Summary The three-dimensional configuration of DNA is integral to all nuclear processes in eukaryotes, yet our knowledge of the chromosome architecture is still limited. Genome-wide chromosome conformation capture studies have uncovered features of chromatin organization in cultured cells, but genome architecture in human tissues has yet to be explored. Here, we report the most comprehensive survey to date of chromatin organization in human tissues. Through integrative analysis of chromatin contact maps in 21 primary human tissues and cell types, we found topologically associating domains highly conserved in different tissues. We also discover genomic regions that exhibit unusually high levels of local chromatin interactions. These frequently interacting regions (FIREs) are enriched for super-enhancers and are near tissue-specifically expressed genes. They display strong tissue-specificity in local chromatin interactions. Additionally, FIRE formation is partially dependent on CTCF and the Cohesin complex. We further show that FIREs can help annotate function of non-coding sequence variants.

Rare genetic variants contribute to complex disease risk; however, the abundance of rare variants in human populations remains unknown. We explored this spectrum of variation by sequencing 202 genes encoding drug targets in 14,002 individuals. We find rare variants are abundant (one every 17 bases) and geographically localized, such that even with large sample sizes, rare variant catalogs will be largely incomplete. We used the observed patterns of variation to estimate population growth parameters, the proportion of variants in a given frequency class that are putatively deleterious, and mutation rates for each gene. Overall we conclude that, due to rapid population growth and weak purifying selection, human populations harbor an abundance of rare variants, many of which are deleterious and have relevance to understanding disease risk.

Large collections of knockout organisms facilitate the elucidation of gene functions. Here we used retroviral insertion or homologous recombination to disrupt 472 genes encoding secreted and membrane proteins in mice, providing a resource for studying a large fraction of this important class of drug target. The knockout mice were subjected to a systematic phenotypic screen designed to uncover alterations in embryonic development, metabolism, the immune system, the nervous system and the cardiovascular system. The majority of knockout lines exhibited altered phenotypes in at least one of these therapeutic areas. To our knowledge, a comprehensive phenotypic assessment of a large number of mouse mutants generated by a gene-specific approach has not been described previously.

Undoubtedly, the age of big data has opened new options for natural disaster management, primarily because of the varied possibilities it provides in visualizing, analyzing, and predicting natural disasters. From this perspective, big data has radically changed the ways through which human societies adopt natural disaster management strategies to reduce human suffering and economic losses. In a world that is now heavily dependent on information technology, the prime objective of computer experts and policy makers is to make the best of big data by sourcing information from varied formats and storing it in ways that it can be effectively used during different stages of natural disaster management. This paper aimed at making a systematic review of the literature in analyzing the role of big data in natural disaster management and highlighting the present status of the technology in providing meaningful and effective solutions in natural disaster management. The paper has presented the findings of several researchers on varied scientific and technological perspectives that have a bearing on the efficacy of big data in facilitating natural disaster management. In this context, this paper reviews the major big data sources, the associated achievements in different disaster management phases, and emerging technological topics associated with leveraging this new ecosystem of Big Data to monitor and detect natural hazards, mitigate their effects, assist in relief efforts, and contribute to the recovery and reconstruction processes.

Physical distancing has been argued as one of the effective means to combat the spread of COVID-19 before a vaccine or therapeutic drug becomes available. How far people can be spatially separated is partly behavioral but partly constrained by population density. Most models developed to predict the spread of COVID-19 in the U.S. do not include population density explicitly. This study shows that population density is an effective predictor of cumulative infection cases in the U.S. at the county level. Daily cumulative cases by counties are converted into 7-day moving averages. Treating the weekly averages as the dependent variable and the county population density levels as the explanatory variable, both in logarithmic scale, this study assesses how population density has shaped the distributions of infection cases across the U.S. from early March to late May, 2020. Additional variables reflecting the percentages of African Americans, Hispanic-Latina, and older adults in logarithmic scale are also included. Spatial regression models with a spatial error specification are also used to account for the spatial spillover effect. Population density alone accounts for 57% of the variation (R-squared) in the aspatial models and up to 76% in the spatial models. Adding the three population subgroup percentage variables raised the R-squared of the aspatial models to 72% and the spatial model to 84%. The influences of the three population subgroups were substantial, but changed over time, while the contributions of population density have been quite stable after the first several weeks, ascertaining the importance of population density in shaping the spread of infection in individual counties, and in their neighboring counties. Thus, population density and sizes of vulnerable population subgroups should be explicitly included in transmission models that predict the impacts of COVID-19, particularly at the sub-county level.

Highlights d Transcriptome of 39,905 single islet cells from healthy, obese, and T2D human donors d Obesity and diabetes cause distinct heterodetic profiles in pancreatic b cells d RePACT can identify disease signatures using single-cell data from very few donors d Functional annotation of disease signature genes using genome-wide CRISPR analysis

Genome-wide mapping of chromatin interactions at high resolution remains experimentally and computationally challenging. Here we used a low-input ''easy Hi-C'' protocol to map the 3D genome architecture in human neurogenesis and brain tissues and also demonstrated that a rigorous Hi-C bias-correction pipeline (HiCorr) can significantly improve the sensitivity and robustness of Hi-C loop identification at sub-TAD level, especially the enhancer-promoter (E-P) interactions. We used HiCorr to compare the high-resolution maps of chromatin interactions from 10 tissue or cell types with a focus on neurogenesis and brain tissues. We found that dynamic chromatin loops are better hallmarks for cellular differentiation than compartment switching. HiCorr allowed direct observation of cell-type-and differentiation-specific E-P aggregates spanning large neighborhoods, suggesting a mechanism that stabilizes enhancer contacts during development. Interestingly, we concluded that Hi-C loop outperforms eQTL in explaining neurological GWAS results, revealing a unique value of high-resolution 3D genome maps in elucidating the disease etiology.

The targeting efficiency of knockin sequences via homologous recombination (HR) is generally low. Here we describe a method we call Tild-CRISPR (targeted integration with linearized dsDNA-CRISPR), a targeting strategy in which a PCR-amplified or precisely enzyme-cut transgene donor with 800-bp homology arms is injected with Cas9 mRNA and single guide RNA into mouse zygotes. Compared with existing targeting strategies, this method achieved much higher knockin efficiency in mouse embryos, as well as brain tissue. Importantly, the Tild-CRISPR method also yielded up to 12-fold higher knockin efficiency than HR-based methods in human embryos, making it suitable for studying gene functions in vivo and developing potential gene therapies.