Project acronym AAREA
Project The Archaeology of Agricultural Resilience in Eastern Africa
Researcher (PI) Daryl Stump
Host Institution (HI) UNIVERSITY OF YORK
Country United Kingdom
Call Details Starting Grant (StG), SH6, ERC-2013-StG
Summary "The twin concepts of sustainability and conservation that are so pivotal within current debates regarding economic development and biodiversity protection both contain an inherent temporal dimension, since both refer to the need to balance short-term gains with long-term resource maintenance. Proponents of resilience theory and of development based on ‘indigenous knowledge’ have thus argued for the necessity of including archaeological, historical and palaeoenvironmental components within development project design. Indeed, some have argued that archaeology should lead these interdisciplinary projects on the grounds that it provides the necessary time depth and bridges the social and natural sciences. The project proposed here accepts this logic and endorses this renewed contemporary relevance of archaeological research. However, it also needs to be admitted that moving beyond critiques of the misuse of historical data presents significant hurdles. When presenting results outside the discipline, for example, archaeological projects tend to downplay the poor archaeological visibility of certain agricultural practices, and computer models designed to test sustainability struggle to adequately account for local cultural preferences. This field will therefore not progress unless there is a frank appraisal of archaeology’s strengths and weaknesses. This project will provide this assessment by employing a range of established and groundbreaking archaeological and modelling techniques to examine the development of two east Africa agricultural systems: one at the abandoned site of Engaruka in Tanzania, commonly seen as an example of resource mismanagement and ecological collapse; and another at the current agricultural landscape in Konso, Ethiopia, described by the UN FAO as one of a select few African “lessons from the past”. The project thus aims to assess the sustainability of these systems, but will also assess the role archaeology can play in such debates worldwide."
Summary
"The twin concepts of sustainability and conservation that are so pivotal within current debates regarding economic development and biodiversity protection both contain an inherent temporal dimension, since both refer to the need to balance short-term gains with long-term resource maintenance. Proponents of resilience theory and of development based on ‘indigenous knowledge’ have thus argued for the necessity of including archaeological, historical and palaeoenvironmental components within development project design. Indeed, some have argued that archaeology should lead these interdisciplinary projects on the grounds that it provides the necessary time depth and bridges the social and natural sciences. The project proposed here accepts this logic and endorses this renewed contemporary relevance of archaeological research. However, it also needs to be admitted that moving beyond critiques of the misuse of historical data presents significant hurdles. When presenting results outside the discipline, for example, archaeological projects tend to downplay the poor archaeological visibility of certain agricultural practices, and computer models designed to test sustainability struggle to adequately account for local cultural preferences. This field will therefore not progress unless there is a frank appraisal of archaeology’s strengths and weaknesses. This project will provide this assessment by employing a range of established and groundbreaking archaeological and modelling techniques to examine the development of two east Africa agricultural systems: one at the abandoned site of Engaruka in Tanzania, commonly seen as an example of resource mismanagement and ecological collapse; and another at the current agricultural landscape in Konso, Ethiopia, described by the UN FAO as one of a select few African “lessons from the past”. The project thus aims to assess the sustainability of these systems, but will also assess the role archaeology can play in such debates worldwide."
Max ERC Funding
1 196 701 €
Duration
Start date: 2014-02-01, End date: 2018-01-31
Project acronym APPLAUSE
Project Adolescent Precursors to Psychiatric Disorders – Learing from Analysis of User-Service Engagement
Researcher (PI) Sara Evans
Host Institution (HI) LONDON SCHOOL OF ECONOMICS AND POLITICAL SCIENCE
Country United Kingdom
Call Details Starting Grant (StG), LS7, ERC-2013-StG
Summary APPLAUSE’s aim is to produce a body of evidence that illustrates how young people with mental health problems currently interact with both formal mental health services and informal social and familial support structures. Careful analysis of data gathered in the UK and Brazil will allow formulation of globally relevant insights into mental health care delivery for young people, which will be presented internationally as a resource for future health care service design.
