Suchergebnisse

The Nagoya Protocol (NP) of the Convention on Biological Diversity requires that genetic resource holders and users obtain, preserve and keep relevant documentation. Users and third parties need to be informed on terms of access, which utilisation is allowed, and which benefits need to be shared when respective genetic resources or associated traditional knowledge is utilised in the meaning of the NP. Following the recommendations in the Code of Conduct & Best Practices of the Consortium of European Taxonomic Facilities (CETAF) CETAF Legislations and Regulations Liaison Group 2019, institutions should implement appropriate data management systems to support compliance with the protocol and keep records on acquisition of biological material, utilization of genetic resources, transfers to third parties, benefits derived and shared, and deaccessioning of specimens or disposal of consumed samples. Here we describe how we have implemented the first set of tools to meet the NP requirements in the Kotka Collection Management System (CMS), which is used by eleven Natural History Museums in Finland. The Kotka CMS is used for storing and managing specimen data and for handling material transactions (loans, exchanges, donations and consumptive loans). Users can enter and store all necessary documentation for both incoming and outgoing material as material transactions, which hold information on e.g., the transaction type, description of the material, important dates, correspondent organization and contact person. Specimens are linked to transactions by their unique identifiers and each transaction also has a unique stable identifier. The first version of the tools for meeting the requirements of the Nagoya protocol on both in situ and ex situ accession of genetic resources have been integrated into the transaction section of the system. For genetic resource users to be able to enter, save and provide all the required information about an incoming genetic resource, we have implemented a set of fields to be completed in the transactions in Kotka CMS (Fig. 1). Users can record, for example, a possible IRCC number (Internationally Recognized Certificate of Compliance), acquisition date and providing country, description of the material, information on Prior Informed Consent, Mutually Agreed Terms, Material Transfer Agreement and other possible permits. The Finnish genomic resource legislation requires a notification within one month of acquisition to the Competent National Authority (CNA; The Finnish Environment Institute and Natural Resources Institute Finland) for any imported genetic resources. The required data for the notification is compiled in Kotka CMS and then sent to the CNA. All the documentation and conditions regulating the utilisation of each specimen and derived samples must follow with the specimen data at all times. To accomplish this all the necessary information and documents are linked from the material transactions to the relevant specimens by unique specimen or sample identifiers. In the specimen view page, links to the full transaction details and history are given, as a single specimen or a derived sample can be part of several different types of transactions. Users also see a summary of the transaction information directly in the specimen view, most importantly whether the specimen is available for genetic research or has any restrictions for use. The Kotka CMS transaction section makes use of the Application Programming Interface (API) provided by the Access and Benefit Sharing Clearing House (ABS-CH). Using the API, Kotka CMS validates the IRCC number if given and provides links to the ABS-CH, for example to the relevant country profile page, the contact details of the CNA, and specific requirements for access to genetic resources when applicable. This way, we provide Kotka CMS users up-to-date information from the original source to support their genetic resource management. We will further improve and develop the tools during the years 2019-2020. Now that the first version is in use, we will make adjustments according to user feedback. We also have a few changes planned, for example, the tools for transferring the necessary information on permits and other details with outgoing specimens to a user in another institution abroad will be updated. All users in Finnish natural history institutions have access to all the information directly in Kotka CMS, as it is a national system. Additionally, both specimen and transaction information searchability will be refined.

RIASSUNTO I minisatelliti e i microsatelliti appartengono ad una classe dei sequenze del DNA ripetute in tandem chiamate VNTR (variable number tandem repeats) (Nakamura e coll. 1987). Visto il loro altissimo grado di polimorfismo trovano grande applicazione in medicina forense e, sempre più frequentemente, in studi di genetica di popolazioni. Le prime applicazioni di questi marcatori allo studio dell'evoluzione umana servirono a dimostrarne l'efficace forza di risoluzione descrittiva in questo campo. La Spagna, o per meglio dire la Penisola Iberica in generale, è una della regioni d'Europa meglio studiate dal punto di vista della variabilità genetica. Sono disponibili mappe sintetiche dei marcatori classici (Cavalli-Sforza e Bertranpetit, 1991), dati con i marcatori mitocondriali (Bertranpetit e Calafell, 1996-2000) e con i polimorfismi del cromosoma Y (Carracedo, Salas, Gonzáles-Neira, 2003). Attualmente vari gruppi di ricercatori effettuano un ampio campionamento della popolazione iberica al fine di immagazzinare dati con marcatori STR (short tandem repeats, microsatelliti) (Paredes et al.2004). La ricchezza di siti archeologici nel territorio spagnolo risalenti sia al Paleolitico che al Neolitico, il suo ruolo storico di ponte fra il mondo arabo e l'occidente, fanno della peniso-la Iberica un interessante campo di indagine per la Genetica di Popolazioni. Nel presente studio sono stati tipizzati 300 individui provenienti da varie zone della Spagna con cinque marcatori autosomici VNTR: tre minisatelliti (D1S80, D4S111,D17S5) e due microsatelliti (D8S566, D8S591). L'intero campione è stato analizzato secondo tre criteri distinti: - secondo un approccio storico-politico - secondo un approccio geografico - secondo un approccio linguistico. Questa scelta è stata dettata dalla necessità di inquadrare gli studi di popolazioni secondo una prospettiva multidisciplinare. Ad un secondo livello di analisi i risultati sulla popolazione in esame sono stati confrontati con i dati presenti in letteratura su altre popolazioni del bacino del Mediterraneo. Gli obiettivi della ricerca sono stati dunque: - tracciare un profilo della popolazione spagnola secondo criteri storico-politici, geo-grafici e linguistici - inserire la popolazione spagnola nel panorama genetico del bacino del Mediterra-neo - fornire dei dati su tale popolazione con nuovi marcatori molecolari autosomici. Dall'analisi dei dati è emersa la presenza di alcune sottostrutture all'interno della popola-zione spagnola: - è stata rilevata la presenza di una probabile componente neolitica nell'attuale pool genetico ispano, dato suffragato da evidenze archeologiche - è stata identificata una condizione di particolarità genetica della popolazione Anda-lusa, probabilmente dovuta al contributo delle popolazioni arabe durante la loro oc-cupazione di quest'area geografica. Per quanto riguarda la posizione della popolazione spagnola nel complesso del bacino del Mediterraneo, è stata osservata una situazione in accordo con la tesi dell'onda di avanza-mento dal Medio Oriente al resto d'Europa (Cavalli-Sforza, 1973). ABSTRACT Minisatellites and microsatellites are a genomic DNA class known as VNTR sequences (variable number tandem repeats) (Nakamura and coll. 1987). Because of their great polymorphism, they are a very powerful tool for forensic science and genetics of populations. Early uses of these markers to reconstruct human evolution were to show their power of description resolution. The Iberian Peninsula is one of the better studied areas in genetic variability. Genetic maps made using classical markers(Cavalli-Sforza e Bertranpetit, 1991), mitochondrial markers (Bertranpetit e Calafell, 1996-2000) and Y-polymorphisms (Carracedo, Salas, Gonzáles-Neira, 2003) are available. At the moment, many research team are working hard to provide data with STR (short tandem repeats) polymorphisms. Iberian Peninsula is an interesting investigation field for genetic of population due to the presence of archeological sites related to Paleolithic and Neolithic times. Moreover, from a historical point of view, it represented a bridge between Arabic cultures and western culture. In our dissertation five VNTR markers: 3 minisatellites and 2 microsatellites were analyzed in 300 unrelated individuals from all over Spain. Data were analyzed according to three different points of view: 1) according to a historical and political approach 2) according to a geographical approach 3) according to a linguistic approach. We decided to consider all these approaches because of the importance to study population from different points of view. Another goal of our dissertation is to locate Spanish population in the Mediterranean population genetic pattern. By combining our data we find some genetic substructure within Spanish population: 1) a probable Neolithic component in the present genetic Spanish pool. This is consistent with archeological data. 2) a particular genetic pool in Andalusian population probably due to 7 centuries of Arabic occupation. Location of the Spanish population in the Mediterranean genetic pattern is consistent with Demic diffusion theory (Cavalli-Sforza, 1973).

