Project acronym Born-Immune
Project Shaping of the Human Immune System by Primal Environmental Exposures In the Newborn Child
Researcher (PI) Klas Erik Petter Brodin
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Starting Grant (StG), LS6, ERC-2015-STG
Summary Immune systems are highly variable, but the sources of this variation are poorly understood. Genetic variation only explains a minor fraction of this, and we are unable to accurately predict the risk of immune mediated disease or severe infection in any given individual. I recently found that immune cells and proteins in healthy twins vary because of non-heritable influences (infections, vaccines, microbiota etc.), with only minor influences from heritable factors (Brodin, et al, Cell 2015). When and how such environmental influences shape our immune system is now important to understand. Birth represents the most transformational change in environment during the life of any individual. I propose, that environmental influences at birth, and during the first months of life could be particularly influential by imprinting on the regulatory mechanisms forming in the developing immune system. Adaptive changes in immune cell frequencies and functional states induced by early-life exposures could determine both the immune competence of the newborn, but potentially also its long-term trajectory towards immunological health or disease. Here, I propose a study of 1000 newborn children, followed longitudinally during their first 1000 days of life. By monitoring immune profiles and recording many environmental influences, we hope to understand how early life exposures can influence human immune system development. We have established a new assay based on Mass Cytometry and necessary data analysis tools (Brodin, et al, PNAS 2014), to simultaneously monitor the frequencies, phenotypes and functional states of more than 200 blood immune cell populations from only 100 microliters of blood. By monitoring environmental influences at regular follow-up visits, by questionnaires, serum measurements of infection, and gut microbiome sequencing, we aim to provide the most comprehensive analysis to date of immune system development in newborn children.
Summary
Immune systems are highly variable, but the sources of this variation are poorly understood. Genetic variation only explains a minor fraction of this, and we are unable to accurately predict the risk of immune mediated disease or severe infection in any given individual. I recently found that immune cells and proteins in healthy twins vary because of non-heritable influences (infections, vaccines, microbiota etc.), with only minor influences from heritable factors (Brodin, et al, Cell 2015). When and how such environmental influences shape our immune system is now important to understand. Birth represents the most transformational change in environment during the life of any individual. I propose, that environmental influences at birth, and during the first months of life could be particularly influential by imprinting on the regulatory mechanisms forming in the developing immune system. Adaptive changes in immune cell frequencies and functional states induced by early-life exposures could determine both the immune competence of the newborn, but potentially also its long-term trajectory towards immunological health or disease. Here, I propose a study of 1000 newborn children, followed longitudinally during their first 1000 days of life. By monitoring immune profiles and recording many environmental influences, we hope to understand how early life exposures can influence human immune system development. We have established a new assay based on Mass Cytometry and necessary data analysis tools (Brodin, et al, PNAS 2014), to simultaneously monitor the frequencies, phenotypes and functional states of more than 200 blood immune cell populations from only 100 microliters of blood. By monitoring environmental influences at regular follow-up visits, by questionnaires, serum measurements of infection, and gut microbiome sequencing, we aim to provide the most comprehensive analysis to date of immune system development in newborn children.
