Anthropogenic noise is still not considered a serious contaminant with an impact on human health. However, the prediction of the number of people who will be affected by hearing and non-hearing diseases in 2050 has been revised upwards by WHO: it has tripled in 3 years, from 700 million to 2.5 billion. While hearing loss, tinnitus and auditory fatigue are identified phenotypes, others such as hyperacusis (associated with attention deficit) or global early hearing loss in certain populations are underestimated and could have important social impact. It becomes urgent for public institutions, both national and local, to recognise that anthropogenic noise is a key source of disturbance for peoples’ health. The Earscape project explores, for the first time, whether the hearing sensitivity (HS) of normohearing individuals is shaped by acoustic environmental factors, and more specifically by the anthropophony component. We will use an innovative approach combining the expertise from ecoacoustics, hearing physiology, anthropology, population genomics and explainable artificial intelligence to unravel the complex interactions between acoustic environmental and individual factors. To reach our objectives, we will sample 9 human populations from 3 different geo-cultural areas (GCAs) and genetic backgrounds: Ecuador-Amazonia/Quechua, Gabon/Fang and France/French. For these 3 GCAs, we will develop a similar sampling scheme by selecting 3 soundscapes (Low-rural, Medium-rural, and High-urban) from inhabiting areas displaying variable levels of anthropization (i.e. sampling strategy is based on population density, lands take and the presumably associated level of anthropophony). This sample scheme will help to compare the different soundscapes within each GCA, but also to test for potential convergent process between rural and urban soundscapes. The soundscape of each population will be characterized using 1-year long ecoacoustic recording data; for the first time in this discipline, a precise measure of the anthropophony component will be developed. We will sample 270 individuals in the selected populations, collect their DNA and HS profiles using oto-acoustic emission. We will sample an equal ratio of men and women, a prerequisite for testing our scientific hypotheses. We will sequence their whole genome at 30x depth and analyse a set of 35 candidate hearing loss genes. We will explore both the genetic variants in coding sequences, as well as non-coding regulatory regions and associated CNV variants; the latter types of genetic variants being highly polymorphic, they are likely to retain the potential signature of ongoing local adaptation. All these data will be combined using explainable AI and machine learning procedures to reveal the relative impact of the different factors shaping hearing sensitivity. The results might lead to new paradigms on how, and by which mechanisms, the deep characteristics of our environment might influence the evolution of the hearing sensory traits. These results will open the discussion on the continuous adaptation of our hearing sensitivity to the current rapidly changing acoustic environment and especially on the potential maladaptive character of new forms of hearing sensitivity. Key information will be collected on rural and urban-specific soundscapes in human population, on population-specific global hearing loss and hyperacusis, on putative new genetic markers to consider in hearing loss genetic screening, and on the factors, ranked, affecting hearing sensitivity. Through an efficient scientific communication and the development of simple and efficient tools for the general public, we propose to increase awareness of hearing fragility.

Hidradenitis Suppurativa (HS; OMIM #142690) is a chronic recurrent inflammatory skin disease affecting hair follicles (HF) leading to draining sinuses, painful skin abscesses and disfiguring scars. HS is a common disease, with a point prevalence of 4% in Europe. HS is an orphan and frequent disease which severely impacts the quality of patients’ life and causes significant costs for health systems. HS is notoriously difficult and challenging to treat with a high morbidity impact and could be classified as an unmet medical need with no efficient therapeutic options. By December 31th 2018, only 17 clinical trials dedicated to HS had been completed in the United States and there is only 1 US FDA-approved therapy. The initial pathological changes of HS are observed in the terminal hair infundibulum. The current understanding of the HS pathogenesis suggests that a fragile acroinfundibulum or an occlusion by hyperproliferative HF epithelial cells can lead to the rupture of the follicular epithelium, which initiates the inflammatory cascade. One of the main obstacles for the development of efficient therapeutic strategies is certainly due to the lack of a clear physiopathological mechanism and the high heterogeneity of patients. To date, the different attempts to classify HS disease for clinical trials and to identify subpopulations prone to respond to specific therapies rely only on the clinical presentation. Despite these efforts to distinguish different HS clinical categories, establishing a robust genotype-phenotype correlation was not achieved so far. The main objective of this project