Project acronym 2SEXES_1GENOME
Project Sex-specific genetic effects on fitness and human disease
Researcher (PI) Edward Hugh Morrow
Host Institution (HI) THE UNIVERSITY OF SUSSEX
Call Details Starting Grant (StG), LS8, ERC-2011-StG_20101109
Summary Darwin’s theory of natural selection rests on the principle that fitness variation in natural populations has a heritable component, on which selection acts, thereby leading to evolutionary change. A fundamental and so far unresolved question for the field of evolutionary biology is to identify the genetic loci responsible for this fitness variation, thereby coming closer to an understanding of how variation is maintained in the face of continual selection. One important complicating factor in the search for fitness related genes however is the existence of separate sexes – theoretical expectations and empirical data both suggest that sexually antagonistic genes are common. The phrase “two sexes, one genome” nicely sums up the problem; selection may favour alleles in one sex, even if they have detrimental effects on the fitness of the opposite sex, since it is their net effect across both sexes that determine the likelihood that alleles persist in a population. This theoretical framework raises an interesting, and so far entirely unexplored issue: that in one sex the functional performance of some alleles is predicted to be compromised and this effect may account for some common human diseases and conditions which show genotype-sex interactions. I propose to explore the genetic basis of sex-specific fitness in a model organism in both laboratory and natural conditions and to test whether those genes identified as having sexually antagonistic effects can help explain the incidence of human diseases that display sexual dimorphism in prevalence, age of onset or severity. This multidisciplinary project directly addresses some fundamental unresolved questions in evolutionary biology: the genetic basis and maintenance of fitness variation; the evolution of sexual dimorphism; and aims to provide novel insights into the genetic basis of some common human diseases.
Summary
Darwin’s theory of natural selection rests on the principle that fitness variation in natural populations has a heritable component, on which selection acts, thereby leading to evolutionary change. A fundamental and so far unresolved question for the field of evolutionary biology is to identify the genetic loci responsible for this fitness variation, thereby coming closer to an understanding of how variation is maintained in the face of continual selection. One important complicating factor in the search for fitness related genes however is the existence of separate sexes – theoretical expectations and empirical data both suggest that sexually antagonistic genes are common. The phrase “two sexes, one genome” nicely sums up the problem; selection may favour alleles in one sex, even if they have detrimental effects on the fitness of the opposite sex, since it is their net effect across both sexes that determine the likelihood that alleles persist in a population. This theoretical framework raises an interesting, and so far entirely unexplored issue: that in one sex the functional performance of some alleles is predicted to be compromised and this effect may account for some common human diseases and conditions which show genotype-sex interactions. I propose to explore the genetic basis of sex-specific fitness in a model organism in both laboratory and natural conditions and to test whether those genes identified as having sexually antagonistic effects can help explain the incidence of human diseases that display sexual dimorphism in prevalence, age of onset or severity. This multidisciplinary project directly addresses some fundamental unresolved questions in evolutionary biology: the genetic basis and maintenance of fitness variation; the evolution of sexual dimorphism; and aims to provide novel insights into the genetic basis of some common human diseases.
Max ERC Funding
1 500 000 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
Project acronym ABYSS
Project ABYSS - Assessment of bacterial life and matter cycling in deep-sea surface sediments
Researcher (PI) Antje Boetius
Host Institution (HI) ALFRED-WEGENER-INSTITUT HELMHOLTZ-ZENTRUM FUR POLAR- UND MEERESFORSCHUNG
Call Details Advanced Grant (AdG), LS8, ERC-2011-ADG_20110310
Summary The deep-sea floor hosts a distinct microbial biome covering 67% of the Earth’s surface, characterized by cold temperatures, permanent darkness, high pressure and food limitation. The surface sediments are dominated by bacteria, with on average a billion cells per ml. Benthic bacteria are highly relevant to the Earth’s element cycles as they remineralize most of the organic matter sinking from the productive surface ocean, and return nutrients, thereby promoting ocean primary production. What passes the bacterial filter is a relevant sink for carbon on geological time scales, influencing global oxygen and carbon budgets, and fueling the deep subsurface biosphere. Despite the relevance of deep-sea sediment bacteria to climate, geochemical cycles and ecology of the seafloor, their genetic and functional diversity, niche differentiation and biological interactions remain unknown. Our preliminary work in a global survey of deep-sea sediments enables us now to target specific genes for the quantification of abyssal bacteria. We can trace isotope-labeled elements into communities and single cells, and analyze the molecular alteration of organic matter during microbial degradation, all in context with environmental dynamics recorded at the only long-term deep-sea ecosystem observatory in the Arctic that we maintain. I propose to bridge biogeochemistry, ecology, microbiology and marine biology to develop a systematic understanding of abyssal sediment bacterial community distribution, diversity, function and interactions, by combining in situ flux studies and different visualization techniques with a wide range of molecular tools. Substantial progress is expected in understanding I) identity and function of the dominant types of indigenous benthic bacteria, II) dynamics in bacterial activity and diversity caused by variations in particle flux, III) interactions with different types and ages of organic matter, and other biological factors.
