Project acronym ARCHAIC ADAPT
Project Admixture accelerated adaptation: signals from modern, ancient and archaic DNA.
Researcher (PI) Emilia HUERTA-SANCHEZ
Host Institution (HI) THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN
Country Ireland
Call Details Starting Grant (StG), LS8, ERC-2018-STG
Summary With the advent of new sequencing technologies, population geneticists now have access to more data than ever before. We have access to thousands of human genomes from a diverse set of populations around the globe, and, thanks to advances in DNA extraction and library preparation, we now are beginning to have access to ancient DNA sequence data. These data have greatly improved our knowledge of human history, human adaptation to different environments and human disease. Genome-wide studies have highlighted many genes or genomic loci that may play a role in adaptive or disease related phenotypes of biological importance.
With these collections of modern and ancient sequence data we want to answer a key evolutionary question: how do human adaptations arise? We strongly believe that the state-of-the-art methodologies for uncovering signatures of adaptation are blind to potential modes of adaptation because they are lacking two critical components – more complete integration of multiple population haplotype data (including archaic, ancient and modern samples), and an account of population interactions that facilitate adaptation.
Therefore I plan to develop new methods to detect shared selective events across populations by creating novel statistical summaries, and to detect admixture-facilitated adaptation which we believe is likely a common mode of natural selection. We will apply these tools to new datasets to characterize the interplay of natural selection, archaic and modern admixture in populations in the Americas and make a comparative analysis of modern and ancient European samples to understand the origin and changing profile of adaptive archaic alleles. As a result our work will reveal evolutionary processes that have played an important role in human evolution and disease.
Summary
With the advent of new sequencing technologies, population geneticists now have access to more data than ever before. We have access to thousands of human genomes from a diverse set of populations around the globe, and, thanks to advances in DNA extraction and library preparation, we now are beginning to have access to ancient DNA sequence data. These data have greatly improved our knowledge of human history, human adaptation to different environments and human disease. Genome-wide studies have highlighted many genes or genomic loci that may play a role in adaptive or disease related phenotypes of biological importance.
With these collections of modern and ancient sequence data we want to answer a key evolutionary question: how do human adaptations arise? We strongly believe that the state-of-the-art methodologies for uncovering signatures of adaptation are blind to potential modes of adaptation because they are lacking two critical components – more complete integration of multiple population haplotype data (including archaic, ancient and modern samples), and an account of population interactions that facilitate adaptation.
Therefore I plan to develop new methods to detect shared selective events across populations by creating novel statistical summaries, and to detect admixture-facilitated adaptation which we believe is likely a common mode of natural selection. We will apply these tools to new datasets to characterize the interplay of natural selection, archaic and modern admixture in populations in the Americas and make a comparative analysis of modern and ancient European samples to understand the origin and changing profile of adaptive archaic alleles. As a result our work will reveal evolutionary processes that have played an important role in human evolution and disease.
Max ERC Funding
1 500 000 €
Duration
Start date: 2020-12-01, End date: 2025-11-30
Project acronym CULTSONG
Project Culture as an evolutionary force: Does song learning accelerate speciation in a bat ring species?
Researcher (PI) Mirjam KNoeRNSCHILD
Host Institution (HI) MUSEUM FUR NATURKUNDE - LEIBNIZ-INSTITUT FUR EVOLUTIONS- UND BIODIVERSITATSFORSCHUNG AN DER HUMBOLDT-UNIVERSITAT ZU BERLIN
Country Germany
Call Details Starting Grant (StG), LS8, ERC-2018-STG
Summary Culture is highly relevant for human evolution but whether animal culture can be an evolutionary force that promotes speciation is an open and highly contested issue. While culturally induced song divergence can be correlated with increased speciation rates in songbirds, it is hard to resolve whether cultural differences are promoting speciation or vice versa. Studying ring species is a perfect solution for this problem since they illustrate divergence in space instead of time, thus allowing us to determine whether cultural differences are causes or consequences of speciation. A ring species originates from a population that expands around an uninhabitable barrier and gradually diverges until the terminal forms are reproductively isolated upon secondary contact. We will study whether culturally induced song divergence accelerates speciation in the bat Saccopteryx bilineata, the first known mammalian ring species. Cultural differences between S. bilineata populations are manifested in distinct and temporally stable song dialects which juvenile males learn from adults. First, we will study song divergence around the ring and the relative contribution of song dialects to reproductive isolation of the co-occurring terminal forms of the ring. Second, we will study potential genetic predispositions for learning specific song dialects and investigate neurogenetic mechanisms involved in mammalian song learning. Third, we will reconstruct the history, evolutionary patterns and processes of speciation in a ring using a genomic approach in S. bilineata and its sympatric sister species. This comparative approach will allow us to unravel factors involved in the rapid divergence of S. bilineata on a small spatial scale. In synthesis, we will be able to determine whether sexually selected, culturally transmitted traits can accelerate speciation and elucidate the role of culture as an evolutionary force.