The common thread of the work presented in this thesis is the development and democratization of tools that facilitate the spatial profiling of genome and transcriptome. Paper I1 describes iFISH, a resource that facilitates the large-scale design and costeffective, flexible production of probes for DNA FISH. More specifically, we created a database of oligos targeting the human genome and a probe design tool which we made publicly available through a user-friendly web interface, which we have named iFISH4U. We used iFISH4U to design hundreds of small probes (<10kb span), targeting equally spaced landmark loci, evenly distributed along all chromosomes. We validated a large fraction of those probes individually and then combined them to create "spotting probes" in order to profile chromosomal territories (CTs) in an unbiased way in 3D fixed cells. We were able to visualize up to 6 different chromosomes in thousands of terminally differentiated fibroblasts and embryonic stem cells and to compare their CTs. In ESCs we observed less distinct CTs, and, in a subset of cells, a remarkable lack of chromosome territoriality. We also assessed whether the degree of chromosomal intermingling differs between pluripotent and differentiated cells. All the tools and probes used in paper I were made available for the community, making iFISH a resource that can greatly facilitate genome architecture studies. In paper II2, we developed genomic loci positioning by sequencing (GPSeq), a next generation sequencing based method for profiling of the radial arrangement of chromatin in fixed cells. In GPSeq, we control the incubation time of a restriction enzyme in order to digest chromatin in a gradual manner, starting from the periphery and moving towards the center. By ligating adapters and sequencing the DNA fragments around the cut sites, we can generate high-resolution, genome-wide radiality maps upon computing of a radiality score. In order to define the best radiality score we compared the different estimates with 3D DNA FISH measurements taking advantage of the tools we developed in iFISH. We used GPSeq maps to profile the radiality of various levels of chromatin organization such as chromosomes, A and B compartments and their subcompartments. Moreover, we integrated those maps with different annotation tracks in order to study the radial localization of features and marks of active and inactive chromatin. We also used GPSeq to assess the radial arrangement of SNVs, SNPs and DNA breaks. Finally, we developed a 3D genome reconstruction algorithm that combines GPSeq and Hi-C data, to predict the chromatin structure in single cells. Altogether, GPSeq is a versatile assay that can be used for radial profiling of the 3D genome. Paper III introduces Deconwolf (DW), a publicly available and easy-to-use software for image deconvolution. Even though DW can be used for different type of images, we tested its performance on data generated by imaging-based spatially resolved omics, technologies that (depending on the method) suffer from 2 different limitations, the requirement for imaging with high magnification objectives and the optical crowding problem, or in other words the inability to resolve densely packed targets. As a proof of concept, we applied DW to images from smFISH experiments and we were able to resolve crowded signal as well as to quantify smFISH signals in tissue sections imaged with 20x magnification. We then applied DW to In Situ Sequencing (ISS) and OligoFISSEQ images and we found that DW greatly increases the sensitivity of transcript calling in hybISS and the barcode detection efficiency in OligoFISSEQ. Our results highlight the potential of DW to improve image deconvolution and consequently the amount of information yielded upon imaging-based spatially-resolved molecular profiling