APPLAUSE will allow the collection of an important data set that does not currently exist in this field, and will look to other disciplines for innovative approaches to data analysis. Whist standard analysis may allow for snapshots of health service use, using innovative life course methods will allow us to to characterise patterns of complete service use of each individual participant’s experience of accessing mental health care and social support.
Adolescence is a critical period in mental health development, which has been largely neglected by public health efforts. Psychiatric disorders rank as the primary cause of disability among individuals aged 10-24 years, worldwide. Moreover, many health risk behaviours emerge during adolescence and 70% of adult psychiatric disorders are preceded by mental health problems during adolescent years. However, delays to receiving care for psychiatric disorders, following disorder onset, avreage more than ten years and little is known about factors which impede access to and continuity of care among young people with mental health problems. APPLAUSE will analyse current access models, reports of individual experiences of positive and negative interactions with health care services and the culturally embedded social factors that impact on such access. Addressing this complex problem from a global perspective will advance the development of a more diverse and innovative set of strategies for improving earlier access to care.
Summary
APPLAUSE’s aim is to produce a body of evidence that illustrates how young people with mental health problems currently interact with both formal mental health services and informal social and familial support structures. Careful analysis of data gathered in the UK and Brazil will allow formulation of globally relevant insights into mental health care delivery for young people, which will be presented internationally as a resource for future health care service design.
APPLAUSE will allow the collection of an important data set that does not currently exist in this field, and will look to other disciplines for innovative approaches to data analysis. Whist standard analysis may allow for snapshots of health service use, using innovative life course methods will allow us to to characterise patterns of complete service use of each individual participant’s experience of accessing mental health care and social support.
Adolescence is a critical period in mental health development, which has been largely neglected by public health efforts. Psychiatric disorders rank as the primary cause of disability among individuals aged 10-24 years, worldwide. Moreover, many health risk behaviours emerge during adolescence and 70% of adult psychiatric disorders are preceded by mental health problems during adolescent years. However, delays to receiving care for psychiatric disorders, following disorder onset, avreage more than ten years and little is known about factors which impede access to and continuity of care among young people with mental health problems. APPLAUSE will analyse current access models, reports of individual experiences of positive and negative interactions with health care services and the culturally embedded social factors that impact on such access. Addressing this complex problem from a global perspective will advance the development of a more diverse and innovative set of strategies for improving earlier access to care.
Max ERC Funding
1 499 948 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym CancerExomesInPlasma
Project Non-invasive genomic analysis of cancer using circulating tumour DNA
Researcher (PI) Nitzan Rosenfeld
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Country United Kingdom
Call Details Starting Grant (StG), LS7, ERC-2013-StG
Summary Non-invasive genomic analysis of cancer can revolutionize the study of tumour evolution, heterogeneity, and drug resistance. Clinically applied, this can transform current practice in cancer diagnosis and management. Cell-free DNA in plasma contains tumour-specific sequences. This circulating tumour DNA (ctDNA) is a promising source of genomic and diagnostic information, readily accessible non-invasively. The study of ctDNA is therefore timely and of great importance. But it is also very challenging. Measurement can be complex, and high-quality samples are not easily obtained. Though progress has been made, much remains to be discovered.
My lab pioneered the use of targeted sequencing to analyse mutations in ctDNA. We recently developed a ground-breaking paradigm for analysing evolving cancer genomes in plasma DNA, combining ctDNA quantification with exome-sequencing of serial plasma samples. Applied to extensive sets of clinical samples my lab has characterized, this will enable large-scale exploration of acquired drug resistance with unprecedented resolution. CancerExomesInPlasma aims to use ctDNA for genome-wide analysis of tumour evolution, as a means for non-invasive, unbiased discovery of genes and pathways involved in resistance to cancer therapy.
Summary
Non-invasive genomic analysis of cancer can revolutionize the study of tumour evolution, heterogeneity, and drug resistance. Clinically applied, this can transform current practice in cancer diagnosis and management. Cell-free DNA in plasma contains tumour-specific sequences. This circulating tumour DNA (ctDNA) is a promising source of genomic and diagnostic information, readily accessible non-invasively. The study of ctDNA is therefore timely and of great importance. But it is also very challenging. Measurement can be complex, and high-quality samples are not easily obtained. Though progress has been made, much remains to be discovered.
