scholarly journals Epigenomic signature of the progeroid Cockayne syndrome exposes distinct and common features with physiological ageing

2021 ◽  
Author(s):  
Clement Crochemore ◽  
Claudia Chica ◽  
Paolo Garagnani ◽  
Giovanna Lattanzi ◽  
Steve Horvath ◽  
...  
Keyword(s):  
Genetic Disorders ◽  
Cockayne Syndrome ◽  
Accelerated Ageing ◽  
Physiological Ageing ◽  
Common Features ◽  
New Genes ◽  
Genome Wide ◽  
Healthy Donors ◽  
Normal Ageing ◽  
Transmembrane Transporters

Cockayne syndrome (CS) and UV-sensitivity syndrome (UVSS) are rare genetic disorders caused by mutation of the DNA repair and chromatin remodelling proteins CSA or CSB, but only CS patients display a progeroid and neurodegenerative phenotype. As epigenetic modifications constitute a well-established hallmark of ageing, we characterized genome-wide DNA methylation (DNAm) of fibroblasts from CS versus UVSS patients and healthy donors. The analysis of differentially methylated positions and regions revealed a CS-specific epigenetic signature, enriched in developmental transcription factors, transmembrane transporters, and cell adhesion factors. The CS-specific signature compared to DNAm changes in other progeroid diseases and regular ageing, identifyied commonalities and differences in epigenetic remodelling. CS shares DNAm changes with normal ageing more than other progeroid diseases do, and according to the methylation clock CS samples show up to 13-fold accelerated ageing. Thus, CS is characterized by a specific epigenomic signature that partially overlaps with and exacerbates DNAm changes occurring in physiological aging. Our results unveil new genes and pathways that are potentially relevant for the progeroid/degenerative CS phenotype.

A genome‐wide association study identifies new genes associated with developmental dysplasia of the hip

2019 ◽  
Vol 95 (3) ◽  
pp. 345-355 ◽  
Author(s):  
Wenjin Yan ◽  
Zheng Hao ◽  
Shuyan Tang ◽  
Jin Dai ◽  
Liming Zheng ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Developmental Dysplasia ◽  
Genome Wide Association ◽  
New Genes ◽  
Genome Wide ◽  
A Genome ◽  
Dysplasia Of The Hip

scholarly journals Genome-wide association analysis of chickpea germplasms differing for salinity tolerance based on DArTseq markers

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0260709
Author(s):  
Shaimaa Mahmoud Ahmed ◽  
Alsamman Mahmoud Alsamman ◽  
Abdulqader Jighly ◽  
Mohamed Hassan Mubarak ◽  
Khaled Al-Shamaa ◽  
...  
Keyword(s):  
Association Analysis ◽  
Salinity Tolerance ◽  
Field Experiments ◽  
Agricultural Research ◽  
Gene Annotation ◽  
Genome Wide Association ◽  
Grain Legume ◽  
Genome Wide Association Analysis ◽  
New Genes ◽  
Genome Wide

Soil salinity is significant abiotic stress that severely limits global crop production. Chickpea (Cicer arietinum L.) is an important grain legume that plays a substantial role in nutritional food security, especially in the developing world. This study used a chickpea population collected from the International Center for Agricultural Research in the Dry Area (ICARDA) genebank using the focused identification of germplasm strategy. The germplasm included 186 genotypes with broad Asian and African origins and genotyped with 1856 DArTseq markers. We conducted phenotyping for salinity in the field (Arish, Sinai, Egypt) and greenhouse hydroponic experiments at 100 mM NaCl concentration. Based on the performance in both hydroponic and field experiments, we identified seven genotypes from Azerbaijan and Pakistan (IGs: 70782, 70430, 70764, 117703, 6057, 8447, and 70249) as potential sources for high salinity tolerance. Multi-trait genome-wide association analysis (mtGWAS) detected one locus on chromosome Ca4 at 10618070 bp associated with salinity tolerance under hydroponic and field conditions. In addition, we located another locus specific to the hydroponic system on chromosome Ca2 at 30537619 bp. Gene annotation analysis revealed the location of rs5825813 within the Embryogenesis-associated protein (EMB8-like), while the location of rs5825939 is within the Ribosomal Protein Large P0 (RPLP0). Utilizing such markers in practical breeding programs can effectively improve the adaptability of current chickpea cultivars in saline soil. Moreover, researchers can use our markers to facilitate the incorporation of new genes into commercial cultivars.