Summary
The deep-sea floor hosts a distinct microbial biome covering 67% of the Earth’s surface, characterized by cold temperatures, permanent darkness, high pressure and food limitation. The surface sediments are dominated by bacteria, with on average a billion cells per ml. Benthic bacteria are highly relevant to the Earth’s element cycles as they remineralize most of the organic matter sinking from the productive surface ocean, and return nutrients, thereby promoting ocean primary production. What passes the bacterial filter is a relevant sink for carbon on geological time scales, influencing global oxygen and carbon budgets, and fueling the deep subsurface biosphere. Despite the relevance of deep-sea sediment bacteria to climate, geochemical cycles and ecology of the seafloor, their genetic and functional diversity, niche differentiation and biological interactions remain unknown. Our preliminary work in a global survey of deep-sea sediments enables us now to target specific genes for the quantification of abyssal bacteria. We can trace isotope-labeled elements into communities and single cells, and analyze the molecular alteration of organic matter during microbial degradation, all in context with environmental dynamics recorded at the only long-term deep-sea ecosystem observatory in the Arctic that we maintain. I propose to bridge biogeochemistry, ecology, microbiology and marine biology to develop a systematic understanding of abyssal sediment bacterial community distribution, diversity, function and interactions, by combining in situ flux studies and different visualization techniques with a wide range of molecular tools. Substantial progress is expected in understanding I) identity and function of the dominant types of indigenous benthic bacteria, II) dynamics in bacterial activity and diversity caused by variations in particle flux, III) interactions with different types and ages of organic matter, and other biological factors.
Max ERC Funding
3 375 693 €
Duration
Start date: 2012-06-01, End date: 2018-05-31
Project acronym aCROBAT
Project Circadian Regulation Of Brown Adipose Thermogenesis
Researcher (PI) Zachary Philip Gerhart-Hines
Host Institution (HI) KOBENHAVNS UNIVERSITET
Call Details Starting Grant (StG), LS4, ERC-2014-STG
Summary Obesity and diabetes have reached pandemic proportions and new therapeutic strategies are critically needed. Brown adipose tissue (BAT), a major source of heat production, possesses significant energy-dissipating capacity and therefore represents a promising target to use in combating these diseases. Recently, I discovered a novel link between circadian rhythm and thermogenic stress in the control of the conserved, calorie-burning functions of BAT. Circadian and thermogenic signaling to BAT incorporates blood-borne hormonal and nutrient cues with direct neuronal input. Yet how these responses coordinately shape BAT energy-expending potential through the regulation of cell surface receptors, metabolic enzymes, and transcriptional effectors is still not understood. My primary goal is to investigate this previously unappreciated network of crosstalk that allows mammals to effectively orchestrate daily rhythms in BAT metabolism, while maintaining their ability to adapt to abrupt changes in energy demand. My group will address this question using gain and loss-of-function in vitro and in vivo studies, newly-generated mouse models, customized physiological phenotyping, and cutting-edge advances in next generation RNA sequencing and mass spectrometry. Preliminary, small-scale validations of our methodologies have already yielded a number of novel candidates that may drive key facets of BAT metabolism. Additionally, we will extend our circadian and thermogenic studies into humans to evaluate the translational potential. Our results will advance the fundamental understanding of how daily oscillations in bioenergetic networks establish a framework for the anticipation of and adaptation to environmental challenges. Importantly, we expect that these mechanistic insights will reveal pharmacological targets through which we can unlock evolutionary constraints and harness the energy-expending potential of BAT for the prevention and treatment of obesity and diabetes.