Max ERC Funding
1 422 339 €
Duration
Start date: 2016-07-01, End date: 2021-06-30
Project acronym ComplexSex
Project Sex-limited experimental evolution of natural and novel sex chromosomes: the role of sex in shaping complex traits
Researcher (PI) Jessica Abbott
Host Institution (HI) LUNDS UNIVERSITET
Call Details Starting Grant (StG), LS8, ERC-2015-STG
Summary The origin and evolution of sexual reproduction and sex differences represents one of the major unsolved problems in evolutionary biology, and although much progress had been made both via theory and empirical research, recent data suggest that sex chromosome evolution may be more complex than previously thought. The concept of sexual antagonism (when there is a positive intersexual genetic correlation in trait expression but opposite fitness effects of the trait(s) in males and females) has become essential to our understanding of sex chromosome evolution. The goal of this proposal is to understand how the interacting effects of sexual antagonism, sex-linked genetic variation, and sex-specific selection shape the genetic architecture of complex traits. I will test the hypotheses that: 1) individual sexually antagonistic loci are common in the genome, both in separate-sexed species and in hermaphrodites, and drive patterns of sexual antagonism often seen on the trait level. 2) That the response to sex-specific selection in sex-linked loci is usually due to standing sexually antagonistic genetic variation. 3) That sexually antagonistic variation is primarily non-additive in nature. To accomplish this, I will use a combination of approaches, including sex-limited experimental evolution of the X chromosome and reciprocal sex chromosome introgression among distantly related populations of Drosophila, quantitative genetic analysis and experimental evolution mimicking the creation of a novel sex chromosome in the hermaphroditic flatworm Macrostomum, and analytical and simulation modeling. This project will serve to confirm or refute the assumption that trait-level sexual antagonism reflects the contributions of many individual sexually antagonistic loci, increase our understanding of the contribution of coevolution of the sex chromosomes to population divergence, and help provide us with a better general understanding of how genotype maps to phenotype.
Summary
The origin and evolution of sexual reproduction and sex differences represents one of the major unsolved problems in evolutionary biology, and although much progress had been made both via theory and empirical research, recent data suggest that sex chromosome evolution may be more complex than previously thought. The concept of sexual antagonism (when there is a positive intersexual genetic correlation in trait expression but opposite fitness effects of the trait(s) in males and females) has become essential to our understanding of sex chromosome evolution. The goal of this proposal is to understand how the interacting effects of sexual antagonism, sex-linked genetic variation, and sex-specific selection shape the genetic architecture of complex traits. I will test the hypotheses that: 1) individual sexually antagonistic loci are common in the genome, both in separate-sexed species and in hermaphrodites, and drive patterns of sexual antagonism often seen on the trait level. 2) That the response to sex-specific selection in sex-linked loci is usually due to standing sexually antagonistic genetic variation. 3) That sexually antagonistic variation is primarily non-additive in nature. To accomplish this, I will use a combination of approaches, including sex-limited experimental evolution of the X chromosome and reciprocal sex chromosome introgression among distantly related populations of Drosophila, quantitative genetic analysis and experimental evolution mimicking the creation of a novel sex chromosome in the hermaphroditic flatworm Macrostomum, and analytical and simulation modeling. This project will serve to confirm or refute the assumption that trait-level sexual antagonism reflects the contributions of many individual sexually antagonistic loci, increase our understanding of the contribution of coevolution of the sex chromosomes to population divergence, and help provide us with a better general understanding of how genotype maps to phenotype.
Max ERC Funding
1 492 011 €
Duration
Start date: 2016-05-01, End date: 2021-04-30
Project acronym DARKJETS
Project Discovery strategies for Dark Matter and new phenomena in hadronic signatures with the ATLAS detector at the Large Hadron Collider
Researcher (PI) Caterina Doglioni
Host Institution (HI) LUNDS UNIVERSITET
Call Details Starting Grant (StG), PE2, ERC-2015-STG
Summary The Standard Model of Particle Physics describes the fundamental components of ordinary matter and their interactions. Despite its success in predicting many experimental results, the Standard Model fails to account for a number of interesting phenomena. One phenomenon of particular interest is the large excess of unobservable (Dark) matter in the Universe. This excess cannot be explained by Standard Model particles. A compelling hypothesis is that Dark Matter is comprised of particles that can be produced in the proton-proton collisions from the Large Hadron Collider (LHC) at CERN.
Within this project, I will build a team of researchers at Lund University dedicated to searches for signals of the presence of Dark Matter particles. The discovery strategies employed seek the decays of particles that either mediate the interactions between Dark and Standard Model particles or are produced in association with Dark Matter. These new particles manifest in detectors as two, three, or four collimated jets of particles (hadronic jets).