scholarly journals Expanding the potential genes of inborn errors of immunity through protein interactions

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Humza A. Khan ◽  
Manish J. Butte
Keyword(s):  
Genetic Variation ◽  
Protein Interactions ◽  
Immune Cell ◽  
Genetic Disorders ◽  
Cell Types ◽  
Protein Protein Interactions ◽  
Inborn Errors ◽  
Post Translational Modifications ◽  
New Genes ◽  
Inborn Errors Of Immunity

Abstract Background Inborn errors of immunity (IEI) are a group of genetic disorders that impair the immune system, with over 400 genes described so far, and hundreds more to be discovered. To facilitate the search for new genes, we need a way to prioritize among all the genes in the genome those most likely to play an important role in immunity. Results Here we identify a new list of genes by linking known IEI genes to new ones by using open-source databases of protein-protein interactions, post-translational modifications, and transcriptional regulation. We analyze this new set of 2,530 IEI-related genes for their tolerance of genetic variation and by their expression levels in various immune cell types. Conclusions By merging genes derived from protein interactions of known IEI genes with transcriptional data, we offer a new list of candidate genes that may play a role in as-yet undiscovered IEIs.

scholarly journals A Tool to Build Up-To-Date Gene Annotations for Affymetrix Microarrays

2017 ◽  
Vol 3 (2) ◽  
pp. 38 ◽  
Author(s):  
Vladislava Milchevskaya ◽  
Grischa Tödt ◽  
Toby James Gibson
Keyword(s):  
Statistical Power ◽  
Gene Annotation ◽  
Clinical Diagnostics ◽  
Specific Gene ◽  
Microarray Probe ◽  
New Genes ◽  
Affymetrix Microarrays ◽  
Genome Wide ◽  
Definition Of ◽  
Genome Annotations

Genome-wide expression profiling and genotyping is widely applied in functional genomics research, ranging from stem cell studies to cancer, in drug response studies, and in clinical diagnostics. The Affymetrix GeneChip microarrays represent the most popular platform for such assays. Nevertheless, due to rapid and continuous improvement of the knowledge about the genome, the definition of many of the genes and transcripts change, and new genes are discovered. Thus the original probe information is out-dated for a number of Affymetrix platforms, and needs to be re-defined. It has been demonstrated, that accurate probe set definition improves both coverage of the gene expression analysis and its statistical power. Therefore we developed a method that incorporates the most recent genome annotations into the annotation of the microarray probe sets, using tools from the next generation sequencing. Additionally our method allows to quickly build project specific gene annotation models, as well as for comparison of microarray to RNAseq data.

scholarly journals DIRC3-IGFBP5 is a shared genetic risk locus and therapeutic target for carpal tunnel syndrome and trigger finger

2021 ◽  
Author(s):  
Benjamin Patel ◽  
Sam O. Kleeman ◽  
Drew Neavin ◽  
Joseph Powell ◽  
Georgios Baskozos ◽  
...  
Keyword(s):  
Carpal Tunnel Syndrome ◽  
Carpal Tunnel ◽  
Genome Wide Association Study ◽  
Trigger Finger ◽  
Eqtl Analysis ◽  
Genome Wide ◽  
Healthy Donors ◽  
A Genome ◽  
Tunnel Syndrome ◽  
Shared Genetic

AbstractTrigger finger (TF) and carpal tunnel syndrome (CTS) are two common non-traumatic hand disorders that frequently co-occur. By identifying TF and CTS cases in UK Biobank (UKB), we confirmed a highly significant phenotypic association between the diseases. To investigate the genetic basis for this association we performed a genome-wide association study (GWAS) including 2,908 TF cases and 436,579 European controls in UKB, identifying five independent loci. Colocalization with CTS summary statistics identified a co-localized locus at DIRC3 (lncRNA), which was replicated in FinnGen and fine-mapped to rs62175241. Single-cell and bulk eQTL analysis in fibroblasts from healthy donors (n=79) and tenosynovium samples from CTS patients (n=77) showed that the disease-protective rs62175241 allele was associated with increased DIRC3 and IGFBP5 expression. IGFBP5 is a secreted antagonist of IGF-1 signaling, and elevated IGF-1 levels were associated with CTS and TF in UKB, thereby implicating IGF-1 as a driver of both diseases.

