using an interdisciplinary, comparative approach. The project combines history, architectural and art history, archaeology and semiotics to analyse princely actions, princely architecture and heraldry. In so doing we will endeavour to determine the strategies developed and deployed by princes in late medieval Europe to represent and improve their rank and thus their significance. The comparison sheds light on several key issues such as whether the emperorship, unique in Europe, enabled the development of a king-like position for (electoral) princes, and how in different political contexts the position of the magnates in relation to each other and the king was communicated and perpetuated. This project breaks new ground on several frontiers. Interconnecting different disciplines, it crosses existing subject boundaries and thus opens up new ways of fruitful cooperation. By comparing the Empire with England the project also transgresses the traditional boundaries of national history, thus helping to establish a European perspective in medieval studies.
Max ERC Funding
900 000 €
Duration
Start date: 2008-10-01, End date: 2014-09-30