My lab pioneered the use of targeted sequencing to analyse mutations in ctDNA. We recently developed a ground-breaking paradigm for analysing evolving cancer genomes in plasma DNA, combining ctDNA quantification with exome-sequencing of serial plasma samples. Applied to extensive sets of clinical samples my lab has characterized, this will enable large-scale exploration of acquired drug resistance with unprecedented resolution. CancerExomesInPlasma aims to use ctDNA for genome-wide analysis of tumour evolution, as a means for non-invasive, unbiased discovery of genes and pathways involved in resistance to cancer therapy.
Max ERC Funding
1 769 380 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym CLOC
Project Cultured Liver Organoids for Investigation and Treatment of Inherited Cholestatic Diseases
Researcher (PI) Paul Gissen
Host Institution (HI) University College London
Country United Kingdom
Call Details Starting Grant (StG), LS7, ERC-2013-StG
Summary "Bile synthesis and secretion are crucial to liver function and involve multiple proteins. Disorders due to defects in this process (Inherited Cholestatic Disorders, ICDs) lead to progressive liver disease. Many ICD patients do not respond to medical treatment and need liver transplantation (LT). Although ICDs are rare, multifactorial cholestatic diseases are common and many patients will benefit from ICD research.
There is acute shortage of liver donors. 10% of patients die while waiting on the liver transplant list. Therefore alternatives to LT are urgently needed. Bioengineered tissues may reduce the need for donor organs but complexity of it's organisation makes generation of functional liver challenging.
The OBJECTIVE of this project is to generate Cultured Liver Organoids (CLOs) using hepatocytes cultured on 3-D scaffolds as novel models for study of liver development and disease and potential treatment of ICDs.
3-D extracellular matrix (ECM) scaffolds derived from decellularised livers and polymeric matrices (PM) have been used to mimic liver architecture but further work is needed to establish functional bile flow.
Human Induced Pluripotent Stem Cells (hIPSCs) derived from reprogrammed skin fibroblasts by overexpression of pluripotency factors can proliferate and be differentiated into various cell types including hepatocytes. hIPSCs enable production of patient specific cells, which are fully immuno-compatible. Genetically corrected mutant hIPSCs differentiated into hepatocytes have been used as cell therapy in animal models of inherited metabolic disorders but direct infusion of hepatocytes into the liver is unlikely to achieve polarised bile flow and correct ICDs.
Therefore hIPSCs developed from ICD patients will be used to culture hepatocytes on decellularised mouse liver ECM to generate in vitro models of ICDs. CLOs containing hepatocytes from genetically corrected hIPSC will be tested in mouse models of ICDs as potential treatment."
Summary
"Bile synthesis and secretion are crucial to liver function and involve multiple proteins. Disorders due to defects in this process (Inherited Cholestatic Disorders, ICDs) lead to progressive liver disease. Many ICD patients do not respond to medical treatment and need liver transplantation (LT). Although ICDs are rare, multifactorial cholestatic diseases are common and many patients will benefit from ICD research.
There is acute shortage of liver donors. 10% of patients die while waiting on the liver transplant list. Therefore alternatives to LT are urgently needed. Bioengineered tissues may reduce the need for donor organs but complexity of it's organisation makes generation of functional liver challenging.
The OBJECTIVE of this project is to generate Cultured Liver Organoids (CLOs) using hepatocytes cultured on 3-D scaffolds as novel models for study of liver development and disease and potential treatment of ICDs.
3-D extracellular matrix (ECM) scaffolds derived from decellularised livers and polymeric matrices (PM) have been used to mimic liver architecture but further work is needed to establish functional bile flow.
Human Induced Pluripotent Stem Cells (hIPSCs) derived from reprogrammed skin fibroblasts by overexpression of pluripotency factors can proliferate and be differentiated into various cell types including hepatocytes. hIPSCs enable production of patient specific cells, which are fully immuno-compatible. Genetically corrected mutant hIPSCs differentiated into hepatocytes have been used as cell therapy in animal models of inherited metabolic disorders but direct infusion of hepatocytes into the liver is unlikely to achieve polarised bile flow and correct ICDs.