Impaired adhesion of neutrophils expressing Slc44a2/HNA-3b to VWF protects against NETosis under venous shear rate

Blood ◽  
2021 ◽  
Author(s):  
Gaia Zirka ◽  
Philippe Robert ◽  
Julia Tilburg ◽  
Victoria Tishkova ◽  
Chrissta X Maracle ◽  
...  
Keyword(s):  
Transmembrane Protein ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Wild Type ◽  
Shear Rates ◽  
Extracellular Traps ◽  
Genome Wide ◽  
Healthy Donors ◽  
Von Willebrand ◽  
Willebrand Factor

Genome wide association studies linked expression of the human neutrophil antigen 3b (HNA-3b) epitope on the Slc44a2 protein with a 30% decreased risk of venous thrombosis (VT) in humans. Slc44a2 is a ubiquitous transmembrane protein identified as a receptor for Von Willebrand factor (VWF). To explain the link between Slc44a2 and VT we wanted to determine how Slc44a2 expressing either HNA-3a or HNA-3b on neutrophils could modulate their adhesion and activation on VWF under flow. Transfected HEK293T cells or neutrophils homozygous for the HNA-3a- or the HNA-3b-coding allele were purified from healthy donors and perfused in flow chambers coated with VWF at venous shear rates (100s-1). HNA-3a expression was required for Slc44a2-mediated neutrophil adhesion to VWF at 100s-1. This adhesion could occur independently of β2 integrin and was enhanced when neutrophils are preactivated with lipopolysaccharide (LPS). Moreover, specific shear conditions with high neutrophil concentration could act as a "second hit", inducing the formation of neutrophil extracellular traps. Neutrophil mobilization was also measured by intravital microscopy in venules from SLC44A2-knockout and wild-type mice after histamine-induced endothelial degranulation. Mice lacking Slc44a2 showed a massive reduction in neutrophil recruitment in inflamed mesenteric venules. Our results show that Slc44a2/HNA-3a is important for the adhesion and activation of neutrophils in veins under inflammation and when submitted to specific shears. Neutrophils expressing Slc44a2/HNA-3b not being associated with these observations, these results could thus explain the association between HNA-3b and a reduced risk for VT in humans.

scholarly journals Transcriptomic and Phenotypic Analyses of the Sigma B-Dependent Characteristics and the Synergism between Sigma B and Sigma L in Listeria monocytogenes EGD-e

2020 ◽  
Vol 8 (11) ◽  
pp. 1644
Author(s):  
Mirjami Mattila ◽  
Panu Somervuo ◽  
Hannu Korkeala ◽  
Roger Stephan ◽  
Taurai Tasara
Keyword(s):  
Cold Stress ◽  
Acid Stress ◽  
Cellular Functions ◽  
Phenotypic Analysis ◽  
Double Deletion ◽  
New Genes ◽  
Genome Wide ◽  
Sigma B ◽  
Single Deletion ◽  
Increased Sensitivity

Numerous gene expression and stress adaptation responses in L. monocytogenes are regulated through alternative sigma factors σB and σL. Stress response phenotypes and transcriptomes were compared between L. monocytogenes EGD-e and its ΔsigB and ΔsigBL mutants. Targeted growth phenotypic analysis revealed that the ΔsigB and ΔsigBL mutants are impaired during growth under cold and organic-acid stress conditions. Phenotypic microarrays revealed increased sensitivity in both mutants to various antimicrobial compounds. Genes de-regulated in these two mutants were identified by genome-wide transcriptome analysis during exponential growth in BHI. The ΔsigB and ΔsigBL strains repressed 198 and 254 genes, respectively, compared to the parent EGD-e strain at 3 °C, whereas 86 and 139 genes, respectively, were repressed in these mutants during growth at 37 °C. Genes repressed in these mutants are involved in various cellular functions including transcription regulation, energy metabolism and nutrient transport functions, and viral-associated processes. Exposure to cold stress induced a significant increase in σB and σL co-dependent genes of L. monocytogenes EGD-e since most (62%) of the down-regulated genes uncovered at 3 °C were detected in the ΔsigBL double-deletion mutant but not in ΔsigB or ΔsigL single-deletion mutants. Overall, the current study provides an expanded insight into σB and σL phenotypic roles and functional interactions in L. monocytogenes. Besides previously known σB- and σL-dependent genes, the transcriptomes defined in ΔsigB and ΔsigBL mutants reveal several new genes that are positively regulated by σB alone, as well as those co-regulated through σB- and σL-dependent mechanisms during L. monocytogenes growth under optimal and cold-stress temperature conditions.