Giardia duodenalis is an enteric parasite commonly detected in children. Exposure to this organism may lead to asymptomatic or symptomatic infection. Additionally, early-life infections by this protozoan have been associated with impaired growth and cognitive function in poor resource settings. The Global Enteric Multicenter Study (GEMS) in Mozambique demonstrated that G. duodenalis was more frequent among controls than in diarrhoeal cases (≥3 loosing stools in the previous 24 hours). However, no molecular investigation was conducted to ascertain the molecular variability of the parasite. Therefore, we describe here the frequency and genetic diversity of G. duodenalis infections in children younger than five years of age with and without diarrhoea from the Manhiça district in southern Mozambique enrolled in the context of GEMS. Genomic DNA from 757 G. duodenalis-positive stool samples by immunoassay collected between 2007-2012, were reanalysed by multiplex PCR targeting the E1-HP and C1-P21 genes for the differentiation of assemblages A and B. Overall, 47% (353) of the samples were successfully amplified in at least one locus. Assemblage B accounted for 90% (319/353) of all positives, followed by assemblage A (8%, 29/353) and mixed A+B infections (1%, 5/353). No association between the presence of a given assemblage and the occurrence of diarrhoea could be demonstrated. A total of 351 samples were further analysed by a multi-locus sequence genotyping (MLSG) approach at the glutamate dehydrogenase (gdh), ß-giardin (bg) and triose phosphate isomerase (tpi) genes. Overall, 63% (222/351) of samples were genotyped and/or sub-genotyped in at least one of the three markers. Sequence analysis revealed the presence of assemblages A (10%; 23/222) and B (90%; 199/222) with high molecular diversity at the nucleotide level within the latter; no mixed infections were identified under the MLSG scheme. Assemblage A sequences were assigned to sub-assemblages AI (0.5%, 1/222), AII (7%, 15/222) or ambiguous AII/AIII (3%, 7/222). Within assemblage B, sequences were assigned to sub-assemblages BIII (13%, 28/222), BIV (14%, 31/222) and ambiguous BIII/BIV (59%, 132/222). BIII/BIV sequences accumulated the majority of the single nucleotide polymorphisms detected, particularly in the form of double peaks at chromatogram inspection. This study demonstrated that the occurrence of gastrointestinal illness (diarrhoea) was not associated to a given genotype of G. duodenalis in Mozambican children younger than five years of age. The assemblage B of the parasite was responsible for nine out of ten infections detected in this paediatric population. The extremely high genetic diversity observed within assemblage B isolates was compatible with an hyperendemic epidemiological scenario where infections and reinfections were common. The obtained molecular data may be indicative of high coinfection rates by different G. duodenalis assemblages/sub-assemblages and/or genetic recombination events, although the exact contribution of both mechanisms to the genetic diversity of the parasite remains unknown. ; GEMS was funded by the Bill and Melinda Gates Foundation through the Center for Vaccine Development at the University of Maryland, School of Medicine who coordinated GEMS-1 and GEMS-1A, with grant number 38874 (MML) and OPP1033572 (MML), respectively. DC received funding from the Health Institute Carlos III, Ministry of Economy and Competitiveness (Spain), under project PI16CIII/00024.TN received funding from the Fundo Nacional de Investigacão, Ministry of Science and Technology (Mozambique) under project 245-INV. Additional funding was obtained from the USAID Country Office of Mozambique under the Fixed Amount Award Grant No. AID-656-F-16-00002 (IM). CISM is supported by the Government of Mozambique and the Spanish Agency for International Development Cooperation (AECID). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. ; Sí

Ruiz-Rodriguez, P.; Frances-Gomez, C.; Chiner-Oms, A.; Lopez, M. G.; Jimenez-Serrano, S.; Cancino-Munoz, I.; Ruiz-Hueso, P.; Torres-Puente, M.; Bracho, M. A.; D'Auria, G.; Martinez-Priego, L.; Guerreiro, M.; Montero-Alonso, M.; Gomez, M. D.; Pinana, J. L.; Seq, Covid-Spain Consortium; Gonzalez-Candelas, F.; Comas, I.; Marina, A.; Geller, R.; Coscolla, M. Evolutionary and Phenotypic Characterization of Two Spike Mutations in European Lineage 20E of SARS-CoV-2 [Preprint] MedRxiv; https://dx.doi.org/10.1101/2021.03.08.21253075 ; We have detected two mutations in the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at amino acid positions 1163 and 1167 that appeared independently in multiple transmission clusters and different genetic backgrounds. Furthermore, both mutations appeared together in a cluster of 1,627 sequences belonging to clade 20E. This cluster is characterized by 12 additional single nucleotide polymorphisms but no deletions. The available structural information on the S protein in the pre- and postfusion conformations predicts that both mutations confer rigidity, which could potentially decrease viral fitness. Accordingly, we observed reduced infectivity of this spike genotype relative to the ancestral 20E sequence in vitro, and the levels of viral RNA in nasopharyngeal swabs were not significantly higher. Furthermore, the mutations did not impact thermal stability or antibody neutralization by sera from vaccinated individuals but moderately reduce neutralization by convalescent-phase sera from the early stages of the pandemic. Despite multiple successful appearances of the two spike mutations during the first year of SARS-CoV-2 evolution, the genotype with both mutations was displaced upon the expansion of the 20I (Alpha) variant. The midterm fate of the genotype investigated was consistent with the lack of advantage observed in the clinical and experimental data. IMPORTANCE We observed repeated, independent emergence of mutations in the SARS-CoV-2 spike involving amino acids 1163 and 1167, within the HR2 functional motif. Conclusions derived from evolutionary and genomic diversity analysis suggest that the co-occurrence of both mutations might pose an advantage for the virus and therefore a threat to effective control of the epidemic. However, biological characterization, including in vitro experiments and analysis of clinical data, indicated no clear benefit in terms of stability or infectivity. In agreement with this, continuous epidemiological surveillance conducted months after the first observations revealed that both mutations did not successfully outcompete other variants and stopped circulating 9 months after their initial detection. Additionally, we evaluated the potential of both mutations to escape neutralizing antibodies, finding that the presence of these two mutations on their own is not likely to confer antibody escape. Our results provide an example of how newly emerged spike mutations can be assessed to better understand the risk posed by new variants and indicate that some spike mutations confer no clear advantage to the virus despite independently emerging multiple times and are eventually displaced by fitter variants. ; This work was funded by the Instituto de Salud Carlos III project COV20/00140 and COV20/00437, Spanish National Research Council project CSIC-COV19-021 and CSIC-COVID19-082, and the Generalitat Valenciana (SEJI/2019/011 and Covid_19-SCI). Action co-financed by the European Union through the Operational Program of the European Regional Development Fund (ERDF) of the Valencian Community 2014-2020. M.C. and R.G. are supported by Ramon y Cajal program from Ministerio de Ciencia. ; Peer reviewed

