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16 Research products

  • European Marine Science
  • Research data
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  • European Commission
  • Wellcome Trust
  • EC|FP7
  • GB
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Ruiz-Arenas, Carlos; Bustamante, Mariona;

    To test associations between DNA methylation levels and gene expression levels in cis (cis eQTMs), we paired each Gene to CpGs closer than 500 kb from its TSS, either upstream or downstream. For each Gene, the TSS was defined based on HTA-2.0 annotation, using the start position for transcripts in the + strand, and the end position for transcripts in the - strand. CpGs position was obtained from Illumina 450K array annotation. Only CpGs in autosomal chromosomes (from chromosome 1 to 22) were tested. In the main analysis, we fitted for each CpG-Gene pair a linear regression model between gene expression and methylation levels adjusted for age, sex, cohort, and blood cell type composition. A second model was run without adjusting for blood cellular composition and it is only reported on the online web catalog, but not discussed in this manuscript. Although some of the unique associations of the unadjusted model might be real, others might be confounded by the large methylation and expression changes among blood cell types. To ensure that CpGs paired to a higher number of Genes do not have higher chances of being part of an eQTM, multiple-testing was controlled at the CpG level, following a procedure previously applied in the Genotype-Tissue Expression (GTEx) project (Gamazon et al., 2018). Briefly, our statistic used to test the hypothesis that a pair CpG-Gene is significantly associated is based on considering the lowest p-value observed for a given CpG and all its paired Gene (e.g., those in the 1 Mb window centered at the TSS). As we do not know the distribution of this statistic under the null, we used a permutation test. We generated 100 permuted gene expression datasets and ran our previous linear regression models obtaining 100 permuted p-values for each CpG-Gene pair. Then, for each CpG, we selected among all CpG-Gene pairs the minimum p-value in each permutation and fitted a beta distribution that is the distribution we obtain when dealing with extreme values (e.g. minimum) (Dudbridge and Gusnanto, 2008). Next, for each CpG, we took the minimum p-value observed in the real data and used the beta distribution to compute the probability of observing a lower p-value. We defined this probability as the empirical p-value of the CpG. Then, we considered as significant those CpGs with empirical p-values to be significant at 5% false discovery rate using Benjamini-Hochberg method. Finally, we applied a last step to identify all significant CpG-Gene pairs for all eCpGs. To do so, we defined a genome-wide empirical p-value threshold as the empirical p-value of the eCpG closest to the 5% false discovery rate threshold. We used this empirical p-value to calculate a nominal p-value threshold for each eCpG, based on the beta distribution obtained from the minimum permuted p-values. This nominal p-value threshold was defined as the value for which the inverse cumulative distribution of the beta distribution was equal to the empirical p-value. Then, for each eCpG, we considered as significant all eCpG-Gene variants with a p-value smaller than nominal p-value. For the meQTLs catalogue, we selected 9.9 M cis and trans meQTLs with a p-value <1e-7 in the ARIES dataset consisting of data from children of 7 years old (Gaunt et al., 2016). Then, we tested whether this subset of 9.9 M SNPs were also meQTLs in HELIX by running meQTL analyses using MatrixEQTL R package (Shabalin, 2012), adjusting for cohort, sex, age, blood cellular composition and the first 20 principal components (PCs) calculated from genome-wide genetic data of the GWAS variability. We confirmed 2.8 M meQTLs in HELIX (p-value <1e-7). Trans meQTLs represented <10% of the 2.8 M meQTLs. Enrichment of eCpGs for meQTLs was computed using a Chi-square test, using non eCpGs as background. Finally, we tested whether meQTLs were also eQTLs for the eGenes linked to the eCpGs. To this end, we run eQTL analyses (gene expression being the outcome and 2.8 M SNPs the predictors) with MatrixEQTL adjusting for cohort, sex, age, blood cellular composition and the first 20 GWAS PCs in HELIX. We considered as significant eQTLs the SNP-Gene pairs with p-value <1e-7 and with the direction of the effect consistent with the direction of the meQTL and the eQTM. Background: The identification of expression quantitative trait methylation (eQTMs), defined as associations between DNA methylation levels and gene expression, might help the biological interpretation of epigenome-wide association studies (EWAS). We aimed to identify autosomal cis eQTMs in children’s blood, using data from 832 children of the Human Early Life Exposome (HELIX) project. Methods: Blood DNA methylation and gene expression were measured with the Illumina 450K and the Affymetrix HTA v2 arrays, respectively. The relationship between methylation levels and expression of nearby genes (1 Mb window centered at the transcription start site, TSS) was assessed by fitting 13.6 M linear regressions adjusting for sex, age, cohort, and blood cell composition. Results: We identified 39,749 blood autosomal cis eQTMs, representing 21,966 unique CpGs (eCpGs, 5.7% of total CpGs) and 8,886 unique transcript clusters (eGenes, 15.3% of total transcript clusters, equivalent to genes). In 87.9% of these cis eQTMs, the eCpG was located at <250 kb from eGene’s TSS; and 58.8% of all eQTMs showed an inverse relationship between the methylation and expression levels. Only around half of the autosomal cis-eQTMs eGenes could be captured through annotation of the eCpG to the closest gene. eCpGs had less measurement error and were enriched for active blood regulatory regions and for CpGs reported to be associated with environmental exposures or phenotypic traits. 40.4% of eQTMs had at least one genetic variant associated with methylation and expression levels. The overlap of autosomal cis eQTMs in children’s blood with those described in adults was small (13.8%), and age-shared cis eQTMs tended to be proximal to the TSS and enriched for genetic variants. See HELIX_Blood_eQTM_READMEfile_20210205.xlsx.