Summary
Obesity and diabetes have reached pandemic proportions and new therapeutic strategies are critically needed. Brown adipose tissue (BAT), a major source of heat production, possesses significant energy-dissipating capacity and therefore represents a promising target to use in combating these diseases. Recently, I discovered a novel link between circadian rhythm and thermogenic stress in the control of the conserved, calorie-burning functions of BAT. Circadian and thermogenic signaling to BAT incorporates blood-borne hormonal and nutrient cues with direct neuronal input. Yet how these responses coordinately shape BAT energy-expending potential through the regulation of cell surface receptors, metabolic enzymes, and transcriptional effectors is still not understood. My primary goal is to investigate this previously unappreciated network of crosstalk that allows mammals to effectively orchestrate daily rhythms in BAT metabolism, while maintaining their ability to adapt to abrupt changes in energy demand. My group will address this question using gain and loss-of-function in vitro and in vivo studies, newly-generated mouse models, customized physiological phenotyping, and cutting-edge advances in next generation RNA sequencing and mass spectrometry. Preliminary, small-scale validations of our methodologies have already yielded a number of novel candidates that may drive key facets of BAT metabolism. Additionally, we will extend our circadian and thermogenic studies into humans to evaluate the translational potential. Our results will advance the fundamental understanding of how daily oscillations in bioenergetic networks establish a framework for the anticipation of and adaptation to environmental challenges. Importantly, we expect that these mechanistic insights will reveal pharmacological targets through which we can unlock evolutionary constraints and harness the energy-expending potential of BAT for the prevention and treatment of obesity and diabetes.
Max ERC Funding
1 497 008 €
Duration
Start date: 2015-05-01, End date: 2020-04-30
Project acronym ADAPT
Project Origins and factors governing adaptation: Insights from experimental evolution and population genomic data
Researcher (PI) Thomas, Martin Jean Bataillon
Host Institution (HI) AARHUS UNIVERSITET
Call Details Starting Grant (StG), LS8, ERC-2012-StG_20111109
Summary "I propose a systematic study of the type of genetic variation enabling adaptation and factors that limit rates of adaptation in natural populations. New methods will be developed for analysing data from experimental evolution and population genomics. The methods will be applied to state of the art data from both fields. Adaptation is generated by natural selection sieving through heritable variation. Examples of adaptation are available from the fossil record and from extant populations. Genomic studies have supplied many instances of genomic regions exhibiting footprint of natural selection favouring new variants. Despite ample proof that adaptation happens, we know little about beneficial mutations– the raw stuff enabling adaptation. Is adaptation mediated by genetic variation pre-existing in the population, or by variation supplied de novo through mutations? We know even less about what factors limit rates of adaptation. Answers to these questions are crucial for Evolutionary Biology, but also for believable quantifications of the evolutionary potential of populations. Population genetic theory makes predictions and allows inference from the patterns of polymorphism within species and divergence between species. Yet models specifying the fitness effects of mutations are often missing. Fitness landscape models will be mobilized to fill this gap and develop methods for inferring the distribution of fitness effects and factors governing rates of adaptation. Insights into the processes underlying adaptation will thus be gained from experimental evolution and population genomics data. The applicability of insights gained from experimental evolution to comprehend adaptation in nature will be scrutinized. We will unite two very different approaches for studying adaptation. The project will boost our understanding of how selection shapes genomes and open the way for further quantitative tests of theories of adaptation."