Attention Deficit Hyperactivity Disorder (ADHD) is a common childhood-onset neurodevelopmental condition characterized by pervasive impairment of attention, hyperactivity, and/or impulsivity that can persist into adulthood. The aetiology of ADHD is complex and multifactorial and, despite the wealth of evidence for its high heritability, genetic studies have provided modest evidence for the involvement of specific genes and have failed to identify consistent and replicable results. Due to the lack of robust findings, we performed gene-wide and pathway enrichment analyses using pre-existing GWAS data from 607 persistent ADHD subjects and 584 controls, produced by our group. Subsequently, expression profiles of genes surpassing a follow-up threshold of P-value < 1e-03 in the gene-wide analyses were tested in peripheral blood mononucleated cells (PBMCs) of 45 medication-naive adults with ADHD and 39 healthy unrelated controls. We found preliminary evidence for genetic association between RNF122 and ADHD and for its overexpression in adults with ADHD. RNF122 encodes for an E3 ubiquitin ligase involved in the proteasome-mediated processing, trafficking, and degradation of proteins that acts as an essential mediator of the substrate specificity of ubiquitin ligation. Thus, our findings support previous data that place the ubiquitin-proteasome system as a promising candidate for its involvement in the aetiology of ADHD. ; Over the course of this investigation, I.G. M. has been a recipient of a predoctoral fellowship from the Vall d'Hebron Research Institute (PRED-VHIR-2012), Barcelona, Spain, and currently she is a recipient of a contract from the 7th Framework Programme for Research, Technological Development and Demonstration, European Commission (AGGRESSOTYPE_FP7HEALTH2013/602805). C.S. M. is a recipient of a Sara Borrell contract from the Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad, Spain (CD15/00199) and a mobility grant from the Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad, Spain (MV16/00039). M.S. A. is a recipient of a contract from the Biomedical Research Networking Centre in Mental Health (CIBERSAM), Madrid, Spain. P.R. is a recipient of a predoctoral fellowship from the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR), Generalitat de Catalunya, Spain (2016FI_B 00899). M.P. is recipient of a predoctoral fellowship from the Vall d'Hebron Research Institute, Barcelona, Spain (PRED-VHIR-2013) and a research grant from the Deutscher Akademischer Austauschdienst (DAAD), Germany (Research Grants - Short-Term Grants, 2017). E.C. S. is a recipient of a predoctoral fellowship from the Collaborative Research Training Programme for Medical Doctors (PhD4MD), Centre for Genomic Regulation (CRG) and Vall d'Hebron Research Institute (VHIR), Barcelona, Spain (II14/00018). M.R. is a recipient of a Miguel de Servet contract from the Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad, Spain (CP09/00119 and CPII15/00023). This investigation was supported by Instituto de Salud Carlos III (PI12/01139, PI14/01700, PI15/01789, PI16/01505), and cofinanced by the European Regional Development Fund (ERDF), Agència de Gestió d'Ajuts Universitaris i de Recerca-AGAUR, Generalitat de Catalunya (2014SGR1357, 2014SGR0932), Ministerio de Economía, Industria y Competitividad, Spain (SAF2012-33484, SAF2015-68341-R), the European College of Neuropsychopharmacology (ECNP network: 'ADHD across the lifespan'), Departament de Salut, Generalitat de Catalunya, Spain, and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. This project has also received funding from the European Union's Horizon 2020 Research and Innovation Programme under the grant agreements No 667302 and 643051.

Funding Information: This work was supported by Project LISBOA-01-0145-FEDER-007660 (?Microbiologia Molecular, Estrutural e Celular?) funded by FEDER funds through COMPETE2020??Programa Operacional Competitividade e Internacionaliza??o? (POCI); ?Funda??o para a Ci?ncia e a Tecnologia? (FCT) grants EXPL/BIA-MIC/2525/2013 and programme IF (IF/00124/2015) to C.P.; grant PTDC/BIA-BQM/31317/2017 to C.V.R.; the European Union?s Horizon 2020 research and innovation programme under grant agreement No. 810856 and 857203; COST Action CA15133, supported by COST (European Cooperation in Science and Technology) and PPBI?Portuguese Platform of BioImaging (PPBI-POCI-01-0145-FEDER-022122) co-funded by national funds from OE??Or?amento de Estado? and by FEDER. C.A. (SFRH/BPD/74294/2010), S.M.C. (SFRH/BD/91077/2012), C.V.R. (SFRH/BPD/94050/2013) and A.G.-C. (SFRH/BD/118866/2016) were supported by FCT contracts or fellowships. Funding Information: Funding: This work was supported by Project LISBOA-01-0145-FEDER-007660 ("Microbiologia Molecular, ?strutural e Celular") funded by F?D?R funds through COMP?T?2020—"Programa Operacional Competitividade e Internacionalização" (POCI); "Fundação para a Ciência e a Tecno-logia" (FCT) grants ?XPL/BIA-MIC/2525/2013 and programme IF (IF/00124/2015) to C.P.; grant PTDC/BIA-BQM/31317/2017 to C.V.R.; the ?uropean Union's Horizon 2020 research and innovation programme under grant agreement No. 810856 and 857203; COST Action CA15133, supported by COST (European Cooperation in Science and Technology) and PPBI—Portuguese Platform of Bi-oImaging (PPBI-POCI-01-0145-FEDER-022122) co-funded by national funds from OE—"Orçamento de Estado" and by FEDER. C.A. (SFRH/BPD/74294/2010), S.M.C. (SFRH/BD/91077/2012), C.V.R. (SFRH/BPD/94050/2013) and A.G.-C. (SFRH/BD/118866/2016) were supported by FCT contracts or fellowships. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. ; In yeast, iron storage and detoxification depend on the Ccc1 transporter that mediates iron accumulation in vacuoles. While deletion of the CCC1 gene renders cells unable to survive under iron overload conditions, the deletion of its previously identified regulators only partially affects survival, indicating that the mechanisms controlling iron storage and detoxification in yeast are still far from well understood. This work reveals that CCC1 is equipped with a complex transcriptional structure comprising several regulatory regions. One of these is located inside the coding sequence of the gene and drives the expression of a short transcript encoding an N-terminally truncated protein, designated as s-Ccc1. s-Ccc1, though less efficiently than Ccc1, is able to promote metal accumulation in the vacuole, protecting cells against iron toxicity. While the expression of the s-Ccc1 appears to be repressed in the normal genomic context, our current data clearly demonstrates that it is functional and has the capacity to play a role under iron overload conditions. ; publishersversion ; published