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    ZENODO
    Dataset . 2021
    License: CC 0
    Data sources: ZENODO
    DRYAD
    Dataset . 2021
    License: CC 0
    Data sources: Datacite
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      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ ZENODOarrow_drop_down
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      ZENODO
      Dataset . 2021
      License: CC 0
      Data sources: ZENODO
      DRYAD
      Dataset . 2021
      License: CC 0
      Data sources: Datacite
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    Authors: Georgakis, Marios; Gill, Dipender; Webb, Alastair; Evangelou, Evangelos; +6 Authors

    Objective: We employed Mendelian Randomization to explore whether the effects of blood pressure (BP) and BP lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology. Methods: We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from a GWAS on 757,601 individuals. Applying two-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of WMH. Results: Genetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not beta blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for CCBs showed particularly strong associations with small vessel stroke and the related radiological phenotype of WMH. Conclusions: This study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease. Objective: We employed Mendelian Randomization to explore whether the effects of blood pressure (BP) and BP lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology. Methods: We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from a GWAS on 757,601 individuals. Applying two-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of WMH. Results: Genetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not beta blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for CCBs showed particularly strong associations with small vessel stroke and the related radiological phenotype of WMH. Conclusions: This study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease. 1

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Spiral - Imperial Co...arrow_drop_down
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    ZENODO
    Dataset . 2021
    License: CC 0
    Data sources: ZENODO
    DRYAD
    Dataset . 2021
    License: CC 0
    Data sources: Datacite
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      ZENODO
      Dataset . 2021
      License: CC 0
      Data sources: ZENODO
      DRYAD
      Dataset . 2021
      License: CC 0
      Data sources: Datacite
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    Authors: Marron, Alan; Cassarino, Lucie; Hatton, Jade; Curnow, Paul; +1 Authors

    The marine silicon cycle is intrinsically linked with carbon cycling in the oceans via biological production of silica by a wide range of organisms. The stable silicon isotopic composition (denoted by δ30Si) of siliceous microfossils extracted from sediment cores can be used as an archive of past oceanic silicon cycling. However, the silicon isotopic composition of biogenic silica has only been measured in diatoms, sponges and radiolarians, and isotopic fractionation relative to seawater is entirely unknown for many other silicifiers. Furthermore, the biochemical pathways and mechanisms that determine isotopic fractionation during biosilicification remain poorly understood. Here, we present the first measurements of the silicon isotopic fractionation during biosilicification by loricate choanoflagellates, a group of protists closely related to animals. We cultured two species of choanoflagellates, Diaphanoeca grandis and Stephanoeca diplocostata, which showed consistently greater isotopic fractionation (approximately −5 ‰ to −7 ‰) than cultured diatoms (−0.5 ‰ to −2.1 ‰). Instead, choanoflagellate silicon isotopic fractionation appears to be more similar to sponges grown under similar dissolved silica concentrations. Our results highlight that there is a taxonomic component to silicon isotope fractionation during biosilicification, possibly via a shared or related biochemical transport pathway. These findings have implications for the use of biogenic silica δ30Si produced by different silicifiers as proxies for past oceanic change.

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Biogeosciences (BG)arrow_drop_down
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    Authors: Leathlobhair, Máire Ní; Perri, Angela R.; Irving-Pease, Evan K.; Witt, Kelsey E.; +46 Authors

    Dogs were present in the Americas prior to the arrival of European colonists, but the origin and fate of these pre-contact dogs are largely unknown. We sequenced 71 mitochondrial and seven nuclear genomes from ancient North American and Siberian dogs spanning ~9,000 years. Our analysis indicates that American dogs were not domesticated from North American wolves. Instead, American dogs form a monophyletic lineage that likely originated in Siberia and dispersed into the Americas alongside people. After the arrival of Europeans, native American dogs almost completely disappeared, leaving a minimal genetic legacy in modern dog populations. Remarkably, the closest detectable extant lineage to pre-contact American dogs is the canine transmissible venereal tumor, a contagious cancer clone derived from an individual dog that lived up to 8,000 years ago. Mitochondrial DNA FASTA fileFASTA file containing 1166 dog mtDNA genomes used in this studyfull_mtDNA_alignment.fastaNEXUS treeMaximum likelihood tree (RAxML) of 1166 dogs mtDNA genomes used in this studyfull_mtDNA_alignment.treExcel sheetPublication source of the 1166 mtDNA genomes used in this studyfull_mtDNA_alignment.xlsxPlink (bed) fileContains genotype for dogs 54 dogsfull_data.bedPlink file (bim)Contains genotype for 54 dogsfull_data.bimPlink file (fam)Contains genotype for 54 dogsfull_data.famNJ tree in Figure 2bNJ tree in Figure 2b (see Table S2 for more info)Figure_b.treNexus fileNexus file used for producing Figure S12 (MKV model in MrBayes)Binary_char_MKV.nexNEXUS treeBayesian tree in Figure S12 (see Table S2 for more info)Figure_S12.tre