Summary
"I propose a systematic study of the type of genetic variation enabling adaptation and factors that limit rates of adaptation in natural populations. New methods will be developed for analysing data from experimental evolution and population genomics. The methods will be applied to state of the art data from both fields. Adaptation is generated by natural selection sieving through heritable variation. Examples of adaptation are available from the fossil record and from extant populations. Genomic studies have supplied many instances of genomic regions exhibiting footprint of natural selection favouring new variants. Despite ample proof that adaptation happens, we know little about beneficial mutations– the raw stuff enabling adaptation. Is adaptation mediated by genetic variation pre-existing in the population, or by variation supplied de novo through mutations? We know even less about what factors limit rates of adaptation. Answers to these questions are crucial for Evolutionary Biology, but also for believable quantifications of the evolutionary potential of populations. Population genetic theory makes predictions and allows inference from the patterns of polymorphism within species and divergence between species. Yet models specifying the fitness effects of mutations are often missing. Fitness landscape models will be mobilized to fill this gap and develop methods for inferring the distribution of fitness effects and factors governing rates of adaptation. Insights into the processes underlying adaptation will thus be gained from experimental evolution and population genomics data. The applicability of insights gained from experimental evolution to comprehend adaptation in nature will be scrutinized. We will unite two very different approaches for studying adaptation. The project will boost our understanding of how selection shapes genomes and open the way for further quantitative tests of theories of adaptation."
Max ERC Funding
1 159 857 €
Duration
Start date: 2013-04-01, End date: 2018-03-31
Project acronym ADaPTIVE
Project Analysing Diversity with a Phenomic approach: Trends in Vertebrate Evolution
Researcher (PI) Anjali Goswami
Host Institution (HI) NATURAL HISTORY MUSEUM
Call Details Starting Grant (StG), LS8, ERC-2014-STG
Summary What processes shape vertebrate diversity through deep time? Approaches to this question can focus on many different factors, from life history and ecology to large-scale environmental change and extinction. To date, the majority of studies on the evolution of vertebrate diversity have focused on relatively simple metrics, specifically taxon counts or univariate measures, such as body size. However, multivariate morphological data provides a more complete picture of evolutionary and palaeoecological change. Morphological data can also bridge deep-time palaeobiological analyses with studies of the genetic and developmental factors that shape variation and must also influence large-scale patterns of evolutionary change. Thus, accurately reconstructing the patterns and processes underlying evolution requires an approach that can fully represent an organism’s phenome, the sum total of their observable traits.
Recent advances in imaging and data analysis allow large-scale study of phenomic evolution. In this project, I propose to quantitatively analyse the deep-time evolutionary diversity of tetrapods (amphibians, reptiles, birds, and mammals). Specifically, I will apply and extend new imaging, morphometric, and analytical tools to construct a multivariate phenomic dataset for living and extinct tetrapods from 3-D scans. I will use these data to rigorously compare extinction selectivity, timing, pace, and shape of adaptive radiations, and ecomorphological response to large-scale climatic shifts across all tetrapod clades. To do so, I will quantify morphological diversity (disparity) and rates of evolution spanning over 300 million years of tetrapod history. I will further analyse the evolution of phenotypic integration by quantifying not just the traits themselves, but changes in the relationships among traits, which reflect the genetic, developmental, and functional interactions that shape variation, the raw material for natural selection.
Summary
What processes shape vertebrate diversity through deep time? Approaches to this question can focus on many different factors, from life history and ecology to large-scale environmental change and extinction. To date, the majority of studies on the evolution of vertebrate diversity have focused on relatively simple metrics, specifically taxon counts or univariate measures, such as body size. However, multivariate morphological data provides a more complete picture of evolutionary and palaeoecological change. Morphological data can also bridge deep-time palaeobiological analyses with studies of the genetic and developmental factors that shape variation and must also influence large-scale patterns of evolutionary change. Thus, accurately reconstructing the patterns and processes underlying evolution requires an approach that can fully represent an organism’s phenome, the sum total of their observable traits.
Recent advances in imaging and data analysis allow large-scale study of phenomic evolution. In this project, I propose to quantitatively analyse the deep-time evolutionary diversity of tetrapods (amphibians, reptiles, birds, and mammals). Specifically, I will apply and extend new imaging, morphometric, and analytical tools to construct a multivariate phenomic dataset for living and extinct tetrapods from 3-D scans. I will use these data to rigorously compare extinction selectivity, timing, pace, and shape of adaptive radiations, and ecomorphological response to large-scale climatic shifts across all tetrapod clades. To do so, I will quantify morphological diversity (disparity) and rates of evolution spanning over 300 million years of tetrapod history. I will further analyse the evolution of phenotypic integration by quantifying not just the traits themselves, but changes in the relationships among traits, which reflect the genetic, developmental, and functional interactions that shape variation, the raw material for natural selection.