Therefore hIPSCs developed from ICD patients will be used to culture hepatocytes on decellularised mouse liver ECM to generate in vitro models of ICDs. CLOs containing hepatocytes from genetically corrected hIPSC will be tested in mouse models of ICDs as potential treatment."
Max ERC Funding
1 500 000 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym Coupled gene circuit
Project Dynamics, noise, and coupling in gene circuit modules
Researcher (PI) James Charles Wallace Locke
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Country United Kingdom
Call Details Starting Grant (StG), LS2, ERC-2013-StG
Summary Cells must integrate output from multiple genetic circuits in order to correctly control cellular processes. Despite much work characterizing regulation in these circuits, how circuits interact to control global cellular programs remains unclear. This is particularly true given that recent research at the single cell level has revealed that genetic circuits often generate variable or stochastic regulation dynamics. In this proposal we will use a multi-disciplinary approach, combining modelling and time-lapse microscopy, to investigate how cells can robustly integrate signals from multiple dynamic genetic circuits. In particular we will answer the following questions: 1) What types of dynamic signal encoding strategies are available for the cell? 2) What are the benefits of dynamic gene activation, whether stochastic or oscillatory, to the cell? 3) How do cells couple and integrate output from diverse gene modules despite the noise and variability observed in gene circuit dynamics?
We will study these questions using 2 key model systems. In Aim 1, we will examine stochastic pulse regulation dynamics and coupling between alternative sigma factors in B. subtilis. Our preliminary data has revealed that multiple B. subtilis sigma factors stochastically pulse under stress. We will look for evidence of any coupling or interactions between these stochastic pulse circuits. This system will serve as a model for how a cell uses stochastic pulsing to control diverse cellular processes. In Aim 2, we will examine coupling between a deterministic oscillator, the circadian clock, and multiple other key pathways in Cyanobacteria. We will examine how the cell can dynamically couple multiple cellular processes using an oscillating signal. This work will provide an excellent base for Aim 3, in which we will use synthetic biology approaches to develop ‘bottom up’ tests of generation of novel dynamic coupling strategies.
Summary
Cells must integrate output from multiple genetic circuits in order to correctly control cellular processes. Despite much work characterizing regulation in these circuits, how circuits interact to control global cellular programs remains unclear. This is particularly true given that recent research at the single cell level has revealed that genetic circuits often generate variable or stochastic regulation dynamics. In this proposal we will use a multi-disciplinary approach, combining modelling and time-lapse microscopy, to investigate how cells can robustly integrate signals from multiple dynamic genetic circuits. In particular we will answer the following questions: 1) What types of dynamic signal encoding strategies are available for the cell? 2) What are the benefits of dynamic gene activation, whether stochastic or oscillatory, to the cell? 3) How do cells couple and integrate output from diverse gene modules despite the noise and variability observed in gene circuit dynamics?
We will study these questions using 2 key model systems. In Aim 1, we will examine stochastic pulse regulation dynamics and coupling between alternative sigma factors in B. subtilis. Our preliminary data has revealed that multiple B. subtilis sigma factors stochastically pulse under stress. We will look for evidence of any coupling or interactions between these stochastic pulse circuits. This system will serve as a model for how a cell uses stochastic pulsing to control diverse cellular processes. In Aim 2, we will examine coupling between a deterministic oscillator, the circadian clock, and multiple other key pathways in Cyanobacteria. We will examine how the cell can dynamically couple multiple cellular processes using an oscillating signal. This work will provide an excellent base for Aim 3, in which we will use synthetic biology approaches to develop ‘bottom up’ tests of generation of novel dynamic coupling strategies.
