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The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world(1). Here we describe the release of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, includingPIEZO1on varicose veins,COL6A1on corneal resistance,MEPEon bone density, andIQGAP2andGMPRon blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenicBRCA1andBRCA2variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community. <br /> Exome sequences from the first 49,960 participants in the UK Biobank highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.
Permafrost-related processes drive regional landscape dynamics in the Arctic terrestrial system. A better understanding of past periods indicative of permafrost degradation and aggradation is important for predicting the future response of Arctic landscapes to climate change. Here, we used a multi-proxy approach to analyse a4m long sediment core from a drained thermokarst lake basin on the northern Seward Peninsula in western Arctic Alaska (USA). Sedimentological, biogeochemical, geochronological, micropalaeontological (ostracoda, testate amoebae) and tephra analyses were used to determine the long-term environmental Early-Wisconsin to Holocene history preserved in our core for central Beringia. Yedoma accumulation dominated throughout the Early to Late-Wisconsin but was interrupted by wetland formation from 44.5 to 41.5ka BP. The latter was terminated by the deposition of 1m of volcanic tephra, most likely originating from the South Killeak Maar eruption at about 42ka BP. Yedoma deposition continued until 22.5ka BP and was followed by a depositional hiatus in the sediment core between 22.5 and 0.23ka BP. We interpret this hiatus as due to intense thermokarst activity in the areas surrounding the site, which served as a sediment source during the Late-Wisconsin to Holocene climate transition. The lake forming the modern basin on the upland initiated around 0.23ka BP and drained catastrophically in spring 2005. The present study emphasises that Arctic lake systems and periglacial landscapes are highly dynamic and that permafrost formation as well as degradation in central Beringia was controlled by regional to global climate patterns as well as by local disturbances. Copyright (c) 2015 John Wiley & Sons, Ltd.