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    DRYAD; NARCIS
    Dataset . 2019
    License: CC 0
    Data sources: Datacite; NARCIS
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    DANS-EASY
    Dataset . 2018
    Data sources: B2FIND
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    ZENODO
    Dataset . 2019
    License: CC 0
    Data sources: ZENODO
    Borealis
    Dataset . 2021
    Data sources: Datacite
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      DRYAD; NARCIS
      Dataset . 2019
      License: CC 0
      Data sources: Datacite; NARCIS
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      DANS-EASY
      Dataset . 2018
      Data sources: B2FIND
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      ZENODO
      Dataset . 2019
      License: CC 0
      Data sources: ZENODO
      Borealis
      Dataset . 2021
      Data sources: Datacite
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    Authors: Puljung, Michael; Vedovato, Natascia; Usher, Samuel; Ashcroft, Frances;

    The response of ATP-sensitive K+ channels (KATP) to cellular metabolism is coordinated by three classes of nucleotide binding site (NBS). We used a novel approach involving labeling of intact channels in a native, membrane environment with a non-canonical fluorescent amino acid and measurement (using FRET with fluorescent nucleotides) of steady-state and time-resolved nucleotide binding to dissect the role of NBS2 of the accessory SUR1 subunit of KATP in channel gating. Binding to NBS2 was Mg2+-independent, but Mg was required to trigger a conformational change in SUR1. Mutation of a lysine (K1384A) in NBS2 that coordinates bound nucleotides increased the EC50 for trinitrophenyl-ADP binding to NBS2, but only in the presence of Mg2+, indicating that this mutation disrupts the ligand-induced conformational change. Comparison of nucleotide-binding with ionic currents suggests a model in which each nucleotide binding event to NBS2 of SUR1 is independent and promotes KATP activation by the same amount. Puljung_data_sets

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    ZENODO
    Dataset . 2019
    License: CC 0
    Data sources: ZENODO
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    DANS-EASY
    Dataset . 2019
    Data sources: B2FIND
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    DRYAD; NARCIS
    Dataset . 2019
    License: CC 0
    Data sources: Datacite; NARCIS
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      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ ZENODOarrow_drop_down
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      ZENODO
      Dataset . 2019
      License: CC 0
      Data sources: ZENODO
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
      DANS-EASY
      Dataset . 2019
      Data sources: B2FIND
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
      DRYAD; NARCIS
      Dataset . 2019
      License: CC 0
      Data sources: Datacite; NARCIS
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Pinharanda, Ana; Rousselle, Marjolaine; Martin, Simon H.; Hanly, Joseph J.; +4 Authors

    orthologous groups of genes in the H. melpomene and the H. erato transcriptomesOrthoFinder was used to identify orthologous groups of genes in the H. melpomene and the H. erato transcriptomes (options: -t 48 -a 6). 1-1 orthologous gene sequences were selected for use in subsequent analysis (Supporting Information Table S2)1_1_melpomene_erato_ortho.txtdivergence_autosomesCalculation of diversity and selection statistics for 1-1 ortholog alignments between H. melpomene and H. eratodivergence_ZCalculation of diversity and selection statistics for 1-1 ortholog alignments between H. melpomene and H. eratopolymorphism_autosomesCalculation of diversity and selection statistics for 1-1 ortholog alignments between H. melpomene and H. eratopolymorphism_autosomesCalculation of diversity and selection statistics for 1-1 ortholog alignments between H. melpomene and H. eratopolymorphism_Z.csvresults_heliconius-otherLepsOverall results for calculation of diversity and selection statistics for 1-1 ortholog alignments between H. melpomene and H. erato & other Leps for comparisonresults_heliconius-1.csvtotal_alignement_autosomes_heliconiusCalculation of diversity and selection statistics for 1-1 ortholog alignments between H. melpomene and H. eratototal_alignement_autosomes_heliconiusCalculation of diversity and selection statistics for 1-1 ortholog alignments between H. melpomene and H. eratototal_alignement_autosomes_heliconiusCalculation of diversity and selection statistics for 1-1 ortholog alignments between H. melpomene and H. eratototal_alignment_Z_heliconiusCalculation of diversity and selection statistics for 1-1 ortholog alignments between H. melpomene and H. eratototal_alignement_Z_heliconius.SFS_DoFEtotal_alignment_Z_heliconiusCalculation of diversity and selection statistics for 1-1 ortholog alignments between H. melpomene and H. eratototal_alignement_Z_heliconius.SFS_sumtotal_alignment_Z_heliconiusCalculation of diversity and selection statistics for 1-1 ortholog alignments between H. melpomene and H. eratototal_alignement_Z_heliconius.sum Sex chromosomes have different evolutionary properties compared to autosomes due to their hemizygous nature. In particular, recessive mutations are more readily exposed to selection, which can lead to faster rates of molecular evolution. Here, we report patterns of gene expression and molecular evolution for a group of butterflies. First, we improve the completeness of the Heliconius melpomene reference annotation, a neotropical butterfly with a ZW sex determination system. Then, we analyse RNA from male and female whole abdomens and sequence female ovary and gut tissue to identify sex and tissue specific gene expression profiles in H. melpomene. Using these expression profiles we compare: 1) sequence divergence and polymorphism; 2) the strength of positive and negative selection; and 3) rates of adaptive evolution, for Z and autosomal genes between two species of Heliconius butterflies, H. melpomene and H. erato. We show that the rate of adaptive substitutions is higher for Z than autosomal genes, but contrary to expectation, it is also higher for male biased than female biased genes. Additionally, we find no significant increase in the rate of adaptive evolution or purifying selection on genes expressed in ovary tissue, a heterogametic specific tissue. Our results contribute to a growing body of literature from other ZW systems that also provide mixed evidence for a fast-Z effect where hemizygosity influences the rate of adaptive substitutions.