[Background] Population demography and gene flow among African groups, as well as the putative archaic introgression of ancient hominins, have been poorly explored at the genome level. ; [Results] Here, we examine 15 African populations covering all major continental linguistic groups, ecosystems, and lifestyles within Africa through analysis of whole-genome sequence data of 21 individuals sequenced at deep coverage. We observe a remarkable correlation among genetic diversity and geographic distance, with the hunter-gatherer groups being more genetically differentiated and having larger effective population sizes throughout most modern-human history. Admixture signals are found between neighbor populations from both hunter-gatherer and agriculturalists groups, whereas North African individuals are closely related to Eurasian populations. Regarding archaic gene flow, we test six complex demographic models that consider recent admixture as well as archaic introgression. We identify the fingerprint of an archaic introgression event in the sub-Saharan populations included in the models (~ 4.0% in Khoisan, ~ 4.3% in Mbuti Pygmies, and ~ 5.8% in Mandenka) from an early divergent and currently extinct ghost modern human lineage. ; [Conclusion] The present study represents an in-depth genomic analysis of a Pan African set of individuals, which emphasizes their complex relationships and demographic history at population level. ; This study was funded by the Spanish MINECO grants CGL-2013-44351-P, CGL-2016-75389-P, and the "Unidad de Excelencia Maria de Maeztu" MDM2014-0370. BLG was supported with a Beatriu de Pinós (BP-DGR 2014) fellowship. O.L. was supported by a Ramón y Cajal grant from the Spanish Ministerio de Economia y Competitividad (MEIC) with reference RYC-2013-14797, a BFU2015-68759-P (MEIC/FEDER) grant and the support of Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat de Catalunya (GRC 2017 SGR 937). O.L. also acknowledges the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership; Centro de Excelencia Severo Ochoa; CERCA Programme / Generalitat de Catalunya; the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) through the Instituto de Salud Carlos III; Generalitat de Catalunya through Departament de Salut and Departament d'Empresa i Coneixement; the co-financing by the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) with funds from the European Regional Development Fund (ERDF) corresponding to the 2014-2020 Smart Growth Operating Program. GSV was supported by a FI (2017FI_B2 00010) scholarship. LFKK was supported by an FPI fellowship associated with BFU2014-55090-P (MINECO/FEDER, UE). VNP was financially supported by the Ministry of Health, Government of Catalonia [grant SLT002/16/00496] and a grant from Otto A. Malmi Foundation (Finland). TMB is supported by BFU2017-86471-P (MINECO/FEDER, UE), U01 MH106874 grant, Howard Hughes International Early Career, Obra Social >La Caixa> and Secretaria d'Universitats i Recerca and CERCA Programme del Departament d'Economia i Coneixement de la Generalitat de Catalunya (GRC 2017 SGR 880).

Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14$^{+}$ monocytes, CD16$^{+}$ neutrophils, and naive CD4$^{+}$ T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of $\textit{cis}$-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk. ; This work was predominantly funded by the EU FP7 High Impact Project BLUEPRINT (HEALTH-F5-2011-282510) and the Canadian Institutes of Health Research (CIHR EP1-120608). The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no 282510 (BLUEPRINT), the European Molecular Biology Laboratory, the Max Planck society, the Spanish Ministry of Economy and Competitiveness, 'Centro de Excelencia Severo Ochoa 2013-2017', SEV-2012-0208 and Spanish National Bioinformatics Institute (INB-ISCIII) PT13/0001/0021 co-funded by FEDER ""Una Manera de hacer Europa". D.G. is supported by a "la Caixa"-Severo Ochoa pre-doctoral fellowship, M.F. was supported by the BHF Cambridge Centre of Excellence [RE/13/6/30180], K.D. is funded as a HSST trainee by NHS Health Education England, S.E. is supported by a fellowship from La Caixa, V.P. is supported by a FEBS long-term fellowship and N.S.'s research is supported by the Wellcome Trust (Grant Codes WT098051 and WT091310), the EU FP7 (EPIGENESYS Grant Code 257082 and BLUEPRINT Grant Code HEALTH-F5-2011-282510) and the NIHR BRC. The Blood and Transplant Unit (BTRU) in Donor Health and Genomics is part of and funded by the National Institute for Health Research (NIHR) and is a partnership between the University of Cambridge and NHS Blood and Transplant (NHSBT) in collaboration with the University of Oxford and the Wellcome Trust Sanger Institute. The T-cell data was produced by the McGill Epigenomics Mapping Centre (EMC McGill). It is funded under the Canadian Epigenetics, Environment, and Health Research Consortium (CEEHRC) by the Canadian Institutes of Health Research and by Genome Quebec (CIHR EP1-120608), with additional support from Genome Canada and FRSQ. T.P. holds a Canada Research Chair.

