TY - JOUR A1 - Van Hout, Cristopher V. A1 - Tachmazidou, Ioanna A1 - Backman, Joshua D. A1 - Hoffman, Joshua D. A1 - Liu, Daren A1 - Pandey, Ashutosh K. A1 - Gonzaga-Jauregui, Claudia A1 - Khalid, Shareef A1 - Ye, Bin A1 - Banerjee, Nilanjana A1 - Li, Alexander H. A1 - O'Dushlaine, Colm A1 - Marcketta, Anthony A1 - Staples, Jeffrey A1 - Schurmann, Claudia A1 - Hawes, Alicia A1 - Maxwell, Evan A1 - Barnard, Leland A1 - Lopez, Alexander A1 - Penn, John A1 - Habegger, Lukas A1 - Blumenfeld, Andrew L. A1 - Bai, Xiaodong A1 - O'Keeffe, Sean A1 - Yadav, Ashish A1 - Praveen, Kavita A1 - Jones, Marcus A1 - Salerno, William J. A1 - Chung, Wendy K. A1 - Surakka, Ida A1 - Willer, Cristen J. A1 - Hveem, Kristian A1 - Leader, Joseph B. A1 - Carey, David J. A1 - Ledbetter, David H. A1 - Cardon, Lon A1 - Yancopoulos, George D. A1 - Economides, Aris A1 - Coppola, Giovanni A1 - Shuldiner, Alan R. A1 - Balasubramanian, Suganthi A1 - Cantor, Michael A1 - Nelson, Matthew R. A1 - Whittaker, John A1 - Reid, Jeffrey G. A1 - Marchini, Jonathan A1 - Overton, John D. A1 - Scott, Robert A. A1 - Abecasis, Goncalo R. A1 - Yerges-Armstrong, Laura M. A1 - Baras, Aris T1 - Exome sequencing and characterization of 49,960 individuals in the UK Biobank JF - Nature : the international weekly journal of science N2 - 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.
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. KW - clinical exome KW - breast-cancer KW - mutations KW - recommendations KW - gene KW - metaanalysis KW - variants, KW - BRCA1 KW - risk KW - susceptibility Y1 - 2020 U6 - https://doi.org/10.1038/s41586-020-2853-0 SN - 0028-0836 SN - 1476-4687 VL - 586 IS - 7831 SP - 749 EP - 756 PB - Macmillan Publishers Limited CY - London ER - TY - JOUR A1 - Brooke, Sam A. S. A1 - Whittaker, Alexander C. A1 - Armitage, John J. A1 - Watkins, Stephen E. A1 - D'Arcy, Mitchell T1 - Quantifying sediment transport dynamics on alluvial fans from spatial and temporal changes in Grain Size, Death Valley, California JF - Journal of geophysical research : Earth surface N2 - How information about sediment transport processes is transmitted to the sedimentary record remains a complex problem for the interpretation of fluvial stratigraphy. Alluvial fan deposits represent the condensed archive of sediment transport, which is at least partly controlled by tectonics and climate. For three coupled catchment-fan systems in northern Death Valley, California, we measure grain size across 12 well-preserved Holocene and late-Pleistocene surfaces, mapped in detail from field observations and remote sensing. Our results show that fan surfaces correlated to the late Pleistocene are, on average, 30-50% coarser than active or Holocene fan surfaces. We adopt a self-similar form of grain size distribution based on the observed stability of the ratio between mean grain size and standard deviation downstream. Using statistical analysis, we show that fan surface grain size distributions are self-similar. We derive a relative mobility function using our self-similar grain size distributions, which describes the relative probability of a given grain size being transported. We show that the largest mobile grain sizes are between 20 and 35mm, a value that varies over time and is clearly lower in the Holocene than in the Pleistocene; a change we suggest is due to a drier climate in the Holocene. These results support recent findings that alluvial fan sedimentology can record past environmental change and that these landscapes are potentially sensitive to climatic change over a glacial-interglacial cycle. We demonstrate that the self-similarity methodology offers a means to explore changes in relative mobility of grain sizes from preserved fluvial deposits. Plain Language Summary A key challenge in Earth Science is understanding how landscapes respond to climate. It may be possible to observe measurable differences in certain landscapes settings such as alluvial fans in desert regions. Alluvial fans are believed to be effective recorders of climate, representing a cumulative store of material transported downstream by rainfall-sensitive river systems. In northern Death Valley, California, we measure at high resolution grain size on three alluvial fans with surfaces that date from the Holocene and the arid climate of today to the 20-40% wetter late-Pleistocene epoch. We find that older late-Pleistocene surfaces are coarser on average than surfaces deposited during the modern and Holocene dry period, suggesting a changing sediment transport regime potentially in response to precipitation. We also show that measured grain size distributions within and between surfaces can be successfully normalized based on the decay in mean grain size and variance downstream, exhibiting a self-similar pattern. Finally, we employ a grain size relative mobility model using our field data to establish which grain sizes are likely to be in transport or locked in the substrate. This model predicts that during the wetter late-Pleistocene mobile grain sizes are up to 40% larger than during the Holocene. KW - alluvial fans KW - grain size KW - sediment transport KW - self-similarity KW - fluvial geomorphology KW - Death Valley Y1 - 2018 U6 - https://doi.org/10.1029/2018JF004622 SN - 2169-9003 SN - 2169-9011 VL - 123 IS - 8 SP - 2039 EP - 2067 PB - American Geophysical Union CY - Washington ER -