Molecular Characterization of Three Canine Models of Human Rare Bone Diseases: Caffey, van den Ende-Gupta, and Raine Syndromes

Peer reviewe

The MIntAct project—IntAct as a common curation platform for 11 molecular interaction databases

IntAct (freely available at http://www.ebi.ac.uk/intact) is an open-source, open data molecular interaction database populated by data either curated from the literature or from direct data depositions. IntAct has developed a sophisticated web-based curation tool, capable of supporting both IMEx- and MIMIx-level curation. This tool is now utilized by multiple additional curation teams, all of whom annotate data directly into the IntAct database. Members of the IntAct team supply appropriate levels of training, perform quality control on entries and take responsibility for long-term data maintenance. Recently, the MINT and IntAct databases decided to merge their separate efforts to make optimal use of limited developer resources and maximize the curation output. All data manually curated by the MINT curators have been moved into the IntAct database at EMBL-EBI and are merged with the existing IntAct dataset. Both IntAct and MINT are active contributors to the IMEx consortium (http://www.imexconsortium.org

The Expression of Allele Changes in NLRP3 (rs35829419) and IL-1β (+3954) Gene Polymorphisms in Periodontitis and Coronary Artery Disease

Background: Inflammasomes have been shown to play a pivotal role in periodontal disease pathogenesis. However, their role in periodontitis subjects with coronary heart disease remains unclear. This study aimed to obtain the expression of NLRP3 (rs35829419) and IL-1β (+3954) gene polymorphisms in the subgingival plaque and blood samples of generalized periodontitis (GP) subjects with and without coronary heart disease (CHD). Methods: A total of 70 subjects were grouped into two; GP and GP with CHD. Demographic variables and periodontal and cardiac parameters were recorded from both the groups. Subgingival plaque and blood samples were obtained from both the groups and were further subjected to the identification of NLRP3 (rs35829419) and IL-1β (+3954) expression and allele change using a conventional polymerase chain reaction (PCR) and gene sequencing (Sanger’s method). Results: Amongst the demographic variables, age and monthly income were statistically significant between the two groups. Plaque index (PI), clinical attachment level (CAL), high-density lipoprotein (HDL), and low density-lipoprotein (LDL) exhibited statistically significant levels between the two groups. The NLRP3 (rs35829419) and IL-1β (+3954) genes showed a statistically significant association with allele change (frequency) among the groups. The general comparison of all the parameters with the allele change of NLRP3 (rs35829419) and IL-1β (+3954) in the subgingival plaque and blood samples showed statistically significant associations among the two groups. Conclusion: The present study highlighted an allele change in IL-1β (+3954) gene polymorphisms which may play an important role in the pathogenesis of periodontitis and coronary heart disease

Genetic analyses in canine craniomandibular osteopathy identify a leaky splicing variant in exon 15 of <i>SLC37A2</i>, resulting in a frameshift that truncates the protein.

<p><b>A</b>. Laterolateral (left) and ventrodorsal (right) radiograph of the skull of two different WHWT affected with CMO. The typical palisade-like periosteal new bone formation is commonly located along the corpus mandibulae (left, white arrowheads) or around the Bulla tympanica (right, black arrowheads). <b>B.</b> Manhattan plot from GWAS indicates the associated region on chromosome 5 (p_genome = 0.02). <b>C.</b> A synonymous variant, c. 1332C>T, in exon 15 of <i>SLC37A2</i>. <b>D</b>. ESEfinder suggests that the synonymous variant affects a splicing enhancer site. The binding scores for the different splicing factors (colored blocks) for 79 nucleotides of exon 15 are shown for the wild-type and mutant allele. The c.1332C>T mutation eliminates a potential binding site for the SF2/ASF splicing factor (shown in purple). Binding scores for different splicing proteins (shown on the y-axis) are based on different weight matrices and cannot be compared directly to each other. <b>E</b>. A semi-quantitative RT-PCR in the wild-type (CC), carrier (CT) and affected (TT) WHWTs confirms the splicing defect (79 bp deletion) caused by the variant, and reveals a splicing leakage in the carrier and affected dogs. <i>B2M</i> was used as a loading control. <b>F</b>. A schematic 12-transmembrane secondary structure of SLC37A2 predicted by TMHMM. The truncated region in the mutated protein is indicated by a dashed line.</p

Genetic analyses in a developmental syndrome in Wire Fox Terriers reveal a deletion in exon 6 of <i>SCARF2</i>, resulting in an early truncation of the predicted protein.

