Background: Non-coding genetic variants that influence gene transcription in pancreatic islets play a major role in the susceptibility to type 2 diabetes (T2D), and likely also contribute to type 1... Show moreBackground: Non-coding genetic variants that influence gene transcription in pancreatic islets play a major role in the susceptibility to type 2 diabetes (T2D), and likely also contribute to type 1 diabetes (T1D) risk. For many loci, however, the mechanisms through which non-coding variants influence diabetes susceptibility are unknown. Results: We examine splicing QTLs (sQTLs) in pancreatic islets from 399 human donors and observe that common genetic variation has a widespread influence on the splicing of genes with established roles in islet biology and diabetes. In parallel, we profile expression QTLs (eQTLs) and use transcriptome-wide association as well as genetic co-localization studies to assign islet sQTLs or eQTLs to T2D and T1D susceptibility signals, many of which lack candidate effector genes. This analysis reveals biologically plausible mechanisms, including the association of T2D with an sQTL that creates a nonsense isoform in ERO1B, a regulator of ER-stress and proinsulin biosynthesis. The expanded list of T2D risk effector genes reveals overrepresented pathways, including regulators of G-protein-mediated cAMP production. The analysis of sQTLs also reveals candidate effector genes for T1D susceptibility such as DCLRE1B, a senescence regulator, and lncRNA MEG3. Conclusions: These data expose widespread effects of common genetic variants on RNA splicing in pancreatic islets. The results support a role for splicing variation in diabetes susceptibility, and offer a new set of genetic targets with potential therapeutic benefit. Show less
Tropical mountains are hot spots of biodiversity and endemism,but the evolutionary origins of their unique biotas are poorlyunderstood. In varying degrees, local and regional extinction,long... Show moreTropical mountains are hot spots of biodiversity and endemism,but the evolutionary origins of their unique biotas are poorlyunderstood. In varying degrees, local and regional extinction,long-distance colonization, and local recruitment may all contribute to the exceptional character of these communities. Also, it isdebated whether mountain endemics mostly originate from locallowland taxa, or from lineages that reach the mountain by long-range dispersal from cool localities elsewhere. Here we investigatethe evolutionary routes to endemism by sampling an entire tropical mountain biota on the 4,095-metre-high Mount Kinabalu inSabah, East Malaysia. We discover that most of its unique biodiversity is younger than the mountain itself (6 million years), andcomprises a mix of immigrant pre-adapted lineages and descendants from local lowland ancestors, although substantial shiftsfrom lower to higher vegetation zones in this latter group wererare. These insights could improve forecasts of the likelihood ofextinction and ‘evolutionary rescue in montane biodiversity hotspots under climate change scenarios. Show less
