A genomic atlas of systemic interindividual epigenetic variation in humans

BACKGROUND: DNA methylation is thought to be an important determinant of human phenotypic variation, but its inherent cell type specificity has impeded progress on this question. At exceptional genomic regions, interindividual variation in DNA methylation occurs systemically. Like genetic variants, systemic interindividual epigenetic variants are stable, can influence phenotype, and can be assessed in any easily biopsiable DNA sample. We describe an unbiased screen for human genomic regions at which interindividual variation in DNA methylation is not tissue-specific. RESULTS: For each of 10 donors from the NIH Genotype-Tissue Expression (GTEx) program, CpG methylation is measured by deep whole-genome bisulfite sequencing of genomic DNA from tissues representing the three germ layer lineages: thyroid (endoderm), heart (mesoderm), and brain (ectoderm). We develop a computational algorithm to identify genomic regions at which interindividual variation in DNA methylation is consistent across all three lineages. This approach identifies 9926 correlated regions of systemic interindividual variation (CoRSIVs). These regions, comprising just 0.1% of the human genome, are inter-correlated over long genomic distances, associated with transposable elements and subtelomeric regions, conserved across diverse human ethnic groups, sensitive to periconceptional environment, and associated with genes implicated in a broad range of human disorders and phenotypes. CoRSIV methylation in one tissue can predict expression of associated genes in other tissues. CONCLUSIONS: In addition to charting a previously unexplored molecular level of human individuality, this atlas of human CoRSIVs provides a resource for future population-based investigations into how interindividual epigenetic variation modulates risk of disease

Position Detecting Module

Senate Research Gran

Position detecting module

SRC/ST/2009/4

Tissue-specific expression and dimerization of the endoplasmic reticulum oxidoreductase Erolb

Endoplasmic reticulum oxidoreductases (Eros) are essential for the formation of disulfide bonds. Understanding disulfide bond catalysis in mammals is important because of the involvement of protein misfolding in conditions such as diabetes, arthritis, cancer, and aging. Mammals express two related Ero proteins, Ero1 and Ero1. Ero1 is incompletely characterized but is of physiological interest because it is induced by the unfolded protein response. Here, we show that Ero1 can form homodimers and mixed heterodimers with Ero1, in addition to Ero-PDI dimers. Ero-Ero dimers require the Ero active site, occur in vivo, and can be modeled onto the Ero1p crystal structure. Our data indicate that the Ero1 protein is constitutively strongly expressed in the stomach and the pancreas, but in a cell-specific fashion. In the stomach, selective expression of Ero1 occurs in the enzyme-producing chief cells. In pancreatic islets, Ero1 expression is high, but is inversely correlated with PDI and PDIp levels, demonstrating that cell-specific differences exist in the regulation of oxidative protein folding in vivo

A data platform to improve rabies prevention, Sri Lanka.

Problem In Sri Lanka, rabies prevention initiatives are hindered by fragmented and delayed information-sharing that limits clinicians’ ability to follow patients and impedes public health surveillance. Approach In a project led by the health ministry, we adapted existing technologies to create an electronic platform for rabies surveillance. Information is entered by trained clinical staff, and both aggregate and individual patient data are visualized in real time. An automated short message system (SMS) alerts patients for vaccination follow-up appointments and informs public health inspectors about incidents of animal bites. Local setting The platform was rolled out in June 2016 in four districts of Sri Lanka, linking six rabies clinics, three laboratories and the public health inspectorate. Relevant changes Over a 9-month period, 12 121 animal bites were reported to clinics and entered in the registry. Via secure portals, clinicians and public health teams accessed live information on treatment and outcomes of patients started on post-exposure prophylaxis (9507) or receiving deferred treatment (2614). Laboratories rapidly communicated the results of rabies virus tests on dead mammals (328/907 positive). In two pilot districts SMS reminders were sent to 1376 (71.2%) of 1933 patients whose contact details were available. Daily SMS reports alerted 17 public health inspectors to bite incidents in their area for investigation. Lessons learnt Existing technologies in low-resource countries can be harnessed to improve public health surveillance. Investment is needed in platform development and training and support for front-line staff. Greater public engagement is needed to improve completeness of surveillance and treatment.</p

A data platform to improve rabies prevention, Sri Lanka.

Problem In Sri Lanka, rabies prevention initiatives are hindered by fragmented and delayed information-sharing that limits clinicians’ ability to follow patients and impedes public health surveillance. Approach In a project led by the health ministry, we adapted existing technologies to create an electronic platform for rabies surveillance. Information is entered by trained clinical staff, and both aggregate and individual patient data are visualized in real time. An automated short message system (SMS) alerts patients for vaccination follow-up appointments and informs public health inspectors about incidents of animal bites. Local setting The platform was rolled out in June 2016 in four districts of Sri Lanka, linking six rabies clinics, three laboratories and the public health inspectorate. Relevant changes Over a 9-month period, 12 121 animal bites were reported to clinics and entered in the registry. Via secure portals, clinicians and public health teams accessed live information on treatment and outcomes of patients started on post-exposure prophylaxis (9507) or receiving deferred treatment (2614). Laboratories rapidly communicated the results of rabies virus tests on dead mammals (328/907 positive). In two pilot districts SMS reminders were sent to 1376 (71.2%) of 1933 patients whose contact details were available. Daily SMS reports alerted 17 public health inspectors to bite incidents in their area for investigation. Lessons learnt Existing technologies in low-resource countries can be harnessed to improve public health surveillance. Investment is needed in platform development and training and support for front-line staff. Greater public engagement is needed to improve completeness of surveillance and treatment.</p