Population genomics of East Asian ethnic groups.

East Asia constitutes one-fifth of the global population and exhibits substantial genetic diversity. However, genetic investigations on populations in this region have been largely under-represented compared with European populations. Nonetheless, the last decade has seen considerable efforts and progress in genome-wide genotyping and whole-genome sequencing of the East-Asian ethnic groups. Here, we review the recent studies in terms of ancestral origin, population relationship, genetic differentiation, and admixture of major East- Asian groups, such as the Chinese, Korean, and Japanese populations. We mainly focus on insights from the whole-genome sequence data and also include the recent progress based on mitochondrial DNA (mtDNA) and Y chromosome data. We further discuss the evolutionary forces driving genetic diversity in East-Asian populations, and provide our perspectives for future directions on population genetics studies, particularly on underrepresented indigenous groups in East Asia.

Genotype Representation Graphs: Enabling Efficient Analysis of Biobank-Scale Data.

Computational analysis of a large number of genomes requires a data structure that can represent the dataset compactly while also enabling efficient operations on variants and samples. Current practice is to store large-scale genetic polymorphism data using tabular data structures and file formats, where rows and columns represent samples and genetic variants. However, encoding genetic data in such formats has become unsustainable. For example, the UK Biobank polymorphism data of 200,000 phased whole genomes has exceeded 350 terabytes (TB) in Variant Call Format (VCF), too large to fit into hard drives in uncompressed form. To mitigate the computational burden, we introduce the Genotype Representation Graph (GRG), an extremely compact data structure to losslessly present phased whole-genome polymorphisms. A GRG is a fully connected hierarchical graph that exploits variant-sharing across samples, leveraging on ideas inspired by Ancestral Recombination Graphs. Capturing variant-sharing in a graph format compresses biobank-scale data to the point where it can fit in a typical server's RAM (5-26GB per chromosome), and enables graph-traversal algorithms to trivially reuse computed values, both of which can significantly reduce computation time. We have developed a command-line tool and a library usable via both C++ and Python for constructing and processing GRG files which scales to a million whole genomes. It takes 160GB disk space to encode the information in 200,000 UK Biobank phased whole genomes as a GRG, more than 2000 times smaller than the size of VCF. Moreover, the size of GRG increases sublinearly with the number of samples stored, making it a sustainable solution to the increasing number of samples in large datasets. We show that summaries of genetic variants can be computed on GRG via graph traversal that runs 230 times faster than on VCF. We anticipate that GRG-based algorithms will improve the scalability of various types of computation and generally lower the cost of analyzing large genomic datasets.

Effect of geomembrane liner on landfill stability under long-term loading: interfacial shear test and numerical simulation.

Clay liners have been widely used in landfill engineering. However, large-scale clay excavation causes secondary environmental damage. This study investigates the feasibility of replacing clay liners with high-density polyethylene (HDPE) geomembranes with different specifications and parameters. Laboratory interface shear tests between municipal solid waste (MSW) samples of different ages and geomembranes were conducted to study the influence of landfill age on interface shear strength. Finite element method was adopted to compare the long-term stability of landfills with HDPE geomembrane versus clay as intermediate liner. The interfacial shear test results show that the cohesion of MSW increases in a short term and then decreases with landfill age. The internal friction angle exhibits an increasing trend with advancing age, however, the rate of its increment declines with age. The rough accuracy of the film surface can increase the interfacial shear strength between MSW. The simulation results show that, unlike clay-lined landfills, the sliding surface of geomembrane-lined landfills is discontinuous at the lining interface, which can delay the penetration of slip surfaces and block the formation of slip zone in the landfill. In addition, the maximum displacement of landfills with geomembrane is 10% lower than that with clay, and the absolute displacement of slope toe decreases with the increase of roughness at the interface of geomembrane. Compared with clay-lined landfills, the overall stability safety factor increased by 18.5-30%. This study provides references for landfill design and on-site stability evaluation, contributing to enhanced long-term stability.

Human A-to-I RNA editing SNP loci are enriched in GWAS signals for autoimmune diseases and under balancing selection.

BACKGROUND: Adenosine-to-inosine (A-to-I) RNA editing plays important roles in diversifying the transcriptome and preventing MDA5 sensing of endogenous dsRNA as nonself. To date, few studies have investigated the population genomic signatures of A-to-I editing due to the lack of editing sites overlapping with SNPs. RESULTS: In this study, we applied a pipeline to robustly identify SNP editing sites from population transcriptomic data and combined functional genomics, GWAS, and population genomics approaches to study the function and evolution of A-to-I editing. We find that the G allele, which is equivalent to edited I, is overrepresented in editing SNPs. Functionally, A/G editing SNPs are highly enriched in GWAS signals of autoimmune and immune-related diseases. Evolutionarily, derived allele frequency distributions of A/G editing SNPs for both A and G alleles as the ancestral alleles are skewed toward intermediate frequency alleles relative to neutral SNPs, a hallmark of balancing selection, suggesting that both A and G alleles are functionally important. The signal of balancing selection is confirmed by a number of additional population genomic analyses. CONCLUSIONS: We uncovered a hidden layer of A-to-I RNA editing SNP loci as a common target of balancing selection, and we propose that the maintenance of such editing SNP variations may be at least partially due to constraints on the resolution of the balance between immune activity and self-tolerance.

