Genetic dissection of diabetes: facing the giant.
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ABSTRACT:
SUBMITTER: Meyre D
PROVIDER: S-EPMC3781438 | biostudies-literature | 2013 Oct
REPOSITORIES: biostudies-literature
Publications
Genetic dissection of diabetes: facing the giant.
Meyre David D Pare Guillaume G
Diabetes 20131001 10
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Project description:Congenic DRF.(f/f) rats are protected from type 1 diabetes (T1D) by 34 Mb of F344 DNA introgressed proximal to the gimap5 lymphopenia gene. To dissect the genetic factor(s) that confer protection from T1D in the DRF.(f/f) rat line, DRF.(f/f) rats were crossed to inbred BBDR or DR.(lyp/lyp) rats to generate congenic sublines that were genotyped and monitored for T1D, and positional candidate genes were sequenced. All (100%) DR.(lyp/lyp) rats developed T1D by 83 days of age. Reduction of the DRF.(f/f) F344 DNA fragment by 26 Mb (42.52-68.51 Mb) retained complete T1D protection. Further dissection revealed that a 2 Mb interval of F344 DNA (67.41-70.17 Mb) (region 1) resulted in 47% protection and significantly delayed onset (P < 0.001 compared with DR.(lyp/lyp)). Retaining <1 Mb of F344 DNA at the distal end (76.49-76.83 Mb) (region 2) resulted in 28% protection and also delayed onset (P < 0.001 compared with DR.(lyp/lyp)). Comparative analysis of diabetes frequency in the DRF.(f/f) congenic sublines further refined the RNO4 region 1 interval to approximately 670 kb and region 2 to the 340 kb proximal to gimap5. All congenic DRF.(f/f) sublines were prone to low-grade pancreatic mononuclear cell infiltration around ducts and vessels, but <20% of islets in nondiabetic rats showed islet infiltration. Coding sequence analysis revealed TCR Vbeta 8E, 12, and 13 as candidate genes in region 1 and znf467 and atp6v0e2 as candidate genes in region 2. Our results show that spontaneous T1D is controlled by at least two genetic loci 7 Mb apart on rat chromosome 4.
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Project description:We performed gene expression studies in worker bees displaying quantitative genetic differences in hygienic behavior derived from backcrosses. We established hybrid queens and backcrossed to high and low performing hygienic behavioral sources and scored the hygienic behavior of single worker bees under same environmental conditions.
2016-03-31 | E-MTAB-4142 | biostudies-arrayexpress
Project description:BackgroundThis Mendelian randomization (MR) study aimed to explore the causal relationship between the genetic predisposition to type 2 diabetes mellitus (T2DM) and aortic dissection (AD), and to assess associations with genetically predicted glycemic traits. The study sought to verify the inverse relationship between T2DM and AD using a more robust and unbiased method, building on the observational studies previously established.Materials and methodsThe study employed a two-sample and multivariable MR approach to analyze genetic data from the DIAbetes Meta-ANalysis of Trans-Ethnic association studies (DIAMANTE) with 74,124 cases and 824,006 controls, and the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) involving up to 196,991 individuals. For AD data, FinnGen Release 10 was used, including 967 cases and 381,977 controls. The research focused on three foundational MR assumptions and controlled for confounders like hypertension. Genetic instruments were selected for their genome-wide significance, and multiple MR methods and sensitivity analyses were conducted.ResultsThe study revealed no significant effect of genetic predisposition to T2DM on the risk of AD. Even after adjusting for potential confounders, the results were consistent, indicating no causal relationship. Additionally, glycemic traits such as fasting glucose, fasting insulin, and HbA1c levels did not show a significant impact on AD susceptibility. The findings remained stable across various MR models and sensitivity analyses. In contrast, genetic liability to T2DM and glycemic traits showed a significant association with coronary artery disease (CAD), aligning with the established understanding.ConclusionContrary to previous observational studies, this study concludes that genetic predisposition to T2DM does not confer protection against AD. These findings underscore the imperative for further research, particularly in exploring the preventative potential of T2DM treatments against AD and to facilitate the development of novel therapeutic interventions.