PUBLISHED ; Risk alleles for complex diseases are widely spread throughout human populations. However, little is known about the geographic distribution and frequencies of risk alleles, which may contribute to differences in disease susceptibility and prevalence among populations. Here, we focus on Crohn's disease (CD) as a model for the evolutionary study of complex disease alleles. Recent genome-wide association studies and classical linkage analyses have identified more than 70 susceptible genomic regions for CD in Europeans, but only a few have been confirmed in non-European populations. Our analysis of eight European-specific susceptibility genes using HapMap data shows that at the NOD2 locus the CD-risk alleles are linked with a haplotype specific to CEU at a frequency that is significantly higher compared with the entire genome. We subsequently examined nine global populations and found that the CD-risk alleles spread through hitchhiking with a high-frequency haplotype (H1) exclusive to Europeans. To examine the neutrality of NOD2, we performed phylogenetic network analyses, coalescent simulation, protein structural prediction, characterization of mutation patterns, and estimations of population growth and time to most recent common ancestor (TMRCA). We found that while H1 was significantly prevalent in European populations, the H1 TMRCA predated human migration out of Africa. H1 is likely to have undergone negative selection because 1) the root of H1 genealogy is defined by a preexisting amino acid substitution that causes serious conformational changes to the NOD2 protein, 2) the haplotype has almost become extinct in Africa, and 3) the haplotype has not been affected by the recent European expansion reflected in the other haplotypes. Nevertheless, H1 has survived in European populations, suggesting that the haplotype is advantageous to this group. We propose that several CD-risk alleles, which destabilize and disrupt the NOD2 protein, have been maintained by natural selection on standing variation because the deleterious haplotype of NOD2 is advantageous in diploid individuals due to heterozygote advantage and/or intergenic interactions. ; We thank Takafumi Katsumura, Dr Yutaka Suzuki, and Dr Sumio Sugano in the Graduate School of Frontier Sciences, University of Tokyo, for his assistance of protein structure analysis and their technical assistance in DNA sequencing, respectively. We also thank three anonymous reviewers for many helpful comments and suggestions. S.N. was sup- ported by a Grant-in-Aid for the Japan Society for the Promotion of Science (JSPS) Research fellow (21-7453). L.K. was supported by the 7th Framework Programme of the European Union (grant HEALTH-PROT, contract number 229676). J.M.B. was supported by the Polish Ministry of Sci- ence and Higher Education (grant POIG.02.03.00-00-003/ 09). H.S. was supported by Priority Area ??Comparative Ge- nomics?? (20017021) from the Ministry of Education, Cul- ture, Sports, Science and Technology of Japan and by a Grant-in-Aid for Scientific Research (C) from JSPS (21590360). J.R.K. and K.K.K. were supported in part by GM057672. S.K. was supported by a Grant-in-Aid for Sci- entific Research (A) from JSPS (22247036). H.O. was sup- ported by a Grant-in-Aid for Scientific Research (B) from JSPS (21370108).

Cardiomyopathy (CMP) is a heritable disorder. Over 50% of cases are gene-elusive on clinical gene panel testing. The contribution of variants in non-coding DNA elements that result in cryptic splicing and regulate gene expression has not been explored. We analyzed whole-genome sequencing (WGS) data in a discovery cohort of 209 pediatric CMP patients and 1953 independent replication genomes and exomes. We searched for protein-coding variants, and non-coding variants predicted to affect the function or expression of genes. Thirty-nine percent of cases harbored pathogenic coding variants in known CMP genes, and 5% harbored high-risk loss-of-function (LoF) variants in additional candidate CMP genes. Fifteen percent harbored high-risk regulatory variants in promoters and enhancers of CMP genes (odds ratio 2.25, p = 6.70 × 10−7 versus controls). Genes involved in α-dystroglycan glycosylation (FKTN, DTNA) and desmosomal signaling (DSC2, DSG2) were most highly enriched for regulatory variants (odds ratio 6.7–58.1). Functional effects were confirmed in patient myocardium and reporter assays in human cardiomyocytes, and in zebrafish CRISPR knockouts. We provide strong evidence for the genomic contribution of functionally active variants in new genes and in regulatory elements of known CMP genes to early onset CMP. ; This project was supported by the Ted Rogers Centre for Heart Research (SM, JE), the Canadian Institutes of Health Research (PJT 175034) (SM, JE) and by the Canadian Institutes of Health Research (ENP 161429), under the frame of ERA PerMed (SM). SM holds the Heart and Stroke Foundation of Canada & Robert M Freedom Chair in Cardiovascular Science. SWS holds the GlaxoSmithKline Endowed Chair in Genome Sciences at the Hospital for Sick Children and the University of Toronto. PGM holds a Canada Research Chair Tier 2 in Non-coding Disease Mechanisms. PGM acknowledges the support of the Government of Canada's New Frontiers in Research Fund (NFRF), [NFRFE-2018-01305]. EO holds the Bitove Family Professorship of Adult Congenital Heart Disease. MM holds a Ramon y Cajal grant from the Spanish Ministry of Science and Innovation (RYC-2017-22249). WO is supported by funding from Fundació La Marató (321/C/2019). JB is funded by a Frans Van de Werf fellowship for clinical cardiovascular research, and by a senior clinical investigator fellowship of the FWO Flanders. KM was a National Science Foundation Graduate Research Fellow under grant no. DGE1144152 during the majority of the project. CS is the recipient of a National Health and Medical Research Council (NHMRC) Practitioner Fellowship (1154992). JI is the recipient of an NHMRC Career Development Fellowship (1162929). RDB is the recipient of a New South Wales Health Cardiovascular Disease Senior Scientist Grant. PSD is supported by the DBT/Wellcome Trust- Indian Alliance. We acknowledge the Labatt Family Heart Centre Biobank at the Hospital for Sick Children for access to DNA samples, and The Centre for Applied Genomics at the Hospital for Sick Children for performing WGS. We thank Xiucheng Cui and Emanuela Pannia for performing the zebrafish experiments at the SickKids Zebrafish Genetics and Disease Models Core (CRISPR-Cas9 and gRNA syntheses, zebrafish embryo microinjections, gRNA PCR validation, qRT-PCR, cardiac imaging). This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. We thank members of the ICGC/PCAWG working groups for generating the variant calls used in our case-control burden analyses. ; Peer Reviewed ; "Article signat per 38 autors/es: Robert Lesurf, Abdelrahman Said, Oyediran Akinrinade, Jeroen Breckpot, Kathleen Delfosse, Ting Liu, Roderick Yao, Gabrielle Persad, Fintan McKenna, Ramil R. Noche, Winona Oliveros, Kaia Mattioli, Shreya Shah, Anastasia Miron, Qian Yang, Guoliang Meng, Michelle Chan Seng Yue, Wilson W. L. Sung, Bhooma Thiruvahindrapuram, Jane Lougheed, Erwin Oechslin, Tapas Mondal, Lynn Bergin, John Smythe, Shashank Jayappa, Vinay J. Rao, Jayaprakash Shenthar, Perundurai S. Dhandapany, Christopher Semsarian, Robert G. Weintraub, Richard D. Bagnall, Jodie Ingles, Genomics England Research Consortium, Marta Melé, Philipp G. Maass, James Ellis, Stephen W. Scherer & Seema Mital" ; Postprint (published version)