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ ZENODOarrow_drop_down
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    ZENODO
    Dataset . 2018
    License: CC 0
    Data sources: ZENODO
    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    DRYAD; NARCIS
    Dataset . 2018
    License: CC 0
    Data sources: Datacite; NARCIS
    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    DANS-EASY
    Dataset . 2018
    Data sources: B2FIND
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      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ ZENODOarrow_drop_down
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      ZENODO
      Dataset . 2018
      License: CC 0
      Data sources: ZENODO
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
      DRYAD; NARCIS
      Dataset . 2018
      License: CC 0
      Data sources: Datacite; NARCIS
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
      DANS-EASY
      Dataset . 2018
      Data sources: B2FIND
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Langat, Pinky; Raghwani, Jayna; Dudas, Gytis; Bowden, Thomas A.; +10 Authors

    Full genomes location summaryTab-delimited text file detailing locations and lineages of 2,651 full-length influenza B virus genomes in this study (Fig 1 source data).fluB_location_summary.txtFull genomes time summaryTab-delimited text file detailing year of isolation and lineage of 2,651 full-length influenza B virus genomes from this study (Fig 1 source data).fluB_timeseries_summary.txtMaximum likelihood treesCompressed file of bootstrapped ML phylogenies inferred using RAxML and used to characterise influenza B virus genotypes.maximum-likelihood-trees.zipBEAST XML filesCompressed file of BEAST input files (xml) used to infer the molecular clock phylogenies as well as ancestral reconstruction and phylodynamic analysis for influenza B virus genes.beast-xml-files.zipMaximum clade credibility (MCC) treesCompressed file comprising of BEAST output MCC trees.mcc-trees.zipSummary of genotypesTab-delimited text file detailing inferred genotypes for influenza B viruses, representing over 10,000 strains including 2,651 complete genomes.genotypes-summary.txtMCC trees annotated with trunk substitutionsCompressed file containing MCC trees for B/Yamagata HA, B/Victoria HA, B/Yamagata PB1, and B/Victoria NA annotated with inferred mutations along the trunk lineages.trunk-substitutions-mcc-trees.zipInput files for antigenic analysisCompressed file comprising of: tab-delimited HI data file, BEAST XML file for generation of set of empirical trees and XML file for running BMDS models for B/Yamagata and B/Victoria.antigenic-evolution-input.zipOutput files from antigenic analysisCompressed file containing MCC trees from BMDS analysis (source data for Figure 4) and tab-delimited file summaries of mean antigenic distance from phylogenetic root inferred across 2,000 posterior trees to calculate mean antigenic drift rates (source data for Table 2). Posterior trees files were too large (>50 MB in compressed form each) to be included.antigenic-evolution-output.zip The global-scale epidemiology and genome-wide evolutionary dynamics of influenza B remain poorly understood compared with influenza A viruses. We compiled a spatio-temporally comprehensive dataset of influenza B viruses, comprising over 2,500 genomes sampled worldwide between 1987 and 2015, including 382 newly-sequenced genomes that fill substantial gaps in previous molecular surveillance studies. Our contributed data increase the number of available influenza B virus genomes in Europe, Africa and Central Asia, improving the global context to study influenza B viruses. We reveal Yamagata-lineage diversity results from co-circulation of two antigenically-distinct groups that also segregate genetically across the entire genome, without evidence of intra-lineage reassortment. In contrast, Victoria-lineage diversity stems from geographic segregation of different genetic clades, with variability in the degree of geographic spread among clades. Differences between the lineages are reflected in their antigenic dynamics, as Yamagata-lineage viruses show alternating dominance between antigenic groups, while Victoria-lineage viruses show antigenic drift of a single lineage. Structural mapping of amino acid substitutions on trunk branches of influenza B gene phylogenies further supports these antigenic differences and highlights two potential mechanisms of adaptation for polymerase activity. Our study provides new insights into the epidemiological and molecular processes shaping influenza B virus evolution globally.

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ DRYAD; NARCISarrow_drop_down
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    DRYAD; NARCIS
    Dataset . 2018
    License: CC 0
    Data sources: Datacite; NARCIS
    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    DANS-EASY
    Dataset . 2018
    Data sources: B2FIND
    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    ZENODO
    Dataset . 2018
    License: CC 0
    Data sources: ZENODO
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      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ DRYAD; NARCISarrow_drop_down
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      DRYAD; NARCIS
      Dataset . 2018
      License: CC 0
      Data sources: Datacite; NARCIS
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
      DANS-EASY
      Dataset . 2018
      Data sources: B2FIND
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
      ZENODO
      Dataset . 2018
      License: CC 0
      Data sources: ZENODO
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Shields, Mallory C.; Bowers, Matthew R.; Fulcer, McKenzie M.; Bollig, Madelyn K.; +7 Authors