Summary
Culture is highly relevant for human evolution but whether animal culture can be an evolutionary force that promotes speciation is an open and highly contested issue. While culturally induced song divergence can be correlated with increased speciation rates in songbirds, it is hard to resolve whether cultural differences are promoting speciation or vice versa. Studying ring species is a perfect solution for this problem since they illustrate divergence in space instead of time, thus allowing us to determine whether cultural differences are causes or consequences of speciation. A ring species originates from a population that expands around an uninhabitable barrier and gradually diverges until the terminal forms are reproductively isolated upon secondary contact. We will study whether culturally induced song divergence accelerates speciation in the bat Saccopteryx bilineata, the first known mammalian ring species. Cultural differences between S. bilineata populations are manifested in distinct and temporally stable song dialects which juvenile males learn from adults. First, we will study song divergence around the ring and the relative contribution of song dialects to reproductive isolation of the co-occurring terminal forms of the ring. Second, we will study potential genetic predispositions for learning specific song dialects and investigate neurogenetic mechanisms involved in mammalian song learning. Third, we will reconstruct the history, evolutionary patterns and processes of speciation in a ring using a genomic approach in S. bilineata and its sympatric sister species. This comparative approach will allow us to unravel factors involved in the rapid divergence of S. bilineata on a small spatial scale. In synthesis, we will be able to determine whether sexually selected, culturally transmitted traits can accelerate speciation and elucidate the role of culture as an evolutionary force.
Max ERC Funding
1 492 911 €
Duration
Start date: 2019-05-01, End date: 2024-04-30
Project acronym evolSingleCellGRN
Project Constraint, Adaptation, and Heterogeneity: Genomic and single-cell approaches to understanding the evolution of developmental gene regulatory networks
Researcher (PI) David GARFIELD
Host Institution (HI) HUMBOLDT-UNIVERSITAET ZU BERLIN
Country Germany
Call Details Starting Grant (StG), LS3, ERC-2018-STG
Summary Cell types in development arise from precise patterns of gene expression driven by differential usage of DNA regulatory elements. Mutations affecting these elements, or proteins binding them, are major contributors to disease and underlie the evolution of new morphologies. To better understand these elements and how they evolve, I introduce a set of single-cell RNA and ATAC-Seq sequencing technologies that: A) Identify tissue-specific regulatory elements and expression profiles by interrogating individual cells, B) Allow for a precise read-out of developmental responses to mutation and perturbation, including cell-fate re-specification, C) Lead to the development of a regulatory-information based concept of homology that will be used to understand developmental evolution. The research makes use of sea urchins. The well-annotated sea urchin regulatory network, a detailed understanding of inductive interactions in early development, and an active body of evolutionary research justify this choice. Using single-cell ATAC-Seq and a new method for resolving single-cell, nascent transcripts, I will build a detailed atlas of sea urchin development and use this atlas to understand how regulatory landscapes change during specification and how they evolve between closely related species. I will also investigate, at single-cell resolution, how larval skeletal cells are regenerated following the loss of a cell lineage that mirrors euechinoid evolution. To better understand the origins of cell types in sea urchins, I will characterize embryos of the cnidarian Nematostella, using shared regulatory sites to define cell types which I will compare to urchins and my previous work in Drosophila. The work will generate single-cell methods for non-traditional model systems and help to resolve the processes by which, and the paths along which, development evolves.
