We introduce MutPred2, a tool that improves the prioritization of pathogenic amino acid substitutions, generates molecular mechanisms potentially causative of disease, and returns interpretable pathogenicity score distributions on individual genomes. While its prioritization performance is state-of-the-art, a novel and distinguishing feature of MutPred2 is the probabilistic modeling of variant impact on specific aspects of protein structure and function that can serve to guide experimental studies of phenotype-altering variants. We demonstrate the utility of MutPred2 in the identification of the structural and functional mutational signatures relevant to Mendelian disorders and the prioritization of de novo mutations associated with complex neurodevelopmental disorders. We then experimentally validate the functional impact of several variants identified in patients with such disorders. We argue that mechanismdriven studies of human inherited diseases have the potential to significantly accelerate the discovery of clinically actionable variants. Availability: http://mutpred.mutdb.org/

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This study aims to understand the global environment of COVID-19 management and guide future policy directions after the pandemic crisis. To this end, we analyzed a series of the World Economic Forum’s COVID-19 response reports through text mining and network analysis. These reports, written by experts in diverse fields, discuss multidimensional changes in socioeconomic situations, various problems created by those changes, and strategies to respond to national crises. Based on 3,897 refined words drawn from a morphological analysis of 26 reports (as of the end of 2020), this study analyzes the frequency of words, the relationships among words, the importance of specific documents, and the connection centrality through text mining. In addition, network analysis helps develop strategies for sustainable response to and management of national crises through identifying clusters of words with a similar structural equivalence.

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Iron deficiency hampers photosynthesis and is associated with chlorosis. We recently showed that iron deficiency-induced chlorosis depends on phosphorus availability. How plants integrate these cues to control chlorophyll accumulation is unknown. Here, we show that iron limitation downregulates photosynthesis genes in a phosphorus-dependent manner. Using transcriptomics and genome-wide association analysis, we identify two genes, a chloroplastic ascorbate transporter (PHT4;4) and a nuclear transcription factor (bZIP58), which prevent the downregulation of photosynthesis genes leading to the stay-green phenotype under iron-phosphorus deficiency. Joint limitation of these nutrients induces ascorbate accumulation by activating expression of an ascorbate biosynthesis gene, VTC4, which requires bZIP58. Exogenous ascorbate prevents iron deficiency-induced chlorosis in vtc4 mutants, but not in bzip58 or pht4;4. Our study demonstrates chloroplastic ascorbate transport is essential for preventing the downregulation of photosynthesis genes under iron-phosphorus combined deficiency. These findings uncover a molecular pathway coordinating chloroplast-nucleus communication to adapt photosynthesis to nutrient availability.