scholarly journals Each of 3,323 metabolic innovations in the evolution ofE. coliarose through the horizontal transfer of a single DNA segment

2018 ◽  
Vol 116 (1) ◽  
pp. 187-192 ◽  
Author(s):  
Tin Yau Pang ◽  
Martin J. Lercher
Keyword(s):  
E Coli ◽  
New Genes ◽  
Metabolic Adaptations ◽  
Genome Wide ◽  
A Genome ◽  
Individual Strain ◽  
History Of ◽  
Phenotype Space ◽  
Genome Content ◽  
Metabolic Models

Even closely related prokaryotes often show an astounding diversity in their ability to grow in different nutritional environments. It has been hypothesized that complex metabolic adaptations—those requiring the independent acquisition of multiple new genes—can evolve via selectively neutral intermediates. However, it is unclear whether this neutral exploration of phenotype space occurs in nature, or what fraction of metabolic adaptations is indeed complex. Here, we reconstruct metabolic models for the ancestors of a phylogeny of 53Escherichia colistrains, linking genotypes to phenotypes on a genome-wide, macroevolutionary scale. Based on the ancestral and extant metabolic models, we identify 3,323 phenotypic innovations in the history of theE. coliclade that arose through changes in accessory genome content. Of these innovations, 1,998 allow growth in previously inaccessible environments, while 1,325 increase biomass yield. Strikingly, every observed innovation arose through the horizontal acquisition of a single DNA segment less than 30 kb long. Although we found no evidence for the contribution of selectively neutral processes, 10.6% of metabolic innovations were facilitated by horizontal gene transfers on earlier phylogenetic branches, consistent with a stepwise adaptation to successive environments. Ninety-eight percent of metabolic phenotypes accessible to the combinedE. colipangenome can be bestowed on any individual strain by transferring a single DNA segment from one of the extant strains. These results demonstrate an amazing ability of theE. colilineage to adapt to novel environments through single horizontal gene transfers (followed by regulatory adaptations), an ability likely mirrored in other clades of generalist bacteria.

scholarly journals Genetic Predisposition to Breast and Ovarian Cancers: How Many and Which Genes to Test?

2020 ◽  
Vol 21 (3) ◽  
pp. 1128 ◽  
Author(s):  
Davide Angeli ◽  
Samanta Salvi ◽  
Gianluca Tedaldi
Keyword(s):  
Ovarian Cancer ◽  
Genetic Predisposition ◽  
Genetic Disorders ◽  
Molecular Techniques ◽  
Ovarian Cancer Risk ◽  
Brca1 And Brca2 ◽  
New Genes ◽  
Ovarian Cancers ◽  
Genes Encoding ◽  
Predisposition Genes

Breast and ovarian cancers are some of the most common tumors in females, and the genetic predisposition is emerging as one of the key risk factors in the development of these two malignancies. BRCA1 and BRCA2 are the best-known genes associated with hereditary breast and ovarian cancer. However, recent advances in molecular techniques, Next-Generation Sequencing in particular, have led to the identification of many new genes involved in the predisposition to breast and/or ovarian cancer, with different penetrance estimates. TP53, PTEN, STK11, and CDH1 have been identified as high penetrance genes for the risk of breast/ovarian cancers. Besides them, PALB2, BRIP1, ATM, CHEK2, BARD1, NBN, NF1, RAD51C, RAD51D and mismatch repair genes have been recognized as moderate and low penetrance genes, along with other genes encoding proteins involved in the same pathways, possibly associated with breast/ovarian cancer risk. In this review, we summarize the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and the associated genetic disorders. Furthermore, we discuss the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches.

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