The LHC will resume delivery of proton-proton collisions to the ATLAS detector in 2015. Searches for new, rare, low mass particles such as Dark Matter mediators have so far been hindered by constraints on the rates of data that can be stored. These constraints will be overcome through the implementation of a novel real-time data analysis technique and a new search signature, both introduced to ATLAS by this project. The coincidence of this project with the upcoming LHC runs and the software and hardware improvements within the ATLAS detector is a unique opportunity to increase the sensitivity to hadronically decaying new particles by a large margin with respect to any previous searches. The results of these searches will be interpreted within a comprehensive and coherent set of theoretical benchmarks, highlighting the strengths of collider experiments in the global quest for Dark Matter.
Summary
The Standard Model of Particle Physics describes the fundamental components of ordinary matter and their interactions. Despite its success in predicting many experimental results, the Standard Model fails to account for a number of interesting phenomena. One phenomenon of particular interest is the large excess of unobservable (Dark) matter in the Universe. This excess cannot be explained by Standard Model particles. A compelling hypothesis is that Dark Matter is comprised of particles that can be produced in the proton-proton collisions from the Large Hadron Collider (LHC) at CERN.
Within this project, I will build a team of researchers at Lund University dedicated to searches for signals of the presence of Dark Matter particles. The discovery strategies employed seek the decays of particles that either mediate the interactions between Dark and Standard Model particles or are produced in association with Dark Matter. These new particles manifest in detectors as two, three, or four collimated jets of particles (hadronic jets).
The LHC will resume delivery of proton-proton collisions to the ATLAS detector in 2015. Searches for new, rare, low mass particles such as Dark Matter mediators have so far been hindered by constraints on the rates of data that can be stored. These constraints will be overcome through the implementation of a novel real-time data analysis technique and a new search signature, both introduced to ATLAS by this project. The coincidence of this project with the upcoming LHC runs and the software and hardware improvements within the ATLAS detector is a unique opportunity to increase the sensitivity to hadronically decaying new particles by a large margin with respect to any previous searches. The results of these searches will be interpreted within a comprehensive and coherent set of theoretical benchmarks, highlighting the strengths of collider experiments in the global quest for Dark Matter.
Max ERC Funding
1 268 076 €
Duration
Start date: 2016-02-01, End date: 2021-01-31
Project acronym DIALOY
Project Mosaic loss of chromosome Y (LOY) in blood cells - a new biomarker for risk of cancer and Alzheimer’s disease in men
Researcher (PI) Lars Anders Forsberg
Host Institution (HI) UPPSALA UNIVERSITET
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary My recent discoveries show that mosaic loss of chromosome Y (LOY) in peripheral blood is associated with increased risks of cancer and Alzheimer’s disease (AD). These conditions are responsible for >50% of morbidity/mortality in aging men. More than 15% of men older than 70 show some degree of LOY and these men survive on average only half as long as men without LOY. Smoking is strongly associated with LOY and remarkably, the fraction of cells with LOY decreases after cessation of smoking. Cells with LOY can be detected, and disease risks predicted, many years before clinical manifestation of disease. These results of associations between LOY, cancer and smoking have been published in Nature Genetics and Science during 2014.
The overall objective of the proposal is to develop LOY as a new, strong and predictive biomarker. To this end, the research program focuses on three objectives: 1) expanding the study of LOY and associations with disease risks in still larger cohorts; 2) investigating functional aspects of LOY; and 3) develop improved technology for LOY-detection. The successful execution of the project is essential before LOY-testing in clinics can be realized.
Diagnosis of cancer and AD in modern medicine is based on clinical symptoms of disease. Through earlier identification of individuals at increased risk for disease, preventive strategies could be applied, before the severe stages appear. Preliminary results affirm the feasibility of the project and provide proof-of-concept that LOY-tests can be used for early identification of men with increased risks for these diseases. In addition to improving diagnostics and therapeutics; implementation of LOY-testing could prevent smoking-related disease and reduce the health care costs. In the end, LOY-testing could decrease male mortality rates and possibly eliminate the sex-difference in life expectancy. The project will therefore benefit individual patients as well as healthcare systems and society at large.