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Project description:The present work was devoted to a multi-level characterization of E. coli exposed to Ag+-mediated stress using for the first time an approach of integrative biology, based on the combination of physiological, biochemical and transcriptomic data sets. Bacterial growth and survival after Ag+ exposure were first quantified and related to the accumulation of intracellular silver, as detected by Nano Secondary Ion Mass Spectroscopy (NanoSIMS) at high lateral resolution. The whole transcriptomic response of E. coli cells under ionic silver-mediated stress was then characterized. Clear correlations were established between (i) cell physiology, (ii) variations in the biochemical characteristics of cell fatty acids and proteins, and (iii) regulation of gene expression. This challenging approach allowed determining key genetic markers of the E. coli response to ionic silver. In particular, we identified Ag+-mediated regulations of gene expression in correlation with growth (e.g. genes of transporters, transcriptional regulators, ribosomal proteins), necessary for ionic silver transport and detoxification (e.g. copA, cueO, mgtA, nhaR) and to cope with various stress (dnaK, pspA, metA,R, oxidoreductase genes). Regulation of gene expression after Ag+ exposure was also correlated to macromolecular modifications, such as acyl chain length (e.g. fadL, lpxA, arnA), protein secondary structure (e.g. dnaJ, htpX, degP) and cell morphology (e.g. ycfS, ycbB).
2017-02-09 | GSE67735 | GEO
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Project description:Knowledge of the fascinating world of DNA repeats is continuously being enriched by newly identified elements and their hypothetical or well-established biological relevance. Genomic approaches can be used for comparative studies of major repeats in any group of genomes, regardless of their size and complexity. Such studies are particularly fruitful in large genomes, and useful mainly in crop plants where they provide a rich source of molecular markers or information on indispensable genomic components (e.g., telomeres, centromeres, or ribosomal RNA genes). Surprisingly, in Allium species, a comprehensive comparative study of repeats is lacking. Here we provide such a study of two economically important species, Allium cepa (onion), and A. sativum (garlic), and their distantly related A. ursinum (wild garlic). We present an overview and classification of major repeats in these species and have paid specific attention to sequence conservation and copy numbers of major representatives in each type of repeat, including retrotransposons, rDNA, or newly identified satellite sequences. Prevailing repeats in all three studied species belonged to Ty3/gypsy elements, however they significantly diverged and we did not detect them in common clusters in comparative analysis. Actually, only a low number of clusters was shared by all three species. Such conserved repeats were for example 5S and 45S rDNA genes and surprisingly a specific and quite rare Ty1/copia lineage. Species-specific long satellites were found mainly in A. cepa and A. sativum. We also show in situ localization of selected repeats that could potentially be applicable as chromosomal markers, e.g., in interspecific breeding.
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2016-06-02 | E-GEOD-78835 | biostudies-arrayexpress
Project description:Interferons (IFNs) are cytokines that play a key role in innate and adaptive immune responses. Despite the large number of immunological studies of these molecules, the relative contributions of the numerous IFNs to human survival remain largely unknown. Here, we evaluated the extent to which natural selection has targeted the human IFNs and their receptors, to provide insight into the mechanisms that govern host defense in the natural setting. We found that some IFN-? subtypes, such as IFN-?6, IFN-?8, IFN-?13, and IFN-?14, as well as the type II IFN-?, have evolved under strong purifying selection, attesting to their essential and nonredundant function in immunity to infection. Conversely, selective constraints have been relaxed for other type I IFNs, particularly for IFN-?10 and IFN-?, which have accumulated missense or nonsense mutations at high frequencies within the population, suggesting redundancy in host defense. Finally, type III IFNs display geographically restricted signatures of positive selection in European and Asian populations, indicating that genetic variation at these genes has conferred a selective advantage to the host, most likely by increasing resistance to viral infection. Our population genetic analyses show that IFNs differ widely in their biological relevance, and highlight evolutionarily important determinants of host immune responsiveness.
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