© 2020 – IOS Press and the authors. ; [Background]: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown. [Objective]: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes. [Methods]: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677). [Results]: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T–N–, A+T+N–, A+T–N+, and A+T+N+) from no AD pathology (A–T–N–) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts. [Conclusions]: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo. ; This research was conducted as part of the EMIF-AD project which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n° 115372, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in-kind contribution. The DESCRIPA study was funded by the European Commission within the 5th framework program (QLRT-2001-2455). The EDAR study was funded by the European Commission within the 5th framework program (contract # 37670). The Leuven cohort was funded by the Stichting voor Alzheimer Onderzoek (grant numbers #11020, #13007 and #15005). The Lausanne cohort study was supported by a grant from the Swiss National Research Foundation to JP (SNF 320030_141179). RV is a senior clinical investigator of the Flemish Research Foundation (FWO). JS is currently an employee of UCB, Braine-l'Alleud, Belgium. The San Sebastian GAP study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H). We acknowledge the contribution of the personnel of the Genomic Service Facility at the VIB-U Antwerp Center for Molecular Neurology. The research at VIB-CMN is funded in part by the University of Antwerp Research Fund. FB is supported by the NIHR biomedical research centre at UCLH. RD is supported by Health Data Research UK, the National Institute for Health Research (NIHR) Biomedical Research Centre at South London, Maudsley NHS Foundation Trust, King's College London and the NIHR University College London Hospitals Biomedical Research Centre. LS is funded by DPUK through MRC (grant no. MR/L023784/2) and the UK Medical Research Council Award to the University of Oxford (grant no. MC_PC_17215). Also support was received from the NIHR Biomedical Research Centre at Oxford Health NHS Foundation Trust.

Background: Low lung function has been associated with increased body mass index (BMI). The aim of this study was to investigate whether the effect of BMI on lung function is mediated by DNA methylation. Methods: We used individual data from 285,495 participants in four population-based cohorts: the European Community Respiratory Health Survey, the Northern Finland Birth Cohort 1966, the Swiss Study on Air Pollution and Lung Disease in Adults, and the UK Biobank. We carried out Mendelian randomisation (MR) analyses in two steps using a two-sample approach with SNPs as instrumental variables (IVs) in each step. In step 1 MR, we estimated the causal effect of BMI on peripheral blood DNA methylation (measured at genome-wide level) using 95 BMI-associated SNPs as IVs. In step 2 MR, we estimated the causal effect of DNA methylation on FEV1, FVC, and FEV1/FVC using two SNPs acting as methQTLs occurring close (in cis) to CpGs identified in the first step. These analyses were conducted after exclusion of weak IVs (F statistic < 10) and MR estimates were derived using the Wald ratio, with standard error from the delta method. Individuals whose data were used in step 1 were not included in step 2. Results: In step 1, we found that BMI might have a small causal effect on DNA methylation levels (less than 1% change in methylation per 1 kg/m2 increase in BMI) at two CpGs (cg09046979 and cg12580248). In step 2, we found no evidence of a causal effect of DNA methylation at cg09046979 on lung function. We could not estimate the causal effect of DNA methylation at cg12580248 on lung function as we could not find publicly available data on the association of this CpG with SNPs. Conclusions: To our knowledge, this is the first paper to report the use of a two-step MR approach to assess the role of DNA methylation in mediating the effect of a non-genetic factor on lung function. Our findings do not support a mediating effect of DNA methylation in the association of lung function with BMI. ; This work was conducted within the Ageing Lungs in European Cohorts (ALEC) project and received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 633212. The funders of this study had no role in study design, data analysis and interpretation of results, or writing of the manuscript. The ECRHS was supported by a contract from the European Commission (018996), Fondo de Investigación Sanitaria (91/0016–060-05/E, 92/0319, 93/0393, 97/0035–01, 99/0034–01 and 99/0034–02), Hospital General de Albacete, Hospital General Ramón Jiménez, Consejería de Sanidad del Principado de Asturias, CIRIT (1997SGR 00079, 1999SGR 00241), and Servicio Andaluz de Salud, SEPAR, Public Health Service (R01 HL62633–01), RCESP (C03/09), Red RESPIRA (C03/011), Basque Health Department, Swiss National Science Foundation, Swiss Federal Office for Education and Science, Swiss National Accident Insurance Fund (SUVA), GSF-National Research Centre for Environment and Health, Deutsche Forschungsgemeinschaft (DFG) (FR 1526/1–1, MA 711/4–1), Programme Hospitalier de Recherche Clinique-DRC de Grenoble 2000 no. 2610, Ministry of Health, Direction de la Recherche Clinique, Ministere de l'Emploi et de la Solidarite, Direction Generale de la Sante, CHU de Grenoble, Comite des Maladies Respiratoires de l'Isere. UCB-Pharma (France), Aventis (France), Glaxo France. Estonian Science Foundation, and Asthma UK (formerly known as National Asthma Campaign UK). The NFBC resource has been supported by grants from the Academy of Finland (project grants 104781, 120315, 129269, 1114194, 24300796, Center of Excellence in Complex Disease Genetics and SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), NHLBI grant 5R01HL087679–02 (1RL1MH083268–01), NIH/NIMH (5R01MH63706:02), ENGAGE project and grant agreement HEALTH-F4–2007-201413, EU FP7 EurHEALTHAgeing − 277849, the Medical Research Council, UK (G0500539, G0600705, G1002319, PrevMetSyn/SALVE) and the MRC, Centenary Early Career Award. H2020 DynaHEALTH (European Union's Horizon 2020 research and innovation programme under grant agreement No 633595); Exposomic, Genomic and Epigenomic Approach to Prediction of Metabolic and Cardiorespiratory function and Ill-Health (EGEA), Academy of Finland, Grant No 285547; ALEC Study (funded by the European Union's Horizon 2020 Research and Innovation programme under grant agreement No. 633212); H2020 / Marie Skłodowska-Curie Actions, CAPICE (Marie Curie Grant agreement Number 721567); National Public Health Institute, Biomedicum Helsinki, Finland. The SAPALDIA study was funded by the Swiss National Science Foundation (grants no 33CS30–148470/1&2, 33CSCO-134276/1, 33CSCO-108796, 324730_135673, 3247BO-104283, 3247BO-104288, 3247BO-104284, 3247–065896, 3100–059302, 3200–052720, 3200–042532, 4026–028099, PMPDP3_129021/1, PMPDP3_141671/1), the Federal Office for the Environment, the Federal Office of Public Health, the Federal Office of Roads and Transport, the canton's government of Aargau, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, Valais, and Zürich, the Swiss Lung League, the canton's Lung League of Basel Stadt/ Basel Landschaft, Geneva, Ticino, Valais, Graubünden and Zurich, Stiftung ehemals Bündner Heilstätten, SUVA, Freiwillige Akademische Gesellschaft, UBS Wealth Foundation, Talecris Biotherapeutics GmbH, Abbott Diagnostics, European Commission 018996 (GABRIEL), Wellcome Trust WT 084703MA, Exposomics EC FP7 grant (Grant agreement No: 308610).