Summary
Cell types in development arise from precise patterns of gene expression driven by differential usage of DNA regulatory elements. Mutations affecting these elements, or proteins binding them, are major contributors to disease and underlie the evolution of new morphologies. To better understand these elements and how they evolve, I introduce a set of single-cell RNA and ATAC-Seq sequencing technologies that: A) Identify tissue-specific regulatory elements and expression profiles by interrogating individual cells, B) Allow for a precise read-out of developmental responses to mutation and perturbation, including cell-fate re-specification, C) Lead to the development of a regulatory-information based concept of homology that will be used to understand developmental evolution. The research makes use of sea urchins. The well-annotated sea urchin regulatory network, a detailed understanding of inductive interactions in early development, and an active body of evolutionary research justify this choice. Using single-cell ATAC-Seq and a new method for resolving single-cell, nascent transcripts, I will build a detailed atlas of sea urchin development and use this atlas to understand how regulatory landscapes change during specification and how they evolve between closely related species. I will also investigate, at single-cell resolution, how larval skeletal cells are regenerated following the loss of a cell lineage that mirrors euechinoid evolution. To better understand the origins of cell types in sea urchins, I will characterize embryos of the cnidarian Nematostella, using shared regulatory sites to define cell types which I will compare to urchins and my previous work in Drosophila. The work will generate single-cell methods for non-traditional model systems and help to resolve the processes by which, and the paths along which, development evolves.
Max ERC Funding
1 499 900 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym mitoUPR
Project Cellular modulation by the mitochondrial unfolded protein response
Researcher (PI) Christian MueNCH
Host Institution (HI) JOHANN WOLFGANG GOETHE-UNIVERSITATFRANKFURT AM MAIN
Country Germany
Call Details Starting Grant (StG), LS3, ERC-2018-STG
Summary Mitochondrial function is central for cellular metabolism and energy balance. However, many diseases, including cancer and neurodegenerative diseases, affect mitochondrial function and proteostasis. Upon mitochondrial protein misfolding, mitochondria activate the mitochondrial unfolded protein response (UPRmt) to restore proteostasis, a poorly characterized pathway in mammalian cells. Notably, the effects of the UPRmt on its direct environment – mitochondria – and on cytosolic homeostasis remain unknown. Strikingly, non-cell autonomous signaling of metabolism and folding state has been described in recent years, particularly in worms. However, the possible role of UPRmt in such processes is undescribed.
Using newly available tools to acutely induce the UPRmt in mammalian cells, combined with cutting-edge quantitative mass spectrometry, microscopy, next generation sequencing, and gene editing approaches, we propose to address these important open questions by studying the influence UPRmt exerts on the environments of i) mitochondria (including to study the composition and regulation of RNA granules), ii) cytosol (adjustments of translation, metabolism, and proliferation) and iii) neighboring cells (modification by non-cell autonomous signaling). Additionally, we aim to develop an iPSC-based UPRmt model.
On cellular and organismal level, there ought to be mechanisms to signal changes in metabolism and proteostasis to increase robustness in neighboring environments. Studying these effects will be crucial for a better understanding of human disease and carries severe implications: i) the possibility of therapeutic treatment by modulating neighboring compartments or cells and ii) the possibility that diseases inducing the UPRmt could have unknown paracrine and endocrine effects on the organism. This proposal holds the potential to uncover a novel layer of regulation of cellular stress with an extensive influence on our understanding of the UPRmt and disease.
Summary
Mitochondrial function is central for cellular metabolism and energy balance. However, many diseases, including cancer and neurodegenerative diseases, affect mitochondrial function and proteostasis. Upon mitochondrial protein misfolding, mitochondria activate the mitochondrial unfolded protein response (UPRmt) to restore proteostasis, a poorly characterized pathway in mammalian cells. Notably, the effects of the UPRmt on its direct environment – mitochondria – and on cytosolic homeostasis remain unknown. Strikingly, non-cell autonomous signaling of metabolism and folding state has been described in recent years, particularly in worms. However, the possible role of UPRmt in such processes is undescribed.