Summary
My recent discoveries show that mosaic loss of chromosome Y (LOY) in peripheral blood is associated with increased risks of cancer and Alzheimer’s disease (AD). These conditions are responsible for >50% of morbidity/mortality in aging men. More than 15% of men older than 70 show some degree of LOY and these men survive on average only half as long as men without LOY. Smoking is strongly associated with LOY and remarkably, the fraction of cells with LOY decreases after cessation of smoking. Cells with LOY can be detected, and disease risks predicted, many years before clinical manifestation of disease. These results of associations between LOY, cancer and smoking have been published in Nature Genetics and Science during 2014.
The overall objective of the proposal is to develop LOY as a new, strong and predictive biomarker. To this end, the research program focuses on three objectives: 1) expanding the study of LOY and associations with disease risks in still larger cohorts; 2) investigating functional aspects of LOY; and 3) develop improved technology for LOY-detection. The successful execution of the project is essential before LOY-testing in clinics can be realized.
Diagnosis of cancer and AD in modern medicine is based on clinical symptoms of disease. Through earlier identification of individuals at increased risk for disease, preventive strategies could be applied, before the severe stages appear. Preliminary results affirm the feasibility of the project and provide proof-of-concept that LOY-tests can be used for early identification of men with increased risks for these diseases. In addition to improving diagnostics and therapeutics; implementation of LOY-testing could prevent smoking-related disease and reduce the health care costs. In the end, LOY-testing could decrease male mortality rates and possibly eliminate the sex-difference in life expectancy. The project will therefore benefit individual patients as well as healthcare systems and society at large.
Max ERC Funding
1 525 000 €
Duration
Start date: 2016-03-01, End date: 2021-02-28
Project acronym HeteroDynamic
Project Evolutionary Stability of Ubiquitous Root Symbiosis
Researcher (PI) Anna Rosling Larsson
Host Institution (HI) UPPSALA UNIVERSITET
Call Details Starting Grant (StG), LS8, ERC-2015-STG
Summary Virtually all terrestrial plants depend on symbiotic interactions with fungi. Arbuscular mycorrhizal (AM) fungi evolved over 450 million years ago, are obligate biotrophs and cannot complete their lifecycle without obtaining carbon from host roots. Mediating nutrient uptake and sequestering carbon in soil this symbiosis lie at the core of all terrestrial ecosystems. Plants on the other hand are facultative mycotrophs but under natural conditions all host roots are colonized as a result of multiple beneficial effects of AM fungi. In the symbiosis, both plants and fungi are promiscuous, forming interactions across individuals and species. In the absence of host-symbiont specificity and given their inability to discriminate among partners prior to interaction, evolutionary theory predicts that “free riders” would evolve and spread. Yet AM fungi remain evolutionary and ecologically successful. I propose that this is thanks to their unique genomic organization, a temporally dynamic heterokaryosis.
Unlike other eukaryotes, AM fungi have no single nucleate stage in their life cycle, instead they reproduce asexually by forming large multinucleate spores. Genetic variation is high and nuclei can migrate and mix within extensive mycelial networks. My group has recently established a single nucleus genomics method to study genetic variation among nuclei within AM fungi. With this method I can resolve the extent of heterokaryosis in AM fungi and its temporal dynamics. I will study the emergence of “free riders” upon intra organismal segregation of genetically distinct nuclei during AM fungal adaptation to host. Further I will study how hyphal fusion and nuclear mixing counteract segregation to stabilize the symbiosis. The research program has great potential for novel discoveries of fundamental importance to evolutionary and environmental biology and will also contribute to agricultural practice and management of terrestrial ecosystems.