Max ERC Funding
1 499 571 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym ECOFLAM
Project The Impact of Plant Evolution on Fire Behaviour in Ancient Ecosystems
Researcher (PI) Claire Michelle Belcher
Host Institution (HI) THE UNIVERSITY OF EXETER
Country United Kingdom
Call Details Starting Grant (StG), LS8, ERC-2013-StG
Summary Fire has played a key role in the evolutionary success of our species and has shaped the abundance of life that we see on our planet today. Wildfires have influenced the history of plant life for 410 million years where 5 key plant evolutionary events have occurred that led to variations in fire behaviour. Variations in fire behaviour determine a fire’s severity and its impact on an ecosystem. In order to assess palaeofire severity the heat delivered by a fire and the duration for which it remains at a site must be estimated. Currently we are unable to estimate palaeofire behaviour and are therefore unable to predict the ecological impact of palaeofires. ECOFLAM will change this by combining for the first time state-of-the-art flammability experiments with innovative modelling approaches to reconstruct variations in palaeofire behaviour due to plant innovations. ECOFLAM will establish relationships between plant traits that are measurable in the fossil record, and their flammability. It will construct simple metrics that can be applied to assess the nature of fires occurring in a fossil flora. Then using a frontier approach ECOFLAM will apply mathematical models to create the first ever estimates of palaeofire behaviour. ECOFLAM will: 1) estimate fire behaviour in Earth’s earliest forests, 2) assess the impact of the evolution of gymnosperm conifers on changes in fire regime and fire behaviour 3) test the hypothesis that early angiosperms utilised fire to invade and out compete gymnosperm forests, 4) test the hypothesis that expansion of neotropical forests led to suppression of fire and 5) track the ability of increases in grass fuel to enhance ecosystem flammability enabling expansion of the savanna biome. ECOFLAM will collaborate with an artist to visually express the relationship between fire and plants to bring fire science to the arts and public. Finally via an exciting link with Morgan Stanley, London ECOFLAM will explore the economic impact of wildfires.
Summary
Fire has played a key role in the evolutionary success of our species and has shaped the abundance of life that we see on our planet today. Wildfires have influenced the history of plant life for 410 million years where 5 key plant evolutionary events have occurred that led to variations in fire behaviour. Variations in fire behaviour determine a fire’s severity and its impact on an ecosystem. In order to assess palaeofire severity the heat delivered by a fire and the duration for which it remains at a site must be estimated. Currently we are unable to estimate palaeofire behaviour and are therefore unable to predict the ecological impact of palaeofires. ECOFLAM will change this by combining for the first time state-of-the-art flammability experiments with innovative modelling approaches to reconstruct variations in palaeofire behaviour due to plant innovations. ECOFLAM will establish relationships between plant traits that are measurable in the fossil record, and their flammability. It will construct simple metrics that can be applied to assess the nature of fires occurring in a fossil flora. Then using a frontier approach ECOFLAM will apply mathematical models to create the first ever estimates of palaeofire behaviour. ECOFLAM will: 1) estimate fire behaviour in Earth’s earliest forests, 2) assess the impact of the evolution of gymnosperm conifers on changes in fire regime and fire behaviour 3) test the hypothesis that early angiosperms utilised fire to invade and out compete gymnosperm forests, 4) test the hypothesis that expansion of neotropical forests led to suppression of fire and 5) track the ability of increases in grass fuel to enhance ecosystem flammability enabling expansion of the savanna biome. ECOFLAM will collaborate with an artist to visually express the relationship between fire and plants to bring fire science to the arts and public. Finally via an exciting link with Morgan Stanley, London ECOFLAM will explore the economic impact of wildfires.
Max ERC Funding
1 519 640 €
Duration
Start date: 2013-10-01, End date: 2018-09-30
Project acronym EPITOOLS
Project Chemical biology approaches to unraveling the histone code
Researcher (PI) Akane Kawamura
Host Institution (HI) UNIVERSITY OF NEWCASTLE UPON TYNE
Country United Kingdom
Call Details Starting Grant (StG), LS9, ERC-2015-STG
Summary Posttranslational modifications on histones play crucial roles in the epigenetic regulation of eukaryotic gene expression. Chemical modifications that occur on histone tails include acetylation, methylation, phosphorylation, ubiquitination, and SUMOylation. This chemical diversity together with the positions and combinations of these modifications give rise to complex networks of highly controlled gene expression programs. The identification and characterisation of chromatin-associated proteins (or epigenetic regulators) in recent years has advanced our understanding of the significance of these histone modifications and the regulatory outcomes in development and in disease.