    Fig2C_Blot3Original blot used to quantify Fig2CFig2C Blot2Original blot to quantify Fig2CFig2C_Blot2.pngFig2C_Blot1Original blot to quantify Fig2CFig2B_Blot2Original blot to quantify Fig2BFig2B_Blot1Original blot to quantify Fig2BFig2A_Blot2Original blot to quantify Fig2AFig2A_Blot1Original blot to quantify Fig2AFig2_2ARaw data values for Fig2A quantificationFig2_2BRaw data values for quantification of Fig2BFig2_2CRaw data values for Fig2C quantificationFig3_Fig 3 A,BRaw counts and percentages for lifespan of both control and experimental adult flies. Figure 3.Fig4_4B ControlRaw response amplitudes per fiber for control evoked responses. Figure 4B.Fig4_4B P-LRaw response amplitudes per fiber for experimental genotype evoked responses. Figure 4B.Fig4_4B STATSStatistical analysis for Fig4BFig4_4DRaw data values and statistical analysis for Fig 4DFig4_4ERaw data values and statistical analysis for Fig4E.Fig5_5ARaw data values and statistical analysis for Fig5A.Fig5_5BRaw data values for Fig5B.Fig5_5CRaw data values and statistical analysis for Fig5C.Fig5_5DRaw data values and statistical analysis for Fig5D.Fig6_6B ControlRaw and normalized data values for control in Fig6B.Fig6_6B P-LRaw and normalized data values for experimental gentoype in Fig6B.Fig7_7B ControlRaw and normalized data values for control in Fig7B.Fig7_7B P-LRaw and normalized data values for experimental gentoype in Fig7B.Fig8_8C Male control averagesRaw data values and averages for control in Fig8CFig8_8C Male P-L averagesRaw data values and averages for experimental genotype in Fig8CFig8_8A Female Control averagesRaw data values and averages for control in Fig8AFig8_8A Female P-L averagesRaw data values and averages for experimental genotype in Fig8AFig8_8B TTESTRaw data and statistical analysis for Fig8BFig8_8D TTESTRaw data and statistical analysis for Fig8D.Fig9 Fig9A-BRaw values and averages for Fig 9A-BFig9_Fig9A-B.csvFig9_BinningAverages for Fig 9 binned into 1-minute intervals During chemical transmission, the function of synaptic proteins must be coordinated to efficiently release neurotransmitter. Synaptotagmin 2, the Ca2+ sensor for fast, synchronized neurotransmitter release at the human neuromuscular junction, has recently been implicated in a dominantly inherited congenital myasthenic syndrome associated with a non-progressive motor neuropathy. In one family, a proline residue within the C2B Ca2+-binding pocket of synaptotagmin is replaced by a leucine. The functional significance of this residue has not been investigated previously. Here we show that in silico modeling predicts disruption of the C2B Ca2+-binding pocket, and we examine the in vivo effects of the homologous mutation in Drosophila. When expressed in the absence of native synaptotagmin, this mutation is lethal, demonstrating for the first time that this residue plays a critical role in synaptotagmin function. To achieve expression similar to human patients, the mutation is expressed in flies carrying one copy of the wild type synaptotagmin gene. We now show that Drosophila carrying this mutation developed neurological and behavioral manifestations similar to those of human patients and provide insight into the mechanisms underlying these deficits. Our Drosophila studies support a role for this synaptotagmin point mutation in disease etiology.

    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ DRYAD; NARCISarrow_drop_down
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    DRYAD; NARCIS
    Dataset . 2018
    License: CC 0
    Data sources: Datacite; NARCIS
    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    DANS-EASY
    Dataset . 2017
    Data sources: B2FIND
    image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    ZENODO
    Dataset . 2018
    License: CC 0
    Data sources: ZENODO
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      DRYAD; NARCIS
      Dataset . 2018
      License: CC 0
      Data sources: Datacite; NARCIS
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
      DANS-EASY
      Dataset . 2017
      Data sources: B2FIND
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
      ZENODO
      Dataset . 2018
      License: CC 0
      Data sources: ZENODO
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    Authors: Frantz, Laurent A.F.; Rudzinski, Anna; Nugraha, Abang Mansyursyah Surya; Evin, Allowen; +38 Authors

    The high degree of endemism on Sulawesi has previously been suggested to have vicariant origins, dating back 40 Myr ago. Recent studies, however, suggest that much of Sulawesi’s fauna assembled over the last 15 Myr. Here, we test the hypothesis that more recent uplift of previously submerged portions of land on Sulawesi promoted diversification, and that much of its faunal assemblage is much younger than the island itself. To do so, we combined palaeogeographical reconstructions with genetic and morphometric data sets derived from Sulawesi’s three largest mammals: the Babirusa, Anoa, and Sulawesi warty pig. Our results indicate that although these species most likely colonized the area that is now Sulawesi at different times (14 Myr ago to 2-3 Myr ago), they experienced an almost synchronous expansion from the central part of the island. Geological reconstructions indicate that this area was above sea level for most of the last 4 Myr, unlike most parts of the island. We conclude that emergence of land on Sulawesi (~1–2 Myr) may have allowed species to expand synchronously. Altogether, our results indicate that the establishment of the highly endemic faunal assemblage on Sulawesi was driven by geological events over the last few million years. Anoa mtDNAFasta files containing Anoa mtDNA dataAnoa_cytb.fastaAnoa microsatelliteTSV files containing Anoa microsatellite dataAnoa_microsat.tsvBabirusa mtDNAFasta files containing Babirusa mtDNA dataBabirusa_dloop.fastaBabirusa microsatelliteTSV files containing Babirusa microsatellite dataBabirusa_microsat.tsvSWP mtDNAFasta files containing SWP mtDNA dataSus_dloop.fastaSWP microsatelliteTSV files containing SWP microsatellite dataSus_microsat.tsvCentroid size of lower second of Babirusa and SWPCentroid size for the lower M2BabSus-lowerM2-CS.NTSShape of lower second molar of Babirusa and SWPShape coordinates after superimposition for the lower M2BabSus-lowerM2-aligned.TPSSample list for second lower molar TPS and NTS filesBabSus-lowerM2-ind.csvShape of third second molar of Babirusa and SWPShape coordinates after superimposition for the lower M3BabSus-lowerM3-aligned.TPSCentroid size of lower third molar of Babirusa and SWPCentroid size for the lower M3BabSus-lowerM3-CS.NTSSample list for third lower molar TPS and NTS filesBabSus-lowerM3-CS-ind.csvTable S1Sample information for all three speciesTable_S1.xlsx