Max ERC Funding
1 482 818 €
Duration
Start date: 2015-06-01, End date: 2021-05-31
Project acronym AdaptiveResponse
Project The evolution of adaptive response mechanisms
Researcher (PI) Franz WEISSING
Host Institution (HI) RIJKSUNIVERSITEIT GRONINGEN
Call Details Advanced Grant (AdG), LS8, ERC-2017-ADG
Summary In an era of rapid climate change there is a pressing need to understand whether and how organisms are able to adapt to novel environments. Such understanding is hampered by a major divide in the life sciences. Disciplines like systems biology or neurobiology make rapid progress in unravelling the mechanisms underlying the responses of organisms to their environment, but this knowledge is insufficiently integrated in eco-evolutionary theory. Current eco-evolutionary models focus on the response patterns themselves, largely neglecting the structures and mechanisms producing these patterns. Here I propose a new, mechanism-oriented framework that views the architecture of adaptation, rather than the resulting responses, as the primary target of natural selection. I am convinced that this change in perspective will yield fundamentally new insights, necessitating the re-evaluation of many seemingly well-established eco-evolutionary principles.
My aim is to develop a comprehensive theory of the eco-evolutionary causes and consequences of the architecture underlying adaptive responses. In three parallel lines of investigation, I will study how architecture is shaped by selection, how evolved response strategies reflect the underlying architecture, and how these responses affect the eco-evolutionary dynamics and the capacity to adapt to novel conditions. All three lines have the potential of making ground-breaking contributions to eco-evolutionary theory, including: the specification of evolutionary tipping points; resolving the puzzle that real organisms evolve much faster than predicted by current theory; a new and general explanation for the evolutionary emergence of individual variation; and a framework for studying the evolution of learning and other general-purpose mechanisms. By making use of concepts from information theory and artificial intelligence, the project will also introduce various methodological innovations.
Summary
In an era of rapid climate change there is a pressing need to understand whether and how organisms are able to adapt to novel environments. Such understanding is hampered by a major divide in the life sciences. Disciplines like systems biology or neurobiology make rapid progress in unravelling the mechanisms underlying the responses of organisms to their environment, but this knowledge is insufficiently integrated in eco-evolutionary theory. Current eco-evolutionary models focus on the response patterns themselves, largely neglecting the structures and mechanisms producing these patterns. Here I propose a new, mechanism-oriented framework that views the architecture of adaptation, rather than the resulting responses, as the primary target of natural selection. I am convinced that this change in perspective will yield fundamentally new insights, necessitating the re-evaluation of many seemingly well-established eco-evolutionary principles.
My aim is to develop a comprehensive theory of the eco-evolutionary causes and consequences of the architecture underlying adaptive responses. In three parallel lines of investigation, I will study how architecture is shaped by selection, how evolved response strategies reflect the underlying architecture, and how these responses affect the eco-evolutionary dynamics and the capacity to adapt to novel conditions. All three lines have the potential of making ground-breaking contributions to eco-evolutionary theory, including: the specification of evolutionary tipping points; resolving the puzzle that real organisms evolve much faster than predicted by current theory; a new and general explanation for the evolutionary emergence of individual variation; and a framework for studying the evolution of learning and other general-purpose mechanisms. By making use of concepts from information theory and artificial intelligence, the project will also introduce various methodological innovations.