Using newly available tools to acutely induce the UPRmt in mammalian cells, combined with cutting-edge quantitative mass spectrometry, microscopy, next generation sequencing, and gene editing approaches, we propose to address these important open questions by studying the influence UPRmt exerts on the environments of i) mitochondria (including to study the composition and regulation of RNA granules), ii) cytosol (adjustments of translation, metabolism, and proliferation) and iii) neighboring cells (modification by non-cell autonomous signaling). Additionally, we aim to develop an iPSC-based UPRmt model.
On cellular and organismal level, there ought to be mechanisms to signal changes in metabolism and proteostasis to increase robustness in neighboring environments. Studying these effects will be crucial for a better understanding of human disease and carries severe implications: i) the possibility of therapeutic treatment by modulating neighboring compartments or cells and ii) the possibility that diseases inducing the UPRmt could have unknown paracrine and endocrine effects on the organism. This proposal holds the potential to uncover a novel layer of regulation of cellular stress with an extensive influence on our understanding of the UPRmt and disease.
Max ERC Funding
1 437 500 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym Neuro-UTR
Project Mechanism and functional impact of ultra-long 3’ UTRs in the Drosophila nervous system
Researcher (PI) Valerie HILGERS
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Country Germany
Call Details Starting Grant (StG), LS3, ERC-2018-STG
Summary Neurons employ cell-specific gene regulatory mechanisms. One particularly striking process is the recently discovered, drastic lengthening of the 3’ untranslated region (3’ UTR) of hundreds of genes, which occurs in neurons from flies to humans. The function of the resulting ultra-long 3’ UTRs is unknown. RNA deregulation plays a central role in neurological diseases; to understand underlying causes, it is essential to study regulatory processes and define the function of these novel 3’ UTRs.
In Drosophila, the neuronal RNA-binding protein ELAV is the main effector of nervous system specific 3’ UTR extension. ELAV’s association with the promoter region of its target genes is required for synthesis of alternative, ultra-long 3’ UTRs. The mechanistic framework of this novel and exciting link between transcription initiation and alternative 3’ end processing is not understood yet.
We hypothesise that mRNAs carrying ultra-long 3’ UTRs create an important communication avenue between transcription regulation and synaptic function. In this proposal, we will study the regulation of ELAV-mediated 3’ UTR extension in a Drosophila model. First, we will provide mechanistic insight into the co-transcriptional processes that give rise to ultra-long 3’ UTRs. Employing genomics, proteomics and biochemistry, we will study the recruitment of ELAV at gene promoters and to nascent mRNA. Second, we will follow the journey of extended mRNAs from their site of synthesis to their destination using imaging, proteomics, and functional genetics. Finally, based on our unpublished results that 3’ UTR plasticity impacts neuronal function, we will analyse the role of ultra-long 3’ UTRs in memory, aging and disease.
Our study will integrate the molecular mechanisms that govern biogenesis and function of ultra-long 3’ UTRs, from nucleus to synapse, in an animal model. The results of this research will create a major impact on our understanding of neuronal gene regulation in health and disease.
Summary
Neurons employ cell-specific gene regulatory mechanisms. One particularly striking process is the recently discovered, drastic lengthening of the 3’ untranslated region (3’ UTR) of hundreds of genes, which occurs in neurons from flies to humans. The function of the resulting ultra-long 3’ UTRs is unknown. RNA deregulation plays a central role in neurological diseases; to understand underlying causes, it is essential to study regulatory processes and define the function of these novel 3’ UTRs.
In Drosophila, the neuronal RNA-binding protein ELAV is the main effector of nervous system specific 3’ UTR extension. ELAV’s association with the promoter region of its target genes is required for synthesis of alternative, ultra-long 3’ UTRs. The mechanistic framework of this novel and exciting link between transcription initiation and alternative 3’ end processing is not understood yet.