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    ZENODO
    Dataset . 2018
    License: CC 0
    Data sources: ZENODO
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    DANS-EASY
    Dataset . 2018
    Data sources: B2FIND
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    DRYAD; NARCIS
    Dataset . 2018
    License: CC 0
    Data sources: Datacite; NARCIS
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      ZENODO
      Dataset . 2018
      License: CC 0
      Data sources: ZENODO
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      DANS-EASY
      Dataset . 2018
      Data sources: B2FIND
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      DRYAD; NARCIS
      Dataset . 2018
      License: CC 0
      Data sources: Datacite; NARCIS
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Radersma, Reinder; Garroway, Colin J.; Santure, Anna W.; De Cauwer, Isabelle; +3 Authors

    Individual genotypes (SNP-markers)Genotypes (SNPs markers) of all individuals in this study. Columns are SNP markers and rows are individuals. This matrix contains a header with SNP-marker names. Identities of the individuals can be found in the "list of individuals in the genotype matrix".SNPs.csvList of individuals in the genotype matrixList of the identities of all individuals in the "individual genotypes" matrix. Each entry corresponds to a row in the "individual genotypes" matrix.list_of_individuals_SNPs.csvList of candidate genesList of candidate genes. This file contains a header. marker_name corresponds to the marker identities (columns) in the " individual genotypes" matrix. gene_cat are the categories investigated in this study. candidate_gene are the corresponding gene names.list_of_candidate_genes.csvIndividual by gathering event matrix 2007This matrix indicates which individuals were present at which gathering events. Columns are gathering events, rows are individuals. Gathering events are ordered by time and date (from early to late). Presence at a gathering event is marked with a 1. The identities of the individuals can be found in the "list of individuals for the I by GE matrix 2007". The locations of the gathering events can be found in the "list of locations of the gathering events 2007".individual_by_gathering_event_2007.csvList of individuals for the I by GE matrix 2007List of the identities of the individuals in the "individual by gathering event matrix 2007". Each entry corresponds to a row in the "individual by gathering event matrix 2007".list_of_individuals_2007.csvList of locations of the gathering events 2007List of the locations of all gathering events in 2007. Each entry corresponds to a column in the "individual by gathering event matrix 2007". The values correspond to the rows and columns in the "spatial distance matrix" and the rows in the "eigen vectors of the spatial weighting matrix".list_of_locations_of_gathering_events_2007.csvIndividual by gathering event matrix 2008This matrix indicates which individuals were present at which gathering events. Columns are gathering events, rows are individuals. Gathering events are ordered by time and date (from early to late). Presence at a gathering event is marked with a 1. The identities of the individuals can be found in the "list of individuals for the I by GE matrix 2008". The locations of the gathering events can be found in the "list of locations of the gathering events 2008".individual_by_gathering_event_2008.csvList of individuals for the I by GE matrix 2008List of the identities of the individuals in the "individual by gathering event matrix 2008". Each entry corresponds to a row in the "individual by gathering event matrix 2008".list_of_individuals_2008.csvList of locations of the gathering events 2008List of the locations of all gathering events in 2008. Each entry corresponds to a column in the "individual by gathering event matrix 2008". The values correspond to the rows and columns in the "spatial distance matrix" and the rows in the "eigen vectors of the spatial weighting matrix".list_of_locations_of_gathering_events_2008.csvIndividual by gathering event matrix 2009This matrix indicates which individuals were present at which gathering events. Columns are gathering events, rows are individuals. Gathering events are ordered by time and date (from early to late). Presence at a gathering event is marked with a 1. The identities of the individuals can be found in the "list of individuals for the I by GE matrix 2009". The locations of the gathering events can be found in the "list of locations of the gathering events 2009".individual_by_gathering_event_2009.csvList of individuals for the I by GE matrix 2009List of the identities of the individuals in the "individual by gathering event matrix 2009". Each entry corresponds to a row in the "individual by gathering event matrix 2009".list_of_individuals_2009.csvList of locations of the gathering events 2009List of the locations of all gathering events in 2009. Each entry corresponds to a column in the "individual by gathering event matrix 2009". The values correspond to the rows and columns in the "spatial distance matrix" and the rows in the "eigen vectors of the spatial weighting matrix".list_of_locations_of_gathering_events_2009.csvSpatial distance matrixThe spatial distances between all feeding stations (in meters). Rows and columns correspond to the locations of the feeding stations, i.e. the values in the "list of locations of gathering events 2007/2008/2009" files.spatial_distance_matrix.csvDistance based Moran's Eigenvector MapsThe distance based Moran's Eigenvector Maps (db-MEMs) for all feeding stations. Rows correspond to the feeding station locations and columns to the 20 Eigenvectors.spatial_weighting_matrix_Eigen_vectors.csvAsymmetric Eigenvector Maps 2007The Asymmetric Eigenvector Maps for the gathering events in 2007. Rows correspond to the gathering events and columns to the first 500 Eigenvectors.asymmetric_eigenvector_maps_2007.csv.zipAsymmetric Eigenvector Maps 2008The Asymmetric Eigenvector Maps for the gathering events in 2008. Rows correspond to the gathering events and columns to the first 500 Eigenvectors.asymmetric_eigenvector_maps_2008.csv.zipAsymmetric Eigenvector Maps 2009The Asymmetric Eigenvector Maps for the gathering events in 2009. Rows correspond to the gathering events and columns to the first 500 Eigenvectors.asymmetric_eigenvector_maps_2009.csv.zip Social interactions are rarely random. In some instances animals exhibit homophily or heterophily, the tendency to interact with similar or dissimilar conspecifics respectively. Genetic homophily and heterophily influence the evolutionary dynamics of populations, because they potentially affect sexual and social selection. Here we investigate the link between social interactions and allele frequencies in foraging flocks of great tits (Parus major) over three consecutive years. We constructed co-occurrence networks which explicitly described the splitting and merging of 85,602 flocks through time (fission-fusion dynamics), at 60 feeding sites. Of the 1711 birds in those flocks we genotyped 962 individuals at 4701 autosomal single-nucleotide polymorphisms (SNPs). By combining genome-wide genotyping with repeated field observations of the same individuals we were able to investigate links between social structure and allele frequencies at a much finer scale than was previously possible. We explicitly accounted for potential spatial effects underlying genetic structure at the population level. We modelled social structure and spatial configuration of great tit fission-fusion dynamics with eigenvector maps. Variance partitioning revealed that allele frequencies were strongly affected by group fidelity (explaining 27-45% of variance) as individuals tended to maintain associations with the same conspecifics. These conspecifics were genetically more dissimilar than expected, shown by genome-wide heterophily for pure social (i.e. space-independent) grouping preferences. Genome-wide homophily was linked to spatial configuration, indicating spatial segregation of genotypes. We did not find evidence for homophily or heterophily for putative socially relevant candidate genes or any other SNP markers. Together, these results demonstrate the importance of distinguishing social and spatial processes in determining population structure.

