25 research outputs found
Pathologic Replication-Independent Endogenous DNA Double-Strand Breaks Repair Defect in Chronological Aging Yeast
Reduction of physiologic replication-independent endogenous DNA double strand breaks (Phy-RIND-EDSBs) in chronological aging yeast increases pathologic RIND-EDSBs (Path-RIND-EDSBs). Path-RIND-EDSBs can occur spontaneously in non-dividing cells without any inductive agents, and they must be repaired immediately otherwise their accumulation can lead to senescence. If yeasts have DSB repair defect, retention of Path-RIND-EDSBs can be found. Previously, we found that Path-RIND-EDSBs are not only produced but also retained in chronological aging yeast. Here, we evaluated if chronological aging yeasts have a DSB repair defect. We found a significant accumulation of Path-RIND-EDSBs around the same level in aging cells and caffeine treated cells and at a much higher level in the DSB repair mutant cells. Especially in the mutant, some unknown sequence was found inserted at the breaks. In addition, % difference of cell viability between HO induced and non-induced cells was significantly greater in aging cells. Our results suggested that RIND-EDSBs repair efficiency declines, but is not absent, in chronological aging yeast which might promote senescence phenotype. When a repair protein is deficient, an alternative pathway might be employed or an end modification process might occur as inserted sequences at the breaks were observed. Restoring repair defects might slow down the deterioration of cells from chronological aging
On the Aggregation of Multimarker Information for Marker-Set and Sequencing Data Analysis: Genotype Collapsing vs. Similarity Collapsing
Methods that collapse information across genetic markers when searching for association signals are gaining momentum in the literature. Although originally developed to achieve a better balance between retaining information and controlling degrees of freedom when performing multimarker association analysis, these methods have recently been proven to be a powerful tool for identifying rare variants that contribute to complex phenotypes. The information among markers can be collapsed at the genotype level, which focuses on the mean of genetic information, or the similarity level, which focuses on the variance of genetic information. The aim of this work is to understand the strengths and weaknesses of these two collapsing strategies. Our results show that neither collapsing strategy outperforms the other across all simulated scenarios. Two factors that dominate the performance of these strategies are the signal-to-noise ratio and the underlying genetic architecture of the causal variants. Genotype collapsing is more sensitive to the marker set being contaminated by noise loci than similarity collapsing. In addition, genotype collapsing performs best when the genetic architecture of the causal variants is not complex (e.g., causal loci with similar effects and similar frequencies). Similarity collapsing is more robust as the complexity of the genetic architecture increases and outperforms genotype collapsing when the genetic architecture of the marker set becomes more sophisticated (e.g., causal loci with various effect sizes or frequencies and potential non-linear or interactive effects). Because the underlying genetic architecture is not known a priori, we also considered a two-stage analysis that combines the two top-performing methods from different collapsing strategies. We find that it is reasonably robust across all simulated scenarios
Recommended from our members
Comparative Genomic Analysis of Rice with Contrasting Photosynthesis and Grain Production under Salt Stress.
Unfavourable environmental conditions, including soil salinity, lead to decreased rice (Oryza sativa L.) productivity, especially at the reproductive stage. In this study, we examined 30 rice varieties, which revealed significant differences in the photosynthetic performance responses under salt stress conditions during the reproductive stage, which ultimately affected yield components after recovery. In rice with a correlation between net photosynthetic rate (PN) and intercellular CO2 concentration (Ci) under salt stress, PN was found to be negatively correlated with filled grain number after recovery. Applying stringent criteria, we identified 130,317 SNPs and 15,396 InDels between two "high-yield rice" varieties and two "low-yield rice" varieties with contrasting photosynthesis and grain yield characteristics. A total of 2,089 genes containing high- and moderate-impact SNPs or InDels were evaluated by gene ontology (GO) enrichment analysis, resulting in over-represented terms in the apoptotic process and kinase activity. Among these genes, 262 were highly expressed in reproductive tissues, and most were annotated as receptor-like protein kinases. These findings highlight the importance of variations in signaling components in the genome and these loci can serve as potential genes in rice breeding to produce a variety with salt avoidance that leads to increased yield in saline soil
Exome-wide association study to identify rare variants influencing COVID-19 outcomes : Results from the Host Genetics Initiative
Publisher Copyright: Copyright: © 2022 Butler-Laporte et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75–10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.Peer reviewe
SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues
Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to
genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility
and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component.
Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci
(eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene),
including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform
genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer
SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the
diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types
A quality control algorithm for filtering SNPs in genome-wide association studies
Motivation: The quality control (QC) filtering of single nucleotide polymorphisms (SNPs) is an important step in genome-wide association studies to minimize potential false findings. SNP QC commonly uses expert-guided filters based on QC variables [e.g. Hardy–Weinberg equilibrium, missing proportion (MSP) and minor allele frequency (MAF)] to remove SNPs with insufficient genotyping quality. The rationale of the expert filters is sensible and concrete, but its implementation requires arbitrary thresholds and does not jointly consider all QC features