Three-phase flow displacement dynamics and Haines jumps in a hydrophobic porous medium.

We use synchrotron X-ray micro-tomography to investigate the displacement dynamics during three-phase-oil, water and gas-flow in a hydrophobic porous medium. We observe a distinct gas invasion pattern, where gas progresses through the pore space in the form of disconnected clusters mediated by double and multiple displacement events. Gas advances in a process we name three-phase Haines jumps, during which gas re-arranges its configuration in the pore space, retracting from some regions to enable the rapid filling of multiple pores. The gas retraction leads to a permanent disconnection of gas ganglia, which do not reconnect as gas injection proceeds. We observe, in situ, the direct displacement of oil and water by gas as well as gas-oil-water double displacement. The use of local in situ measurements and an energy balance approach to determine fluid-fluid contact angles alongside the quantification of capillary pressures and pore occupancy indicate that the wettability order is oil-gas-water from most to least wetting. Furthermore, quantifying the evolution of Minkowski functionals implied well-connected oil and water, while the gas connectivity decreased as gas was broken up into discrete clusters during injection. This work can be used to design CO2 storage, improved oil recovery and microfluidic devices.

Product Quality Research Institute evaluation of cascade impactor profiles of pharmaceutical aerosols: part 2--evaluation of a method for determining equivalence.

The purpose of this article is to present the thought process, methods, and interim results of a PQRI Working Group, which was charged with evaluating the chi-square ratio test as a potential method for determining in vitro equivalence of aerodynamic particle size distribution (APSD) profiles obtained from cascade impactor measurements. Because this test was designed with the intention of being used as a tool in regulatory review of drug applications, the capability of the test to detect differences in APSD profiles correctly and consistently was evaluated in a systematic way across a designed space of possible profiles. To establish a "base line," properties of the test in the simplest case of pairs of identical profiles were studied. Next, the test's performance was studied with pairs of profiles, where some difference was simulated in a systematic way on a single deposition site using realistic product profiles. The results obtained in these studies, which are presented in detail here, suggest that the chi-square ratio test in itself is not sufficient to determine equivalence of particle size distributions. This article, therefore, introduces the proposal to combine the chi-square ratio test with a test for impactor-sized mass based on Population Bioequivalence and describes methods for evaluating discrimination capabilities of the combined test. The approaches and results described in this article elucidate some of the capabilities and limitations of the original chi-square ratio test and provide rationale for development of additional tests capable of comparing APSD profiles of pharmaceutical aerosols.

Product Quality Research Institute evaluation of cascade impactor profiles of pharmaceutical aerosols, part 1: background for a statistical method.

The purpose of this article is 2-fold: (1) to document in the public domain the considerations that led to the development of a regulatory statistical test for comparison of aerodynamic particle size distribution (APSD) of aerosolized drug formulations, which was proposed in a US Food and Drug Administration (FDA) draft guidance for industry; and (2) to explain the background and process for evaluation of that test through a working group involving scientists from the FDA, industry, academia, and the US Pharmacopeia, under the umbrella of the Product Quality Research Institute (PQRI). The article and the referenced additional statistical information posted on the PQRI Web site explain the reasoning and methods used in the development of the APSD test, which is one of the key tests required for demonstrating in vitro equivalence of orally inhaled and nasal aerosol drug products. The article also describes the process by which stakeholders with different perspectives have worked collaboratively to evaluate properties of the test by drawing on statistical models, historical and practical information, and scientific reasoning. Overall, this article provides background information to accompany the companion article's discussion of the study's methods and results.

Product Quality Research Institute evaluation of cascade impactor profiles of pharmaceutical aerosols. Part 3. Final report on a statistical procedure for determining equivalence.

The purpose of this article is to report final results of the evaluation of a chi-square ratio test proposed by the US Food and Drug Administration (FDA) for demonstrating equivalence of aerodynamic particle size distribution (APSD) profiles of nasal and orally inhaled drug products. A working group of the Product Quality Research Institute previously published results demonstrating some limitations of the proposed test. In an effort to overcome the test's limited discrimination, the group proposed a supplemental test, a population bioequivalence (PBE) test for impactor-sized mass (ISM). In this final report the group compares the chi-square ratio test to the ISM-PBE test and to the combination of both tests. The basis for comparison is a set of 55 realistic scenarios of cascade impactor data, which were evaluated for equivalence by the statistical tests and independently by the group members. In many instances, the combined application of these 2 tests appeared to increase the discriminating ability of the statistical procedure compared with the chi-square ratio test alone. In certain situations the chi-square ratio test alone was sufficient to determine equivalence of APSD profiles, while in other situations neither of the tests alone nor their combination was adequate. This report describes all of these scenarios and results. In the end, the group did not recommend a statistical test for APSD profile equivalence. The group did not investigate other in vitro tests, in vivo issues, or other statistical tests for APSD profile comparisons. The studied tests are not intended for routine quality control of APSD.