Postzygotic single-nucleotide mutations (pSNMs) have been studied in cancer and a few other overgrowth human disorders at whole-genome scale and found to play critical roles. However, in clinically unremarkable individuals, pSNMs have never been identified at whole-genome scale largely due to technical difficulties and lack of matched control tissue samples, and thus the genome-wide characteristics of pSNMs remain unknown. We developed a new Bayesian-based mosaic genotyper and a series of effective error filters, using which we were able to identify 17 SNM sites from ∼80× whole-genome sequencing of peripheral blood DNAs from three clinically unremarkable adults. The pSNMs were thoroughly validated using pyrosequencing, Sanger sequencing of individual cloned fragments, and multiplex ligation-dependent probe amplification. The mutant allele fraction ranged from 5%-31%. We found that C→T and C→A were the predominant types of postzygotic mutations, similar to the somatic mutation profile in tumor tissues. Simulation data showed that the overall mutation rate was an order of magnitude lower than that in cancer. We detected varied allele fractions of the pSNMs among multiple samples obtained from the same individuals, including blood, saliva, hair follicle, buccal mucosa, urine, and semen samples, indicating that pSNMs could affect multiple sources of somatic cells as well as germ cells. Two of the adults have children who were diagnosed with Dravet syndrome. We identified two non-synonymous pSNMs in SCN1A, a causal gene for Dravet syndrome, from these two unrelated adults and found that the mutant alleles were transmitted to their children, highlighting the clinical importance of detecting pSNMs in genetic counseling.
A series of aromatic amides incorporated with N-heterocycles or triptycene units are synthesized and studied for probing the effects of such chemical modifications on the intermolecular interactions. Single crystals of a number of heterocyclic amides and the triptycene-containing amide were obtained. Crystal structures, hydrogen bonds, lattice energy, solubility, and melting points were compared amongst relevant molecules. Suitably positioned nitrogen atoms from heterocycles are found to form intramolecular H-bonds with amide NHs at the expense of weakening or disrupting the intermolecular H-bonds. The effects of such H-bonding changes on solubility and melting point are nonetheless limited. Uniquely, the triptycene unit effectively improves the solubility of the amide without tempering the thermal resistance of the molecule.
China is confronting the challenge of accelerated lake eutrophication, where Lake Dianchi is considered as the most serious one. Eutrophication control for Lake Dianchi began in the mid-1980s. However, decision makers have been puzzled by the lack of visible water quality response to past efforts given the tremendous investment. Therefore, decision makers desperately need a scientifically sound way to quantitatively evaluate the response of lake water quality to proposed management measures and engineering works. We used a water quality modeling based scenario analysis approach to quantitatively evaluate the eutrophication responses of Lake Dianchi to an under-construction water diversion project. The primary analytic framework was built on a three-dimensional hydrodynamic, nutrient fate and transport, as well as algae dynamics model, which has previously been calibrated and validated using historical data. We designed 16 scenarios to analyze the water quality effects of three driving forces, including watershed nutrient loading, variations in diverted inflow water, and lake water level. A two-step statistical analysis consisting of an orthogonal test analysis and linear regression was then conducted to distinguish the contributions of various driving forces to lake water quality. The analysis results show that (a) the different ways of managing the diversion projects would result in different water quality response in Lake Dianchi, though the differences do not appear to be significant; (b) the maximum reduction in annual average and peak Chl-a concentration from the various ways of diversion project operation are respectively 11% and 5%; (c) a combined 66% watershed load reduction and water diversion can eliminate the lake hypoxia volume percentage from the existing 6.82% to 3.00%; and (d) the water diversion will decrease the occurrence of algal blooms, and the effect of algae reduction can be enhanced if diverted water are seasonally allocated such that wet season has more flows. (C) 2013 Elsevier B.V. All rights reserved.