The project aims to generate new classes of highly selective and potent chemical probes for epigenetic regulators, focusing on enzymes and proteins associated with methyl-lysine marks. A novel modified peptide-based discovery platform, which combines molecular, chemical, biophysical and cellular techniques, will be developed and applied. These chemical probes will be useful for biological and biomedical research, and will serve as potential starting points for therapeutic epigenetic intervention.
Summary
Posttranslational modifications on histones play crucial roles in the epigenetic regulation of eukaryotic gene expression. Chemical modifications that occur on histone tails include acetylation, methylation, phosphorylation, ubiquitination, and SUMOylation. This chemical diversity together with the positions and combinations of these modifications give rise to complex networks of highly controlled gene expression programs. The identification and characterisation of chromatin-associated proteins (or epigenetic regulators) in recent years has advanced our understanding of the significance of these histone modifications and the regulatory outcomes in development and in disease.
The project aims to generate new classes of highly selective and potent chemical probes for epigenetic regulators, focusing on enzymes and proteins associated with methyl-lysine marks. A novel modified peptide-based discovery platform, which combines molecular, chemical, biophysical and cellular techniques, will be developed and applied. These chemical probes will be useful for biological and biomedical research, and will serve as potential starting points for therapeutic epigenetic intervention.
Max ERC Funding
1 758 846 €
Duration
Start date: 2016-04-01, End date: 2021-09-30
Project acronym GRASP
Project The evolution of the human hand: grasping trees and tools
Researcher (PI) Tracy Lynne Kivell
Host Institution (HI) UNIVERSITY OF KENT
Country United Kingdom
Call Details Starting Grant (StG), SH6, ERC-2013-StG
Summary The unique manipulative abilities of the human hand have fascinated scientists since the time of Darwin. However, we know little about how these unique abilities evolved because we have lacked, (1) the necessary fossil human (hominin) evidence and (2) the appropriate methods to investigate if, when and how our early ancestors used their hands for locomotion (climbing) and manipulation (tool-use). The GRASP project will use novel morphological, experimental and biomechanical methods to investigate different locomotor and manipulative behaviours in humans and other apes, and will use this knowledge to reconstruct hand use in the most complete early hominin hand fossils, those of Australopithecus sediba. The goal of GRASP is to determine the evolutionary history of the human hand by addressing two fundamental, yet unresolved, questions: (1) Were our fossil hominin ancestors still using their hands for climbing? (2) When and in which fossil hominin species did stone tool-use and tool-making first evolve? These questions will be addressed via three objectives: First, microtomography and a novel, holistic method (MedTool®) will be used to analyse the internal bony structure of human, ape and fossil hominin hand bones. Second, collection of the necessary biomechanical data on (a) the loads experienced by the human hand during tool-use and tool-making, (b) hand use and hand postures used by African apes during locomotion in the wild and, (c) the loads experienced by the bonobo hand during arboreal locomotion. Third, data from the first two objectives will be used to adapt musculoskeletal models of the human and bonobo hand and, through the creation of 3D biomechanical (finite-element) models, simulate natural loading of individual hand bones in humans, bonobos and fossil hominins. With this detailed understanding of hand function, we will determine how the locomotor and manipulative behaviours of Au. sediba and other early hominins shaped the evolution of the human hand.
