RESUMO
Although genome-wide association studies (GWAS) have successfully linked genetic risk loci to various disorders, identifying underlying cellular biological mechanisms remains challenging due to the complex nature of common diseases. We established a framework using human peripheral blood cells, physical, chemical and pharmacological perturbations, and flow cytometry-based functional readouts to reveal latent cellular processes and performed GWAS based on these evoked traits in up to 2,600 individuals. We identified 119 genomic loci implicating 96 genes associated with these cellular responses and discovered associations between evoked blood phenotypes and subsets of common diseases. We found a population of pro-inflammatory anti-apoptotic neutrophils prevalent in individuals with specific subsets of cardiometabolic disease. Multigenic models based on this trait predicted the risk of developing chronic kidney disease in type 2 diabetes patients. By expanding the phenotypic space for human genetic studies, we could identify variants associated with large effect response differences, stratify patients and efficiently characterize the underlying biology.
Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Predisposição Genética para Doença , Fenótipo , Células Sanguíneas , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Levels of protein translation by ribosomes are governed both by features of the translation machinery as well as sequence properties of the mRNAs themselves. We focus here on a striking three-nucleotide periodicity, characterized by overrepresentation of GCN codons and underrepresentation of G at the second position of codons, that is observed in Open Reading Frames (ORFs) of mRNAs. Our examination of mRNA sequences in Saccharomyces cerevisiae revealed that this periodicity is particularly pronounced in the initial codons-the ramp region-of ORFs of genes with high protein expression. It is also found in mRNA sequences immediately following non-standard AUG start sites, located upstream or downstream of the standard annotated start sites of genes. To explore the possible influences of the ramp GCN periodicity on translation efficiency, we tested edited ramps with accentuated or depressed periodicity in two test genes, SKN7 and HMT1. Greater conformance to (GCN)n was found to significantly depress translation, whereas disrupting conformance had neutral or positive effects on translation. Our recent Molecular Dynamics analysis of a subsystem of translocating ribosomes in yeast revealed an interaction surface that H-bonds to the +1 codon that is about to enter the ribosome decoding center A site. The surface, comprised of 16S/18S rRNA C1054 and A1196 (E. coli numbering) and R146 of ribosomal protein Rps3, preferentially interacts with GCN codons, and we hypothesize that modulation of this mRNA-ribosome interaction may underlie GCN-mediated regulation of protein translation. Integration of our expression studies with large-scale reporter studies of ramp sequence variants suggests a model in which the C1054-A1196-R146 (CAR) interaction surface can act as both an accelerator and braking system for ribosome translation.
Assuntos
Códon de Iniciação/genética , Biossíntese de Proteínas/genética , Ribossomos/metabolismo , Saccharomyces cerevisiae/genética , Composição de Bases/genética , Códon de Iniciação/metabolismo , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Simulação de Dinâmica Molecular , Fases de Leitura Aberta/genética , Proteína-Arginina N-Metiltransferases/biossíntese , Proteína-Arginina N-Metiltransferases/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Repressoras/biossíntese , Proteínas Repressoras/genética , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/biossíntese , Proteínas de Saccharomyces cerevisiae/genética , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genéticaRESUMO
In highly urbanized area where traffic condition fluctuates constantly, transportation infrastructure is one of the major contributing factors to Emergency Medical Service (EMS) availability and patient outcome. In this paper, we assess the impact of traffic fluctuation to the EMS first response availability in urban area, by evaluating the k-minute coverage under 21 traffic scenarios. The set of traffic scenarios represents the time-of-day and day-of-week effects, and is generated by combining road link speed information from multiple historical speed databases. In addition to the k-minute area coverage calculation, the k-minute population coverage is also evaluated for every 100m by 100m grid that partitions the case study area of Seoul, South Korea. In the baseline case of traveling at the speed limit, both the area and population coverage reached nearly 100% when compared to the five-minute travel time national target. Employing the proposed LoST (Loss of Serviceability due to Traffic) index, which measures coverage reduction in percentage compared to the baseline case, we find that the citywide average LoST for area and population coverage are similar at 34.2% and 33.8%. However, district-wise analysis reveals that such reduction varies significantly by district, and the magnitude of area and population coverage reduction is not always proportional. We conclude that the effect of traffic variation is significant to successful urban EMS first response performance, and regional variation is evident among local districts. Complexity in the urban environment requires a more adaptive approach in public health resource management and EMS performance target determination.