Max ERC Funding
2 500 000 €
Duration
Start date: 2018-12-01, End date: 2023-11-30
Project acronym AdaptoSCOPE
Project Using cis-regulatory mutations to highlight polygenic adaptation in natural plant systems
Researcher (PI) Juliette de Meaux
Host Institution (HI) UNIVERSITAET ZU KOELN
Call Details Consolidator Grant (CoG), LS8, ERC-2014-CoG
Summary The goal of this project is to demonstrate that novel aspects of the molecular basis of Darwinian adaptation can be discovered if the polygenic basis of adaptation is taken into account. This project will use the genome-wide distribution of cis-regulatory variants to discover the molecular pathways that are optimized during adaptation via accumulation of small effect mutations. Current approaches include scans for outlier genes with strong population genetics signatures of selection, or large effect QTL associating with fitness. They can only reveal a small subset of the molecular changes recruited along adaptive paths. Here, instead, the distribution of small effect mutations will be used to make inferences on the targets of polygenic adaptation across divergent populations in each of the two closely related species, A. thaliana and A. lyrata. These species are both found at diverse latitudes and show sign of local adaptation to climatic differences. Mutations affecting cis-regulation will be identified in leaves of plants exposed to various temperature regimes triggering phenotypic responses of adaptive relevance. Their distribution in clusters of functionally connected genes will be quantified. The phylogeographic differences in the distribution of the mutations will be used to disentangle neutral from adaptive clusters of functionally connected genes in each of the two species. This project will identify the molecular pathways subjected collectively to natural selection and provide a completely novel view on adaptive landscapes. It will further examine whether local adaptation occurs by convergent evolution of molecular systems in plants. This approach has the potential to find broad applications in ecology and agriculture.
Summary
The goal of this project is to demonstrate that novel aspects of the molecular basis of Darwinian adaptation can be discovered if the polygenic basis of adaptation is taken into account. This project will use the genome-wide distribution of cis-regulatory variants to discover the molecular pathways that are optimized during adaptation via accumulation of small effect mutations. Current approaches include scans for outlier genes with strong population genetics signatures of selection, or large effect QTL associating with fitness. They can only reveal a small subset of the molecular changes recruited along adaptive paths. Here, instead, the distribution of small effect mutations will be used to make inferences on the targets of polygenic adaptation across divergent populations in each of the two closely related species, A. thaliana and A. lyrata. These species are both found at diverse latitudes and show sign of local adaptation to climatic differences. Mutations affecting cis-regulation will be identified in leaves of plants exposed to various temperature regimes triggering phenotypic responses of adaptive relevance. Their distribution in clusters of functionally connected genes will be quantified. The phylogeographic differences in the distribution of the mutations will be used to disentangle neutral from adaptive clusters of functionally connected genes in each of the two species. This project will identify the molecular pathways subjected collectively to natural selection and provide a completely novel view on adaptive landscapes. It will further examine whether local adaptation occurs by convergent evolution of molecular systems in plants. This approach has the potential to find broad applications in ecology and agriculture.
Max ERC Funding
1 683 120 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
Project acronym AgeingStemCellFate
Project The Role of Ectopic Adipocyte Progenitors in Age-related Stem Cell Dysfunction, Systemic Inflammation, and Metabolic Disease
Researcher (PI) Tim Julius Schulz
Host Institution (HI) DEUTSCHES INSTITUT FUER ERNAEHRUNGSFORSCHUNG POTSDAM REHBRUECKE
Call Details Starting Grant (StG), LS4, ERC-2012-StG_20111109
Summary Ageing is accompanied by ectopic white adipose tissue depositions in skeletal muscle and other anatomical locations, such as brown adipose tissue and the bone marrow. Ectopic fat accrual contributes to organ dysfunction, systemic insulin resistance, and other perturbations that have been implicated in metabolic diseases.
This research proposal aims to identify the regulatory cues that control the development of ectopic progenitor cells that give rise to this type of fat. It is hypothesized that an age-related dysfunction of the stem cell niche leads to an imbalance between (1) tissue-specific stem cells and (2) fibroblast-like, primarily adipogenic progenitors that reside within many tissues. Novel methodologies that assess stem/progenitor cell characteristics on the single cell level will be combined with animal models of lineage tracing to determine the developmental origin of these adipogenic progenitors and processes that regulate their function.
Notch signalling is a key signalling pathway that relies on direct physical interaction to control stem cell fate. It is proposed that impaired Notch activity contributes to the phenotypical shift of precursor cell distribution in aged tissues.
Lastly, the role of the stem cell niche in ectopic adipocyte progenitor formation will be analyzed. External signals originating from the surrounding niche cells regulate the developmental fate of stem cells. Secreted factors and their role in the formation of ectopic adipocyte precursors during senescence will be identified using a combination of biochemical and systems biology approaches.
Accomplishment of these studies will help to understand the basic processes of stem cell ageing and identify mechanisms of age-related functional decline in tissue regeneration. By targeting the population of tissue-resident adipogenic progenitor cells, therapeutic strategies could be developed to counteract metabolic complications associated with the ageing process.
