Bistability in Apoptosis by Receptor Clustering

Apoptosis is a highly regulated cell death mechanism involved in many physiological processes. A key component of extrinsically activated apoptosis is the death receptor Fas, which, on binding to its cognate ligand FasL, oligomerize to form the death-inducing signaling complex. Motivated by recent experimental data, we propose a mathematical model of death ligand-receptor dynamics where FasL acts as a clustering agent for Fas, which form locally stable signaling platforms through proximity-induced receptor interactions. Significantly, the model exhibits hysteresis, providing an upstream mechanism for bistability and robustness. At low receptor concentrations, the bistability is contingent on the trimerism of FasL. Moreover, irreversible bistability, representing a committed cell death decision, emerges at high concentrations, which may be achieved through receptor pre-association or localization onto membrane lipid rafts. Thus, our model provides a novel theory for these observed biological phenomena within the unified context of bistability. Importantly, as Fas interactions initiate the extrinsic apoptotic pathway, our model also suggests a mechanism by which cells may function as bistable life/death switches independently of any such dynamics in their downstream components. Our results highlight the role of death receptors in deciding cell fate and add to the signal processing capabilities attributed to receptor clustering.Comment: Accepted by PLoS Comput Bio

Inclusion of diverse populations in genomic research and health services: Genomix workshop report

Clinical genetic services and genomic research are rapidly developing but, historically, those with the greatest need are the least to benefit from these advances. This encompasses low-income communities, including those from ethnic minority and indigenous backgrounds. The “Genomix” workshop at the European Society of Human Genetics (ESHG) 2016 conference offered the opportunity to consider possible solutions for these disparities from the experiences of researchers and genetic healthcare practitioners working with underserved communities in the USA, UK and Australia. Evident from the workshop and corresponding literature is that a multi-faceted approach to engaging communities is essential. This needs to be complemented by redesigning healthcare systems that improves access and raises awareness of the needs of these communities. At a more strategic level, institutions involved in funding research, commissioning and redesigning genetic health services also need to be adequately represented by underserved populations with intrinsic mechanisms to disseminate good practice and monitor participation. Further, as genomic medicine is mainstreamed, educational programmes developed for clinicians should incorporate approaches to alleviate disparities in accessing genetic services and improving study participation

Prospective functional classification of all possible missense variants in PPARG.

Clinical exome sequencing routinely identifies missense variants in disease-related genes, but functional characterization is rarely undertaken, leading to diagnostic uncertainty. For example, mutations in PPARG cause Mendelian lipodystrophy and increase risk of type 2 diabetes (T2D). Although approximately 1 in 500 people harbor missense variants in PPARG, most are of unknown consequence. To prospectively characterize PPARγ variants, we used highly parallel oligonucleotide synthesis to construct a library encoding all 9,595 possible single-amino acid substitutions. We developed a pooled functional assay in human macrophages, experimentally evaluated all protein variants, and used the experimental data to train a variant classifier by supervised machine learning. When applied to 55 new missense variants identified in population-based and clinical sequencing, the classifier annotated 6 variants as pathogenic; these were subsequently validated by single-variant assays. Saturation mutagenesis and prospective experimental characterization can support immediate diagnostic interpretation of newly discovered missense variants in disease-related genes.This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (1K08DK102877-01, to A.R.M.; 1R01DK097768-01, to D.A.), NIH/Harvard Catalyst (1KL2TR001100-01, to A.R.M.), the Broad Institute (SPARC award, to A.R.M. and T.M.), and the Wellcome Trust (095564, to K.C.; 107064, to D.B.S.).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.370

The Medical Genome Reference Bank contains whole genome and phenotype data of 2570 healthy elderly