Summary
Virtually all terrestrial plants depend on symbiotic interactions with fungi. Arbuscular mycorrhizal (AM) fungi evolved over 450 million years ago, are obligate biotrophs and cannot complete their lifecycle without obtaining carbon from host roots. Mediating nutrient uptake and sequestering carbon in soil this symbiosis lie at the core of all terrestrial ecosystems. Plants on the other hand are facultative mycotrophs but under natural conditions all host roots are colonized as a result of multiple beneficial effects of AM fungi. In the symbiosis, both plants and fungi are promiscuous, forming interactions across individuals and species. In the absence of host-symbiont specificity and given their inability to discriminate among partners prior to interaction, evolutionary theory predicts that “free riders” would evolve and spread. Yet AM fungi remain evolutionary and ecologically successful. I propose that this is thanks to their unique genomic organization, a temporally dynamic heterokaryosis.
Unlike other eukaryotes, AM fungi have no single nucleate stage in their life cycle, instead they reproduce asexually by forming large multinucleate spores. Genetic variation is high and nuclei can migrate and mix within extensive mycelial networks. My group has recently established a single nucleus genomics method to study genetic variation among nuclei within AM fungi. With this method I can resolve the extent of heterokaryosis in AM fungi and its temporal dynamics. I will study the emergence of “free riders” upon intra organismal segregation of genetically distinct nuclei during AM fungal adaptation to host. Further I will study how hyphal fusion and nuclear mixing counteract segregation to stabilize the symbiosis. The research program has great potential for novel discoveries of fundamental importance to evolutionary and environmental biology and will also contribute to agricultural practice and management of terrestrial ecosystems.
Max ERC Funding
1 500 000 €
Duration
Start date: 2016-04-01, End date: 2021-03-31
Project acronym inHForm
Project Integrative omics of heart failure to inform discovery of novel drug targets and clinical biomarkers
Researcher (PI) J. Gustav Smith
Host Institution (HI) LUNDS UNIVERSITET
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary Heart failure is a leading cause of morbidity and mortality in the aging European populations. It is the end-stage of myocardial and valvular disease, arising from loss of viable or functional muscle cells in the heart. Therapy is complicated by the multitude of causes and comorbidities of heart failure. New therapeutic targets and clinical biomarkers to individually tailor therapy (‘precision medicine’) are greatly needed. This research program aims to realize the promise of precision medicine by applying an integrated proteomic, genomic and epidemiological approach to the underlying causes, mechanisms and consequences for heart failure. The program builds on unique Swedish nation-wide disease registers and large biobanks, the translational research profile of the investigator and experience in genomics, epidemiology and proteomics. The program includes five work packages: (1) comprehensive plasma protein profiling through a discovery pipeline including novel microarray-based methods and mass spectrometry in a population-based cohort of 6000 subjects and clinical cases to identify subjects at risk for heart disease (2) assessment of heritable components to outcomes in heart disease using nation-wide Swedish registers (3) genome-wide discovery of variants associated with risk of and outcomes in heart disease as well as endophenotypes for cardiac structure and function, using resequencing and DNA microarrays in large population-based cohorts including >70,000 subjects from three generations (4) expression profiling in human heart samples and a novel human cardiomyocyte strain assay to translate genomic and proteomic findings to understanding of pathophysiological mechanisms (5) evaluate the clinical importance of plasma proteins and genetic variants in >3000 clinical cases. This research program is anticipated to result in new insights into the pathophysiology of heart failure and discovery of drug targets and clinical biomarkers.
Summary
Heart failure is a leading cause of morbidity and mortality in the aging European populations. It is the end-stage of myocardial and valvular disease, arising from loss of viable or functional muscle cells in the heart. Therapy is complicated by the multitude of causes and comorbidities of heart failure. New therapeutic targets and clinical biomarkers to individually tailor therapy (‘precision medicine’) are greatly needed. This research program aims to realize the promise of precision medicine by applying an integrated proteomic, genomic and epidemiological approach to the underlying causes, mechanisms and consequences for heart failure. The program builds on unique Swedish nation-wide disease registers and large biobanks, the translational research profile of the investigator and experience in genomics, epidemiology and proteomics. The program includes five work packages: (1) comprehensive plasma protein profiling through a discovery pipeline including novel microarray-based methods and mass spectrometry in a population-based cohort of 6000 subjects and clinical cases to identify subjects at risk for heart disease (2) assessment of heritable components to outcomes in heart disease using nation-wide Swedish registers (3) genome-wide discovery of variants associated with risk of and outcomes in heart disease as well as endophenotypes for cardiac structure and function, using resequencing and DNA microarrays in large population-based cohorts including >70,000 subjects from three generations (4) expression profiling in human heart samples and a novel human cardiomyocyte strain assay to translate genomic and proteomic findings to understanding of pathophysiological mechanisms (5) evaluate the clinical importance of plasma proteins and genetic variants in >3000 clinical cases. This research program is anticipated to result in new insights into the pathophysiology of heart failure and discovery of drug targets and clinical biomarkers.