Summary
Ageing is accompanied by ectopic white adipose tissue depositions in skeletal muscle and other anatomical locations, such as brown adipose tissue and the bone marrow. Ectopic fat accrual contributes to organ dysfunction, systemic insulin resistance, and other perturbations that have been implicated in metabolic diseases.
This research proposal aims to identify the regulatory cues that control the development of ectopic progenitor cells that give rise to this type of fat. It is hypothesized that an age-related dysfunction of the stem cell niche leads to an imbalance between (1) tissue-specific stem cells and (2) fibroblast-like, primarily adipogenic progenitors that reside within many tissues. Novel methodologies that assess stem/progenitor cell characteristics on the single cell level will be combined with animal models of lineage tracing to determine the developmental origin of these adipogenic progenitors and processes that regulate their function.
Notch signalling is a key signalling pathway that relies on direct physical interaction to control stem cell fate. It is proposed that impaired Notch activity contributes to the phenotypical shift of precursor cell distribution in aged tissues.
Lastly, the role of the stem cell niche in ectopic adipocyte progenitor formation will be analyzed. External signals originating from the surrounding niche cells regulate the developmental fate of stem cells. Secreted factors and their role in the formation of ectopic adipocyte precursors during senescence will be identified using a combination of biochemical and systems biology approaches.
Accomplishment of these studies will help to understand the basic processes of stem cell ageing and identify mechanisms of age-related functional decline in tissue regeneration. By targeting the population of tissue-resident adipogenic progenitor cells, therapeutic strategies could be developed to counteract metabolic complications associated with the ageing process.
Max ERC Funding
1 496 444 €
Duration
Start date: 2013-03-01, End date: 2018-02-28
Project acronym AGINGSEXDIFF
Project Aging Differently: Understanding Sex Differences in Reproductive, Demographic and Functional Senescence
Researcher (PI) Alexei Maklakov
Host Institution (HI) UPPSALA UNIVERSITET
Call Details Starting Grant (StG), LS8, ERC-2010-StG_20091118
Summary Sex differences in life span and aging are ubiquitous across the animal kingdom and represent a
long-standing challenge in evolutionary biology. In most species, including humans, sexes differ not
only in how long they live and when they start to senesce, but also in how they react to
environmental interventions aimed at prolonging their life span or decelerating the onset of aging.
Therefore, sex differences in life span and aging have important implications beyond the questions
posed by fundamental science. Both evolutionary reasons and medical implications of sex
differences in demographic, reproductive and physiological senescence are and will be crucial
targets of present and future research in the biology of aging. Here I propose a two-step approach
that can provide a significant breakthrough in our understanding of the biological basis of sex
differences in aging. First, I propose to resolve the age-old conundrum regarding the role of sexspecific
mortality rate in sex differences in aging by developing a series of targeted experimental
evolution studies in a novel model organism – the nematode, Caenorhabditis remanei. Second, I
address the role of intra-locus sexual conflict in the evolution of aging by combining novel
methodology from nutritional ecology – the Geometric Framework – with artificial selection
approach using the cricket Teleogryllus commodus and the fruitfly Drosophila melanogaster. I will
directly test the hypothesis that intra-locus sexual conflict mediates aging by restricting the
adaptive evolution of diet choice. By combining techniques from evolutionary biology and
nutritional ecology, this proposal will raise EU’s profile in integrative research, and contribute to
the training of young scientists in this rapidly developing field.
Summary
Sex differences in life span and aging are ubiquitous across the animal kingdom and represent a
long-standing challenge in evolutionary biology. In most species, including humans, sexes differ not
only in how long they live and when they start to senesce, but also in how they react to
environmental interventions aimed at prolonging their life span or decelerating the onset of aging.