We hypothesise that mRNAs carrying ultra-long 3’ UTRs create an important communication avenue between transcription regulation and synaptic function. In this proposal, we will study the regulation of ELAV-mediated 3’ UTR extension in a Drosophila model. First, we will provide mechanistic insight into the co-transcriptional processes that give rise to ultra-long 3’ UTRs. Employing genomics, proteomics and biochemistry, we will study the recruitment of ELAV at gene promoters and to nascent mRNA. Second, we will follow the journey of extended mRNAs from their site of synthesis to their destination using imaging, proteomics, and functional genetics. Finally, based on our unpublished results that 3’ UTR plasticity impacts neuronal function, we will analyse the role of ultra-long 3’ UTRs in memory, aging and disease.
Our study will integrate the molecular mechanisms that govern biogenesis and function of ultra-long 3’ UTRs, from nucleus to synapse, in an animal model. The results of this research will create a major impact on our understanding of neuronal gene regulation in health and disease.
Max ERC Funding
1 497 500 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym THEMISS
Project Thermal Evolution Modeling of Icy objects in the Solar System
Researcher (PI) Aurelie GUILBERT-LEPOUTRE
Host Institution (HI) CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Country France
Call Details Starting Grant (StG), PE9, ERC-2018-STG
Summary Comets can be used as tracers of the conditions prevailing during the formation of the solar system. We have been studying them for decades, yet we still have not answered this foreground question: how do comets work? To answer that question is to understand which of comets properties are actually relevant to characterize the early solar system, and how primitive comets really are. Icy objects in the solar system are stored in different reservoirs, where they evolve very slowly owing irradiation, collisions and thermal processing. When they enter the inner solar system, they become comets, i.e. objects loosing mass. If comets are deemed very primitive due, for example, to their high content in very volatile species, some observations including ESA/Rosetta’s, have brought us a conundrum. Indeed, some comet properties indicate that they could have suffered from a long-term processing, which lead their basic properties (like shape, composition or size) to evolve significantly since the time they were formed. This proposal will explore the thermal processing of comets from their storage in the Oort Cloud, the Kuiper Belt and the Main Belt, and the thermally-induced variations in their physical and chemical characteristics, in order to understand whether such effects were important for shaping comets as we observe them today. Based on observational constraints obtained both from the ground and the latest space missions, an unprecedented modeling effort will be undertaken to evaluate under which conditions comets can preserve pristine material, what the long-lasting effects of thermal processing are for the various comet populations, and provide tools for deciphering between primitive properties and properties affected by evolution. Finally, this work will be shared via a web application, allowing the community to work from this foundation to prepare the future of our field, including the next generation of space missions exploring comets from sample returns.
Summary
Comets can be used as tracers of the conditions prevailing during the formation of the solar system. We have been studying them for decades, yet we still have not answered this foreground question: how do comets work? To answer that question is to understand which of comets properties are actually relevant to characterize the early solar system, and how primitive comets really are. Icy objects in the solar system are stored in different reservoirs, where they evolve very slowly owing irradiation, collisions and thermal processing. When they enter the inner solar system, they become comets, i.e. objects loosing mass. If comets are deemed very primitive due, for example, to their high content in very volatile species, some observations including ESA/Rosetta’s, have brought us a conundrum. Indeed, some comet properties indicate that they could have suffered from a long-term processing, which lead their basic properties (like shape, composition or size) to evolve significantly since the time they were formed. This proposal will explore the thermal processing of comets from their storage in the Oort Cloud, the Kuiper Belt and the Main Belt, and the thermally-induced variations in their physical and chemical characteristics, in order to understand whether such effects were important for shaping comets as we observe them today. Based on observational constraints obtained both from the ground and the latest space missions, an unprecedented modeling effort will be undertaken to evaluate under which conditions comets can preserve pristine material, what the long-lasting effects of thermal processing are for the various comet populations, and provide tools for deciphering between primitive properties and properties affected by evolution. Finally, this work will be shared via a web application, allowing the community to work from this foundation to prepare the future of our field, including the next generation of space missions exploring comets from sample returns.
Max ERC Funding
1 494 494 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