Max ERC Funding
1 496 625 €
Duration
Start date: 2016-04-01, End date: 2021-03-31
Project acronym NORVAS
Project Therapeutic and Biomarker Potential of long non-coding RNAs in Vascular Disease
Researcher (PI) Lars Maegdefessel
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Starting Grant (StG), LS7, ERC-2015-STG
Summary The contribution of cardiovascular disease to human morbidity and mortality continues to steadily increase in our aging European society. In response, extraordinary efforts have been launched to determine the molecular and pathophysiological characteristics of its etiology. The collective work of multiple research groups has uncovered a complex transcriptional and post-transcriptional regulatory milieu, which is believed to be essential for maintaining cardiovascular homeostasis. Recently, non-coding RNAs, especially the ones with antisense capabilities such as microRNAs or ‘natural antisense transcripts’ (NATs) have received much attention. They have been identified as important transcriptional and post-transcriptional inhibitors of gene expression.
This current proposal describes the development of novel diagnostic and therapeutic strategies to limit the burden of cardiovascular disease in general, and abdominal aortic aneurysms as well as carotid stenosis and subsequent stroke in particular. Using transcriptomic profiling techniques on human diseased tissue samples, we have identified two NATs (SLFNL-AS1 and NUDT6) as novel crucial regulators of smooth muscle cell survival via targeting CTPS1 and the fibroblast growth factor 2 (FGF2) in the vascular system. We are using disease-relevant experimental in vivo models (rodents and LDLR-/- mini-pigs) to functionally assess how inhibition of these two NATs influences aneurysm progression and atherosclerotic plaque vulnerability. One focus of our studies is to utilize local delivery mechanisms for non-coding RNA modulators, such as drug eluting balloons and stents, to enhance the translational feasibility of our findings. Furthermore, we have access to unique human plasma material from patients with early and advanced forms of aneurysm disease, enabling us to investigate the biomarker value of non-coding RNAs in recognizing patients with acutely ruptured aneurysms, as well as predicting the future risk of rupture.
Summary
The contribution of cardiovascular disease to human morbidity and mortality continues to steadily increase in our aging European society. In response, extraordinary efforts have been launched to determine the molecular and pathophysiological characteristics of its etiology. The collective work of multiple research groups has uncovered a complex transcriptional and post-transcriptional regulatory milieu, which is believed to be essential for maintaining cardiovascular homeostasis. Recently, non-coding RNAs, especially the ones with antisense capabilities such as microRNAs or ‘natural antisense transcripts’ (NATs) have received much attention. They have been identified as important transcriptional and post-transcriptional inhibitors of gene expression.
This current proposal describes the development of novel diagnostic and therapeutic strategies to limit the burden of cardiovascular disease in general, and abdominal aortic aneurysms as well as carotid stenosis and subsequent stroke in particular. Using transcriptomic profiling techniques on human diseased tissue samples, we have identified two NATs (SLFNL-AS1 and NUDT6) as novel crucial regulators of smooth muscle cell survival via targeting CTPS1 and the fibroblast growth factor 2 (FGF2) in the vascular system. We are using disease-relevant experimental in vivo models (rodents and LDLR-/- mini-pigs) to functionally assess how inhibition of these two NATs influences aneurysm progression and atherosclerotic plaque vulnerability. One focus of our studies is to utilize local delivery mechanisms for non-coding RNA modulators, such as drug eluting balloons and stents, to enhance the translational feasibility of our findings. Furthermore, we have access to unique human plasma material from patients with early and advanced forms of aneurysm disease, enabling us to investigate the biomarker value of non-coding RNAs in recognizing patients with acutely ruptured aneurysms, as well as predicting the future risk of rupture.