<p><b>A</b>. A Manhattan plot from a GWAS indicates a locus on chromosome 26 (p_genome = 0.05). <b>B</b>. A 3.3-Mb disease-associated haplotype in the affected dogs. <b>C</b>. Targeted resequencing revealed a 2-bp deletion in exon 6 (c.865-866delTC), resulting in a severe truncation at Ser289 that removes the transmembrane and cytoplasmic domains of the predicted protein as indicated by a dashed line in the schematic structure. <b>D</b>. RT-PCR in the affected and control Wire Fox Terrier indicate expression of <i>SCARF2</i> mRNA and suggest that the mutated <i>SCARF2</i> transcript is not directed to nonsense-mediated RNA decay.</p

Genome sequencing of 2000 canids by the Dog10K consortium advances the understanding of demography, genome function and architecture

International audienceBackground: The international Dog10K project aims to sequence and analyze several thousand canine genomes. Incorporating 20 × data from 1987 individuals, including 1611 dogs (321 breeds), 309 village dogs, 63 wolves, and four coyotes, we identify genomic variation across the canid family, setting the stage for detailed studies of domestication, behavior, morphology, disease susceptibility, and genome architecture and function.Results: We report the analysis of > 48 M single-nucleotide, indel, and structural variants spanning the autosomes, X chromosome, and mitochondria. We discover more than 75% of variation for 239 sampled breeds. Allele sharing analysis indicates that 94.9% of breeds form monophyletic clusters and 25 major clades. German Shepherd Dogs and related breeds show the highest allele sharing with independent breeds from multiple clades. On average, each breed dog differs from the UU_Cfam_GSD_1.0 reference at 26,960 deletions and 14,034 insertions greater than 50 bp, with wolves having 14% more variants. Discovered variants include retrogene insertions from 926 parent genes. To aid functional prioritization, single-nucleotide variants were annotated with SnpEff and Zoonomia phyloP constraint scores. Constrained positions were negatively correlated with allele frequency. Finally, the utility of the Dog10K data as an imputation reference panel is assessed, generating high-confidence calls across varied genotyping platform densities including for breeds not included in the Dog10K collection.Conclusions: We have developed a dense dataset of 1987 sequenced canids that reveals patterns of allele sharing, identifies likely functional variants, informs breed structure, and enables accurate imputation. Dog10K data are publicly available

Genome sequencing of 2000 canids by the Dog10K consortium advances the understanding of demography, genome function and architecture

Abstract Background The international Dog10K project aims to sequence and analyze several thousand canine genomes. Incorporating 20 × data from 1987 individuals, including 1611 dogs (321 breeds), 309 village dogs, 63 wolves, and four coyotes, we identify genomic variation across the canid family, setting the stage for detailed studies of domestication, behavior, morphology, disease susceptibility, and genome architecture and function. Results We report the analysis of > 48 M single-nucleotide, indel, and structural variants spanning the autosomes, X chromosome, and mitochondria. We discover more than 75% of variation for 239 sampled breeds. Allele sharing analysis indicates that 94.9% of breeds form monophyletic clusters and 25 major clades. German Shepherd Dogs and related breeds show the highest allele sharing with independent breeds from multiple clades. On average, each breed dog differs from the UU_Cfam_GSD_1.0 reference at 26,960 deletions and 14,034 insertions greater than 50 bp, with wolves having 14% more variants. Discovered variants include retrogene insertions from 926 parent genes. To aid functional prioritization, single-nucleotide variants were annotated with SnpEff and Zoonomia phyloP constraint scores. Constrained positions were negatively correlated with allele frequency. Finally, the utility of the Dog10K data as an imputation reference panel is assessed, generating high-confidence calls across varied genotyping platform densities including for breeds not included in the Dog10K collection. Conclusions We have developed a dense dataset of 1987 sequenced canids that reveals patterns of allele sharing, identifies likely functional variants, informs breed structure, and enables accurate imputation. Dog10K data are publicly available