Maize (Zea mays) is one of the most important crops in the world. However, few agronomically important maize genes have been cloned and used for trait improvement, due to its complex genome and genetic architecture. Here, we integrated multiplexed CRISPR/Cas9-based high-throughput targeted mutagenesis with genetic mapping and genomic approaches to successfully target 743 candidate genes corresponding to traits relevant for agronomy and nutrition. After low-cost barcode-based deep sequencing, 412 edited sequences covering 118 genes were precisely identified from individuals showing clear phenotypic changes. The profiles of the associated gene-editing events were similar to those identified in human cell lines and consequently are predictable using an existing algorithm originally designed for human studies. We observed unexpected but frequent homology-directed repair through endogenous templates that was likely caused by spatial contact between distinct chromosomes. Based on the characterization and interpretation of gene function from several examples, we demonstrate that the integration of forward and reverse genetics via a targeted mutagenesis library promises rapid validation of important agronomic genes for crops with complex genomes. Beyond specific findings, this study also guides further optimization of high-throughput CRISPR experiments in plants.
Background: Identifying genotype-phenotype links and causative genes from quantitative trait loci (QTL) is challenging for complex agronomically important traits. To accelerate maize gene discovery and breeding, we present the Complete-diallel design plus Unbalanced Breeding-like Inter-Cross (CUBIC) population, consisting of 1404 individuals created by extensively inter-crossing 24 widely used Chinese maize founders. Results: Hundreds of QTL for 23 agronomic traits are uncovered with 14 million high-quality SNPs and a high-resolution identity-by-descent map, which account for an average of 75% of the heritability for each trait. We find epistasis contributes to phenotypic variance widely. Integrative cross-population analysis and cross-omics mapping allow effective and rapid discovery of underlying genes, validated here with a case study on leaf width. Conclusions: Through the integration of experimental genetics and genomics, our study provides useful resources and gene mining strategies to explore complex quantitative traits.
BACKGROUND: There is a growing focus on improving the quality and value of health care delivery for high-cost patients. Compared to fee-for-service Medicare, less is known about the clinical composition of high-cost Medicare Advantage populations. OBJECTIVE: To describe a high-cost Medicare Advantage population and identify clinically and operationally significant subgroups of patients. DESIGN: We used a density-based clustering algorithm to group high-cost patients (top 10% of spending) according to 161 distinct demographic, clinical, and claims-based variables. We then examined rates of utilization, spending, and mortality among subgroups. PARTICIPANTS: Sixty-one thousand five hundred fortysix Medicare Advantage beneficiaries. MAIN MEASURES: Spending, utilization, and mortality. KEY RESULTS: High-cost patients (n = 6154) accounted for 55% of total spending. High-cost patients were more likely to be younger, male, and have higher rates of comorbid illnesses. We identified ten subgroups of high-cost patients: acute exacerbations of chronic disease (mixed); end-stage renal disease (ESRD); recurrent gastrointestinal bleed (GIB); orthopedic trauma (trauma); vascular disease (vascular); surgical infections and other complications (complications); cirrhosis with hepatitis C (liver); ESRD with increased medical and behavioral comorbidity (ESRD+); cancer with high-cost imaging and radiation therapy (oncology); and neurologic disorders (neurologic). The average number of inpatient days ranged from 3.25 (oncology) to 26.09 (trauma). Preventable spending (as a percentage of total spending) ranged from 0.8% (oncology) to 9.5% (complications) and the percentage of spending attributable to prescription medications ranged from 7.9% (trauma and oncology) to 77.0% (liver). The percentage of patients who were persistently high-cost ranged from 11.8% (trauma) to 100.0% (ESRD+). One-year mortality ranged from 0.0% (liver) to 25.8% (ESRD+). CONCLUSIONS:We identified clinically distinct subgroups of patients within a heterogeneous high-cost Medicare Advantage population using cluster analysis. These subgroups, defined by condition-specific profiles and illness trajectories, had markedly different patterns of utilization, spending, and mortality, holding important implications for clinical strategy.KEY WORDS: high-cost patients; care management; medicare advantage.
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