Max ERC Funding
1 493 125 €
Duration
Start date: 2016-05-01, End date: 2021-04-30
Project acronym Optimal-Immunity
Project Optimal diversity in immunity – to overcome pathogens and maximize fitness; moving from correlative associations to a more mechanistic understanding using wild songbirds.
Researcher (PI) Karin Helena Westerdahl
Host Institution (HI) LUNDS UNIVERSITET
Call Details Starting Grant (StG), LS8, ERC-2015-STG
Summary The Major Histocompatibility Complex (MHC) genes are intensively studied genes in association with disease resistance. MHC proteins are essential for initiating every adaptive immune response and MHC is probably the most extreme example of how selection from a wide range of pathogens maintains high diversity in host immunity genes. However, the functions of the MHC proteins are only known in humans and model organisms, species that cannot be studied under natural conditions. There is therefore a need to study function of MHC proteins in species that can be thoroughly monitored in their natural habitat under varying pathogen regimes and over several generations. These parameters can be assessed in wild songbirds making them excellent study systems. Songbirds have large numbers of MHC gene copies, although little is known about how these affect their immune responses. Does high MHC copy number indicate that songbirds can recognize and combat more pathogens than other animals? They do fight infections satisfactory at their breeding, stopover and overwintering sites.
In this proposal my overarching aim is a more mechanistic understanding for survival and fitness linked to MHC in animals from wild populations and to take this field of research beyond the simple correlative associations that hitherto have been the rule. To reach this goal I must first characterize songbird MHC, now possible with ‘single molecule real time sequencing’. Therefore a rather substantial part of this proposal is technology. I will use two different songbird study systems; long-distance migratory great reed warblers and sedentary house sparrows and malaria-like pathogens infecting both these species. I am an experienced researcher on MHC and together with my team I will (1) characterize the MHC genomic region, (2) measure expression of MHC genes, (3) build MHC proteins and (4) measure functional MHC diversity in relation to fitness in wild birds, both in nature and in experimental set-ups.
Summary
The Major Histocompatibility Complex (MHC) genes are intensively studied genes in association with disease resistance. MHC proteins are essential for initiating every adaptive immune response and MHC is probably the most extreme example of how selection from a wide range of pathogens maintains high diversity in host immunity genes. However, the functions of the MHC proteins are only known in humans and model organisms, species that cannot be studied under natural conditions. There is therefore a need to study function of MHC proteins in species that can be thoroughly monitored in their natural habitat under varying pathogen regimes and over several generations. These parameters can be assessed in wild songbirds making them excellent study systems. Songbirds have large numbers of MHC gene copies, although little is known about how these affect their immune responses. Does high MHC copy number indicate that songbirds can recognize and combat more pathogens than other animals? They do fight infections satisfactory at their breeding, stopover and overwintering sites.
In this proposal my overarching aim is a more mechanistic understanding for survival and fitness linked to MHC in animals from wild populations and to take this field of research beyond the simple correlative associations that hitherto have been the rule. To reach this goal I must first characterize songbird MHC, now possible with ‘single molecule real time sequencing’. Therefore a rather substantial part of this proposal is technology. I will use two different songbird study systems; long-distance migratory great reed warblers and sedentary house sparrows and malaria-like pathogens infecting both these species. I am an experienced researcher on MHC and together with my team I will (1) characterize the MHC genomic region, (2) measure expression of MHC genes, (3) build MHC proteins and (4) measure functional MHC diversity in relation to fitness in wild birds, both in nature and in experimental set-ups.
Max ERC Funding
1 498 732 €
Duration
Start date: 2016-04-01, End date: 2021-03-31