Summary
The unique manipulative abilities of the human hand have fascinated scientists since the time of Darwin. However, we know little about how these unique abilities evolved because we have lacked, (1) the necessary fossil human (hominin) evidence and (2) the appropriate methods to investigate if, when and how our early ancestors used their hands for locomotion (climbing) and manipulation (tool-use). The GRASP project will use novel morphological, experimental and biomechanical methods to investigate different locomotor and manipulative behaviours in humans and other apes, and will use this knowledge to reconstruct hand use in the most complete early hominin hand fossils, those of Australopithecus sediba. The goal of GRASP is to determine the evolutionary history of the human hand by addressing two fundamental, yet unresolved, questions: (1) Were our fossil hominin ancestors still using their hands for climbing? (2) When and in which fossil hominin species did stone tool-use and tool-making first evolve? These questions will be addressed via three objectives: First, microtomography and a novel, holistic method (MedTool®) will be used to analyse the internal bony structure of human, ape and fossil hominin hand bones. Second, collection of the necessary biomechanical data on (a) the loads experienced by the human hand during tool-use and tool-making, (b) hand use and hand postures used by African apes during locomotion in the wild and, (c) the loads experienced by the bonobo hand during arboreal locomotion. Third, data from the first two objectives will be used to adapt musculoskeletal models of the human and bonobo hand and, through the creation of 3D biomechanical (finite-element) models, simulate natural loading of individual hand bones in humans, bonobos and fossil hominins. With this detailed understanding of hand function, we will determine how the locomotor and manipulative behaviours of Au. sediba and other early hominins shaped the evolution of the human hand.
Max ERC Funding
1 618 253 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym HAPSELA
Project Haploid selection in animals: investigating the importance of genetic and epigenetic effects in sperm
Researcher (PI) Simone Immler Maklakov
Host Institution (HI) UNIVERSITY OF EAST ANGLIA
Country United Kingdom
Call Details Starting Grant (StG), LS8, ERC-2013-StG
Summary An inescapable consequence of sex in eukaryotes is the evolution of a biphasic life cycle with alternating diploid and haploid phases. The occurrence of selection during both phases has far reaching consequences for fundamental evolutionary processes including the rate of adaptation, the extent of inbreeding depression and the load of deleterious mutations, as well as for applied research into assisted fertilization. It has been a long-standing dogma that, unlike in plants, selection at the haploid gametic level in animals is of no great importance. However, empirical evidence for postmeiotic haploid gene expression is increasing and with the recent recognition of the importance of epigenetic effects for evolutionary mechanisms it is paramount to revisit haploid selection in animals. The aim of the proposed project is to reconsider haploid selection in animals and to investigate the relative importance of genetic and epigenetic effects in sperm for the subsequent generation. The project consists of three logically connected parts, which tackle the question from different angles using the zebrafish Danio rerio as the main model system. In Part I, I will disentangle genetic from epigenetic effects and identify epigenetic effects that affect sperm and offspring performance by combining experimental evolution with next-generation sequencing data. In Part II, I will pinpoint genes that are expressed at the postmeiotic haploid stage of spermatogenesis and determine which of these genes may be under haploid selection. In Part III, I will get to the core of the question and perform single-cell genotyping to explore possible links between sperm phenotype and the underlying sperm genotype. By combining aspects from evolutionary biology, mathematical modeling, genomics and developmental biology this project will advance our understanding of how epigenetic and genetic differences among gametes shape phenotypes and mediate evolutionary change in animals.
Summary
An inescapable consequence of sex in eukaryotes is the evolution of a biphasic life cycle with alternating diploid and haploid phases. The occurrence of selection during both phases has far reaching consequences for fundamental evolutionary processes including the rate of adaptation, the extent of inbreeding depression and the load of deleterious mutations, as well as for applied research into assisted fertilization. It has been a long-standing dogma that, unlike in plants, selection at the haploid gametic level in animals is of no great importance. However, empirical evidence for postmeiotic haploid gene expression is increasing and with the recent recognition of the importance of epigenetic effects for evolutionary mechanisms it is paramount to revisit haploid selection in animals. The aim of the proposed project is to reconsider haploid selection in animals and to investigate the relative importance of genetic and epigenetic effects in sperm for the subsequent generation. The project consists of three logically connected parts, which tackle the question from different angles using the zebrafish Danio rerio as the main model system. In Part I, I will disentangle genetic from epigenetic effects and identify epigenetic effects that affect sperm and offspring performance by combining experimental evolution with next-generation sequencing data. In Part II, I will pinpoint genes that are expressed at the postmeiotic haploid stage of spermatogenesis and determine which of these genes may be under haploid selection. In Part III, I will get to the core of the question and perform single-cell genotyping to explore possible links between sperm phenotype and the underlying sperm genotype. By combining aspects from evolutionary biology, mathematical modeling, genomics and developmental biology this project will advance our understanding of how epigenetic and genetic differences among gametes shape phenotypes and mediate evolutionary change in animals.