is to propose a new approach to characterize patients based on the new tools, and on the pathophysiological advances that they have enabled in recent years. The hypothesis behind this project relies on our recent demonstration that a subgroup of HS patients exhibited hair follicle stem cells (HF-SC) with features of replicative stress abnormalities. Our recent research has provided sound evidence that genomic DNA damage triggers an inflammatory response through the accumulation of cytosolic DNA fragments and the activation of STING. Accumulation of ssDNA and micronuclei in the cytosol of HF-SC isolated from HS patients was found to contribute to STING activation via the DNA sensor IFI16. Finally, our results showed that STING pathway activation induces IFN type I production in HF-SC (Orvain, JCI,2020). Globally, these findings support the concept that impaired HF-SC homeostasis promotes chronic inflammation in HS patients. This observation: i) reconciles HF development abnormalities and chronic inflammation; ii) opens the way to identify new epigenetic and genetic hypotheses associated with these biological abnormalities; iii) provides new tools for defining biomarkers allowing the identification of a subgroup of patients and possibly new therapeutic avenues. To reach these goals we have developed a 3-year program with 3 Work Packages : i) In WP1, we will expand our biobank of ORS from HS patients to better define patients with or without HF-SC replicative stress; ii) WP2 will be focused on deciphering molecular mechanisms driving HF-SC replicative stress using well-categorized patients with or without replicative stress through an OMICs approach; iii) WP3 will use an integrated approach of clinical, biological and OMICs determinants in order to dissect HS heterogeneity. Expected impacts of our results will help to elucidate if any distinct immunological signatures can be identified as related to specific clinical phenotypes that can be used as potential biomarkers for disease prognosis and patient care.

Forest trees are sessile, long-lived organisms with a major role in the ecology of the Earth. They have developed sensitivity to environmental variation and the potential to adapt, through their high level of standing genetic variations and remarkable phenotypic plasticity. However, forest die-off has been observed in recent years following episodes of drought and high temperatures, which are predicted to become more frequent in the future, due to climate change. Studies of the genetic basis of tree adaptation have focused principally on the contribution of standing structural variation to local adaptation. Surprisingly, epigenetic mechanisms have remained largely unstudied, despite their known importance in long-lived organisms, in which they facilitate rapid phenotypic modifications in response to environmental changes. In this context, DNA methylation has been extensively studied in the model plant Arabidopsis thaliana and several crop species, and shown to have effects extending from gene expression to integrated phenotypes. A few studies involving EPITREE partners have already shown that epigenomic approaches are useful for improving our understanding of the development and response to environmental constraints of forest trees. However, no epigenomic study of forest tree populations has ever been published, despite the demonstrated value of this emerging approach in Arabidopsis. Epigenomic variation is particularly relevant for studies of tree meristems, the morphogenetic centre for specific tree traits, such as the regulation of vegetative bud dormancy and secondary xylogenesis. We will study two complementary model species with large genomic resources and of economic interest: poplar and oak. The general objective of EPITREE is to study the impact of epigenetic mark (DNA methylation) together with gene expression, and allelic variation on forest tree adaptation to local environments and phenotypic plasticity. In particular, we will explore the benefits of considering epigenetic marks in addition to genetic polymorphisms and phenotypes in plant breeding and the characterisation of genetic resources, to provide proof-of-concept in two major forest tree species, with a view to establishing ambitious objectives for tree breeders and the managers of genetic resources. To this end, EPITREE brings together experts in tree epigenetics, genomics, statistics, mathematical modelling, breeding and ecophysiology. EPITREE will achieve its objectives through five workpackages (WPs): (WP1) Comprehensive identification of candidate regions for epigenomic analysis by whole-genome bisulphite sequencing; (WP2) Characterisation of the extent of epigenomic variation in natural populations and its functional consequences, using previously identified candidate regions and a sequence capture-based approach followed by bisulphite sequencing; (WP3) Characterisation of the extent of epigenomic plasticity in response to environmental constraints and its functional consequences; (WP4) Modelling the multiscale relationships between quantitative traits and their molecular determinants; and (WP5) Coordination and dissemination of the project results to the international scientific community, scientific clusters, professionals, students, and the general public.