In this study, the population structure, incidence, and potential sources of human infection caused by the D-tartrate-fermenting variant of Salmonella enterica serovar Paratyphi B [S. Paratyphi B (DT+)] was investigated. In Germany, the serovar is frequently isolated from broilers. Therefore, a selection of 108 epidemiologically unrelated S. enterica serovar Paratyphi B (DT+) strains isolated in Germany between 2002 and 2010 especially from humans, poultry/poultry meat, and reptiles was investigated by phenotypic and genotypic methods. Strains isolated from poultry and products thereof were strongly associated with multilocus sequence type ST28 and showed antimicrobial multiresistance profiles. Pulsed-field gel electrophoresis XbaI profiles were highly homogeneous, with only a few minor XbaI profile variants. All strains isolated from reptiles, except one, were strongly associated with ST88, another distantly related type. Most of the strains were susceptible to antimicrobial agents, and XbaI profiles were heterogeneous. Strains isolated from humans yielded seven sequence types (STs) clustering in three distantly related lineages. The first lineage, comprising five STs, represented mainly strains belonging to ST43 and ST149. The other two lineages were represented only by one ST each, ST28 and ST88. The relatedness of strains based on the pathogenicity gene repertoire (102 markers tested) was mostly in agreement with the multilocus sequence type. Because ST28 was frequently isolated from poultry but rarely in humans over the 9-year period investigated, overall, this study indicates that in Germany S. enterica serovar Paratyphi B (DT+) poses a health risk preferentially by contact with reptiles and, to a less extent, by exposure to poultry or poultry meat.

[Background]: Since their domestication 10,500 years ago, goat populations with distinctive genetic backgrounds have adapted to a broad variety of environments and breeding conditions. The VarGoats project is an international 1000-genome resequencing program designed to understand the consequences of domestication and breeding on the genetic diversity of domestic goats and to elucidate how speciation and hybridization have modeled the genomes of a set of species representative of the genus Capra. ; [Findings]: A dataset comprising 652 sequenced goats and 507 public goat sequences, including 35 animals representing eight wild species, has been collected worldwide. We identified 74,274,427 single nucleotide polymorphisms (SNPs) and 13,607,850 insertion-deletions (InDels) by aligning these sequences to the latest version of the goat reference genome (ARS1). A Neighbor-joining tree based on Reynolds genetic distances showed that goats from Africa, Asia and Europe tend to group into independent clusters. Because goat breeds from Oceania and Caribbean (Creole) all derive from imported animals, they are distributed along the tree according to their ancestral geographic origin. ; [Conclusions]: We report on an unprecedented international effort to characterize the genome-wide diversity of domestic goats. This large range of sequenced individuals represents a unique opportunity to ascertain how the demographic and selection processes associated with post-domestication history have shaped the diversity of this species. Data generated for the project will also be extremely useful to identify deleterious mutations and polymorphisms with causal effects on complex traits, and thus will contribute to new knowledge that could be used in genomic prediction and genome-wide association studies. ; We are grateful to France Génomique "Call for high impact projects" (ANR‐10‐INBS‐09‐08) for selecting our project and providing us the resources to sequence 400 goats. We would like to mention that APIS-GENE funded some WGS sequences through ACTIVEGOAT & CAPRISNP projects. We thank the Occitanie region and the Animal Genetics Division of the French National Institute for Agriculture, Food and Environment (INRAE-GA) for financing the PhD of ET. We thank the Ministère de l'Enseignement supérieur, de la Recherche et de l'Innovation for financing LD. We thank André Eggen (Illumina) for providing chips to genotype 192 animals. We thank the Animal Genetics Division of the French National Institute for Agriculture, Food and Environment (INRAE-GA) for funding VarGoats2 grant, which allowed DNA extraction and genotyping of 384 animals and CRB-Anim, Grant Agreement ANR-11-INBS-0003, (https://crb-anim.fr/) for funding French local breeds sampling. We thank the Italian Goat and Sheep Breeders Association (AssoNaPa) for supporting in sampling. Whole-genome sequencing libraries for the African goats were prepared and sequenced by Edinburgh Genomics and funded via Biotechnology and Biological Sciences Research Council research grant (BBS/OS/GC/000012F) 'Reference genome and population sequencing of African goats' awarded to The Roslin Institute. USDA-ARS with funding from USAID funded the collection of samples from Uganda, Tanzania, Malawi, Mozambique and Zimbabwe. EC and MS were partially supported by the Bill & Melinda Gates Foundation and with UK aid from the UK Government's Department for International Development (Grant Agreement OPP1127286) under the auspices of the Centre for Tropical Livestock Genetics and Health (CTLGH), established jointly by the University of Edinburgh, SRUC (Scotland's Rural College), and the International Livestock Research Institute. The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the Bill & Melinda Gates Foundation nor the UK Government. ; Peer reviewed