Max ERC Funding
1 440 248 €
Duration
Start date: 2013-12-01, End date: 2018-11-30
Project acronym HNAEPISOME
Project Directed evolution of a synthetic episome based on hexitol nucleic acids (HNA)
Researcher (PI) Vitor Bernardo Bernardes Pinheiro
Host Institution (HI) University College London
Country United Kingdom
Call Details Starting Grant (StG), LS9, ERC-2013-StG
Summary A long term goal of synthetic biology is the assembly of a cell from its individual components. A genetic element based on synthetic nucleic acids capable of stable propagation, a synthetic episome, is the minimal genetic element required for the systematic development of all cellular components of a synthetic organism based on artificial nucleic acids. Recent progress in DNA polymerase engineering has successfully isolated variants with expanded substrate spectra capable of efficiently synthesising hexitol nucleic acids (HNA) from DNA templates, and capable of synthesising DNA from HNA templates. Together, they demonstrate that HNA can serve as a genetic material. However, the unavoidable DNA intermediate in HNA replication and their limited processivity greatly limit the potential of these polymerases for the development of an HNA episome.
To establish an HNA episome, processive HNA-directed HNA polymerases as well as accessory proteins to support episome maintenance and replication are required. The bacteriophage phi29 requires only four proteins (including polymerase, terminal protein, single-stranded and double-stranded DNA binding proteins) and two DNA elements (origin of replication and high affinity sites for its double-stranded DNA binding protein) to replicate and maintain its linear genome, making it a suitable starting point for the development of an HNA episome.
We propose to develop novel in vitro selection methodologies that will allow the directed evolution of a minimal HNA episome based on the phi29 system – including the isolation of an HNA-dependent HNA polymerase, a modified terminal protein and single-stranded as well as double-stranded HNA binding proteins. In addition to being a landmark result in synthetic biology, such HNA episome can form the basis of safer genetically modified organisms, in which the traits are encoded outside biology in an HNA episome dependent on the continued supply of artificial substrates for its maintenance.
Summary
A long term goal of synthetic biology is the assembly of a cell from its individual components. A genetic element based on synthetic nucleic acids capable of stable propagation, a synthetic episome, is the minimal genetic element required for the systematic development of all cellular components of a synthetic organism based on artificial nucleic acids. Recent progress in DNA polymerase engineering has successfully isolated variants with expanded substrate spectra capable of efficiently synthesising hexitol nucleic acids (HNA) from DNA templates, and capable of synthesising DNA from HNA templates. Together, they demonstrate that HNA can serve as a genetic material. However, the unavoidable DNA intermediate in HNA replication and their limited processivity greatly limit the potential of these polymerases for the development of an HNA episome.
To establish an HNA episome, processive HNA-directed HNA polymerases as well as accessory proteins to support episome maintenance and replication are required. The bacteriophage phi29 requires only four proteins (including polymerase, terminal protein, single-stranded and double-stranded DNA binding proteins) and two DNA elements (origin of replication and high affinity sites for its double-stranded DNA binding protein) to replicate and maintain its linear genome, making it a suitable starting point for the development of an HNA episome.
We propose to develop novel in vitro selection methodologies that will allow the directed evolution of a minimal HNA episome based on the phi29 system – including the isolation of an HNA-dependent HNA polymerase, a modified terminal protein and single-stranded as well as double-stranded HNA binding proteins. In addition to being a landmark result in synthetic biology, such HNA episome can form the basis of safer genetically modified organisms, in which the traits are encoded outside biology in an HNA episome dependent on the continued supply of artificial substrates for its maintenance.
Max ERC Funding
1 188 594 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