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    DANS-EASY
    Dataset . 2017
    Data sources: B2FIND
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    DRYAD; NARCIS
    Dataset . 2017
    License: CC 0
    Data sources: Datacite; NARCIS
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    ZENODO
    Dataset . 2017
    License: CC 0
    Data sources: ZENODO
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      DANS-EASY
      Dataset . 2017
      Data sources: B2FIND
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      DRYAD; NARCIS
      Dataset . 2017
      License: CC 0
      Data sources: Datacite; NARCIS
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      ZENODO
      Dataset . 2017
      License: CC 0
      Data sources: ZENODO
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16 Research products
  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Ruiz-Arenas, Carlos; Bustamante, Mariona;

    To test associations between DNA methylation levels and gene expression levels in cis (cis eQTMs), we paired each Gene to CpGs closer than 500 kb from its TSS, either upstream or downstream. For each Gene, the TSS was defined based on HTA-2.0 annotation, using the start position for transcripts in the + strand, and the end position for transcripts in the - strand. CpGs position was obtained from Illumina 450K array annotation. Only CpGs in autosomal chromosomes (from chromosome 1 to 22) were tested. In the main analysis, we fitted for each CpG-Gene pair a linear regression model between gene expression and methylation levels adjusted for age, sex, cohort, and blood cell type composition. A second model was run without adjusting for blood cellular composition and it is only reported on the online web catalog, but not discussed in this manuscript. Although some of the unique associations of the unadjusted model might be real, others might be confounded by the large methylation and expression changes among blood cell types. To ensure that CpGs paired to a higher number of Genes do not have higher chances of being part of an eQTM, multiple-testing was controlled at the CpG level, following a procedure previously applied in the Genotype-Tissue Expression (GTEx) project (Gamazon et al., 2018). Briefly, our statistic used to test the hypothesis that a pair CpG-Gene is significantly associated is based on considering the lowest p-value observed for a given CpG and all its paired Gene (e.g., those in the 1 Mb window centered at the TSS). As we do not know the distribution of this statistic under the null, we used a permutation test. We generated 100 permuted gene expression datasets and ran our previous linear regression models obtaining 100 permuted p-values for each CpG-Gene pair. Then, for each CpG, we selected among all CpG-Gene pairs the minimum p-value in each permutation and fitted a beta distribution that is the distribution we obtain when dealing with extreme values (e.g. minimum) (Dudbridge and Gusnanto, 2008). Next, for each CpG, we took the minimum p-value observed in the real data and used the beta distribution to compute the probability of observing a lower p-value. We defined this probability as the empirical p-value of the CpG. Then, we considered as significant those CpGs with empirical p-values to be significant at 5% false discovery rate using Benjamini-Hochberg method. Finally, we applied a last step to identify all significant CpG-Gene pairs for all eCpGs. To do so, we defined a genome-wide empirical p-value threshold as the empirical p-value of the eCpG closest to the 5% false discovery rate threshold. We used this empirical p-value to calculate a nominal p-value threshold for each eCpG, based on the beta distribution obtained from the minimum permuted p-values. This nominal p-value threshold was defined as the value for which the inverse cumulative distribution of the beta distribution was equal to the empirical p-value. Then, for each eCpG, we considered as significant all eCpG-Gene variants with a p-value smaller than nominal p-value. For the meQTLs catalogue, we selected 9.9 M cis and trans meQTLs with a p-value <1e-7 in the ARIES dataset consisting of data from children of 7 years old (Gaunt et al., 2016). Then, we tested whether this subset of 9.9 M SNPs were also meQTLs in HELIX by running meQTL analyses using MatrixEQTL R package (Shabalin, 2012), adjusting for cohort, sex, age, blood cellular composition and the first 20 principal components (PCs) calculated from genome-wide genetic data of the GWAS variability. We confirmed 2.8 M meQTLs in HELIX (p-value <1e-7). Trans meQTLs represented <10% of the 2.8 M meQTLs. Enrichment of eCpGs for meQTLs was computed using a Chi-square test, using non eCpGs as background. Finally, we tested whether meQTLs were also eQTLs for the eGenes linked to the eCpGs. To this end, we run eQTL analyses (gene expression being the outcome and 2.8 M SNPs the predictors) with MatrixEQTL adjusting for cohort, sex, age, blood cellular composition and the first 20 GWAS PCs in HELIX. We considered as significant eQTLs the SNP-Gene pairs with p-value <1e-7 and with the direction of the effect consistent with the direction of the meQTL and the eQTM. Background: The identification of expression quantitative trait methylation (eQTMs), defined as associations between DNA methylation levels and gene expression, might help the biological interpretation of epigenome-wide association studies (EWAS). We aimed to identify autosomal cis eQTMs in children’s blood, using data from 832 children of the Human Early Life Exposome (HELIX) project. Methods: Blood DNA methylation and gene expression were measured with the Illumina 450K and the Affymetrix HTA v2 arrays, respectively. The relationship between methylation levels and expression of nearby genes (1 Mb window centered at the transcription start site, TSS) was assessed by fitting 13.6 M linear regressions adjusting for sex, age, cohort, and blood cell composition. Results: We identified 39,749 blood autosomal cis eQTMs, representing 21,966 unique CpGs (eCpGs, 5.7% of total CpGs) and 8,886 unique transcript clusters (eGenes, 15.3% of total transcript clusters, equivalent to genes). In 87.9% of these cis eQTMs, the eCpG was located at <250 kb from eGene’s TSS; and 58.8% of all eQTMs showed an inverse relationship between the methylation and expression levels. Only around half of the autosomal cis-eQTMs eGenes could be captured through annotation of the eCpG to the closest gene. eCpGs had less measurement error and were enriched for active blood regulatory regions and for CpGs reported to be associated with environmental exposures or phenotypic traits. 40.4% of eQTMs had at least one genetic variant associated with methylation and expression levels. The overlap of autosomal cis eQTMs in children’s blood with those described in adults was small (13.8%), and age-shared cis eQTMs tended to be proximal to the TSS and enriched for genetic variants. See HELIX_Blood_eQTM_READMEfile_20210205.xlsx.

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    ZENODO
    Dataset . 2021
    License: CC 0
    Data sources: ZENODO
    DRYAD
    Dataset . 2021
    License: CC 0
    Data sources: Datacite
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      ZENODO
      Dataset . 2021
      License: CC 0
      Data sources: ZENODO
      DRYAD
      Dataset . 2021
      License: CC 0
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Georgakis, Marios; Gill, Dipender; Webb, Alastair; Evangelou, Evangelos; +6 Authors

    Objective: We employed Mendelian Randomization to explore whether the effects of blood pressure (BP) and BP lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology. Methods: We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from a GWAS on 757,601 individuals. Applying two-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of WMH. Results: Genetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not beta blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for CCBs showed particularly strong associations with small vessel stroke and the related radiological phenotype of WMH. Conclusions: This study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease. Objective: We employed Mendelian Randomization to explore whether the effects of blood pressure (BP) and BP lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology. Methods: We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from a GWAS on 757,601 individuals. Applying two-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of WMH. Results: Genetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not beta blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for CCBs showed particularly strong associations with small vessel stroke and the related radiological phenotype of WMH. Conclusions: This study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease. 1

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    ZENODO
    Dataset . 2021
    License: CC 0
    Data sources: ZENODO
    DRYAD
    Dataset . 2021
    License: CC 0
    Data sources: Datacite
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      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/ Spiral - Imperial Co...arrow_drop_down
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
      image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
      ZENODO
      Dataset . 2021
      License: CC 0
      Data sources: ZENODO
      DRYAD
      Dataset . 2021
      License: CC 0
      Data sources: Datacite
      addClaim

      This Research product is the result of merged Research products in OpenAIRE.

      You have already added works in your ORCID record related to the merged Research product.