Population health research is increasingly focused on the genetic determinants of healthy ageing, but there is no public resource of whole genome sequences and phenotype data from healthy elderly individuals. Here we describe the first release of the Medical Genome Reference Bank (MGRB), comprising whole genome sequence and phenotype of 2570 elderly Australians depleted for cancer, cardiovascular disease, and dementia. We analyse the MGRB for single-nucleotide, indel and structural variation in the nuclear and mitochondrial genomes. MGRB individuals have fewer disease-associated common and rare germline variants, relative to both cancer cases and the gnomAD and UK Biobank cohorts, consistent with risk depletion. Age-related somatic changes are correlated with grip strength in men, suggesting blood-derived whole genomes may also provide a biologic measure of age-related functional deterioration. The MGRB provides a broadly applicable reference cohort for clinical genetics and genomic association studies, and for understanding the genetics of healthy ageing

Occult Metabolic Bone Disease in Chronic Pancreatitis

Background: Chronic pancreatitis (CP) leads to malabsorption and metabolic bone disease (MBD). Alcoholic CP (ACP) and tropical CP (TCP) are the two common types of CP. Objective: We investigated the presence of occult MBD in patients with CP and compared the same between ACP and TCP. Materials and Methods: In this cross‑sectional, observational study, we included serial patients of CP in different stages and are grouped as ACP (Group 1; n = 67) and TCP (Group 2; n = 35). We determined serum calcium, phosphorus, alkaline phosphatase, 25‑hydroxyvitamin D (25OHD), and intact parathyroid hormone (PTH) levels. Bone mineral density (BMD) was measured by dual‑energy X‑ray absorptiometry in the neck of the left femur. MBD was defined by the presence of either low bone mass (Z‑score <−2) or osteomalacia. The results were analyzed using appropriate statistical methods. Results: The study participants (85 males; 17 females) had a mean age of 40.8 ± 12.6 years, CP duration of 3.7 ± 4.7 years, and Body Mass Index of 22.5 ± 3.2 kg/m2. A total of 37 (36%) patients had MBD (osteomalacia in 31 and low bone mass in 6). The frequency of MBD was same in the TCP (16/35) and ACP (21/65) groups (P = 0.1940). Elevated PTH (>70 pg/mL) was seen in 14 patients with 25OHD deficiency and low calcium (<8.5 mg/dL) in 29 patients. BMD did not show a significant correlation with the duration of CP. Conclusion: Occult MBD is seen in a third of patients with CP and is similar irrespective of the etiology. The disease is silent and mandates active screening in all susceptible individuals.Keywords: Chronic pancreatitis, metabolic bone disease, osteomalacia, osteopenia, osteoporosi

Comparisons of polyexposure, polygenic, and clinical risk scores in risk prediction of type 2 diabetes

OBJECTIVE: To establish a polyexposure score (PXS) for type 2 diabetes (T2D) incorporating 12 nongenetic exposures and examine whether a PXS and/or a polygenic risk score (PGS) improves diabetes prediction beyond traditional clinical risk factors. RESEARCH DESIGN AND METHODS: We identified 356,621 unrelated individuals from the UK Biobank of White British ancestry with no prior diagnosis of T2D and normal HbA1c levels. Using self-reported and hospital admission information, we deployed a machine learning procedure to select the most predictive and robust factors out of 111 nongenetically ascertained exposure and lifestyle variables for the PXS in prospective T2D. We computed the clinical risk score (CRS) and PGS by taking a weighted sum of eight established clinical risk factors and >6 million single nucleotide polymorphisms, respectively. RESULTS: In the study population, 7,513 had incident T2D. The C-statistics for the PGS, PXS, and CRS models were 0.709, 0.762, and 0.839, respectively. Individuals in the top 10% of PGS, PXS, and CRS had 2.00-, 5.90-, and 9.97-fold greater risk, respectively, compared to the remaining population. Addition of PGS and PXS to CRS improved T2D classification accuracy, with a continuous net reclassification index of 15.2% and 30.1% for cases, respectively, and 7.3% and 16.9% for controls, respectively. CONCLUSIONS: For T2D, the PXS provides modest incremental predictive value over established clinical risk factors. However, the concept of PXS merits further consideration in T2D risk stratification and is likely to be useful in other chronic disease risk prediction models