Therefore, sex differences in life span and aging have important implications beyond the questions
posed by fundamental science. Both evolutionary reasons and medical implications of sex
differences in demographic, reproductive and physiological senescence are and will be crucial
targets of present and future research in the biology of aging. Here I propose a two-step approach
that can provide a significant breakthrough in our understanding of the biological basis of sex
differences in aging. First, I propose to resolve the age-old conundrum regarding the role of sexspecific
mortality rate in sex differences in aging by developing a series of targeted experimental
evolution studies in a novel model organism – the nematode, Caenorhabditis remanei. Second, I
address the role of intra-locus sexual conflict in the evolution of aging by combining novel
methodology from nutritional ecology – the Geometric Framework – with artificial selection
approach using the cricket Teleogryllus commodus and the fruitfly Drosophila melanogaster. I will
directly test the hypothesis that intra-locus sexual conflict mediates aging by restricting the
adaptive evolution of diet choice. By combining techniques from evolutionary biology and
nutritional ecology, this proposal will raise EU’s profile in integrative research, and contribute to
the training of young scientists in this rapidly developing field.
Max ERC Funding
1 391 904 €
Duration
Start date: 2010-12-01, End date: 2016-05-31
Project acronym AGRICON
Project Ancient genomic reconstruction of convergent evolution to agriculture
Researcher (PI) Pontus Rickard Otto Peter Skoglund
Host Institution (HI) THE FRANCIS CRICK INSTITUTE LIMITED
Call Details Starting Grant (StG), LS8, ERC-2019-STG
Summary As global climates warmed ca. 10,000 years ago came a remarkable convergent transformation of human lifestyles that occurred independently in multiple continents and human populations. This transition from hunter-gatherer subsistence to food-production catalysed large-scale population growth, offering the opportunity for increased rates of adaptation, but also rapidly presented a large number of independent human populations with a new evolutionary challenge. This project will use ancient population genomics—the only way to directly reconstruct human genetic evolution—to study whether evolutionary processes during the agricultural transition differed in differed regions. Which genomic adaptations were associated with the agricultural transition? Did adaptation to hunter-gatherer and agricultural lifestyles act on similar genetic architecture in different instances? To which extent did adaptation in domestic dogs—the only species domesticated prior to the agricultural transition—occur in convergence with humans? To answer these questions, the project will generate ancient genomic data from pre-agricultural and early agricultural populations from multiple human- and domestic dog populations from Africa, Central America, and Southeast Asia. This will be achieved with direct sequencing as well as a new human ~850,000 SNP capture panel designed to avoid bias towards Eurasian ancestry. We will also develop new computational methods robust to the challenges posed by ancient genomes to identify adaptive admixture, analyse copy number variation, test continuous population models, and statistically assess convergence in the genomic architecture of adaptation. Leveraging cutting-edge ancient genomics and two model organisms for the genomic basis of phenotypic variation, this project aims to reconstruct the universal evolutionary phenomena underpinning a watershed evolutionary episode that shapes global biodiversity and the human condition to this day.
Summary
As global climates warmed ca. 10,000 years ago came a remarkable convergent transformation of human lifestyles that occurred independently in multiple continents and human populations. This transition from hunter-gatherer subsistence to food-production catalysed large-scale population growth, offering the opportunity for increased rates of adaptation, but also rapidly presented a large number of independent human populations with a new evolutionary challenge. This project will use ancient population genomics—the only way to directly reconstruct human genetic evolution—to study whether evolutionary processes during the agricultural transition differed in differed regions. Which genomic adaptations were associated with the agricultural transition? Did adaptation to hunter-gatherer and agricultural lifestyles act on similar genetic architecture in different instances? To which extent did adaptation in domestic dogs—the only species domesticated prior to the agricultural transition—occur in convergence with humans? To answer these questions, the project will generate ancient genomic data from pre-agricultural and early agricultural populations from multiple human- and domestic dog populations from Africa, Central America, and Southeast Asia. This will be achieved with direct sequencing as well as a new human ~850,000 SNP capture panel designed to avoid bias towards Eurasian ancestry. We will also develop new computational methods robust to the challenges posed by ancient genomes to identify adaptive admixture, analyse copy number variation, test continuous population models, and statistically assess convergence in the genomic architecture of adaptation. Leveraging cutting-edge ancient genomics and two model organisms for the genomic basis of phenotypic variation, this project aims to reconstruct the universal evolutionary phenomena underpinning a watershed evolutionary episode that shapes global biodiversity and the human condition to this day.
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-11-01, End date: 2024-10-31
