scholarly journals Widespread transcriptional scanning in the testis modulates gene evolution rates

2018 ◽  
Author(s):  
Bo Xia ◽  
Yun Yan ◽  
Maayan Baron ◽  
Florian Wagner ◽  
Dalia Barkley ◽  
...  
Keyword(s):  
Dna Sequence ◽  
Gene Evolution ◽  
Immune Defense ◽  
Mutation Rates ◽  
Evolutionary Time ◽  
Male Germline ◽  
Specific Subset ◽  
Low Diversity ◽  
Human And Mouse ◽  
Fast Evolution

The testis expresses the largest number of genes of any mammalian organ, a finding that has long puzzled molecular biologists. Analyzing our single-cell transcriptomic maps of human and mouse spermatogenesis, we provide evidence that this widespread transcription serves to maintain DNA sequence integrity in the male germline by correcting DNA damage through 'transcriptional scanning'. Supporting this model, we find that genes expressed during spermatogenesis display lower mutation rates on the transcribed strand and have low diversity in the population. Moreover, this effect is fine-tuned by the level of gene expression during spermatogenesis. The unexpressed genes, which in our model do not benefit from transcriptional scanning, diverge faster over evolutionary time-scales and are enriched for sensory and immune-defense functions. Collectively, we propose that transcriptional scanning modulates germline mutation rates in a gene-specific manner, maintaining DNA sequence integrity for the bulk of genes but allowing for fast evolution in a specific subset.

scholarly journals Transfer RNA genes experience exceptionally elevated mutation rates

2018 ◽  
Vol 115 (36) ◽  
pp. 8996-9001 ◽  
Author(s):  
Bryan P. Thornlow ◽  
Josh Hough ◽  
Jacquelyn M. Roger ◽  
Henry Gong ◽  
Todd M. Lowe ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Trna Gene ◽  
Gene Evolution ◽  
Purifying Selection ◽  
Mutation Rates ◽  
Model Organisms ◽  
Biological Synthesis ◽  
Human Populations ◽  
Trna Genes ◽  
Simple Method

Transfer RNAs (tRNAs) are a central component for the biological synthesis of proteins, and they are among the most highly conserved and frequently transcribed genes in all living things. Despite their clear significance for fundamental cellular processes, the forces governing tRNA evolution are poorly understood. We present evidence that transcription-associated mutagenesis and strong purifying selection are key determinants of patterns of sequence variation within and surrounding tRNA genes in humans and diverse model organisms. Remarkably, the mutation rate at broadly expressed cytosolic tRNA loci is likely between 7 and 10 times greater than the nuclear genome average. Furthermore, evolutionary analyses provide strong evidence that tRNA genes, but not their flanking sequences, experience strong purifying selection acting against this elevated mutation rate. We also find a strong correlation between tRNA expression levels and the mutation rates in their immediate flanking regions, suggesting a simple method for estimating individual tRNA gene activity. Collectively, this study illuminates the extreme competing forces in tRNA gene evolution and indicates that mutations at tRNA loci contribute disproportionately to mutational load and have unexplored fitness consequences in human populations.

DNA Sequence Analysis of Spontaneous Mutagenesis in Saccharomyces cerevisiae

Genetics ◽  
1998 ◽  
Vol 148 (4) ◽  
pp. 1491-1505 ◽  
Author(s):  
Bernard A Kunz ◽  
Karthikeyan Ramachandran ◽  
Edward J Vonarx
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Sequence Analysis ◽  
Dna Sequencing ◽  
Dna Sequence ◽  
Budding Yeast ◽  
Spontaneous Mutation ◽  
Dna Sequence Analysis ◽  
Mutation Rates ◽  
Yeast Saccharomyces Cerevisiae ◽  
Spontaneous Mutagenesis

AbstractTo help elucidate the mechanisms involved in spontaneous mutagenesis, DNA sequencing has been applied to characterize the types of mutation whose rates are increased or decreased in mutator or antimutator strains, respectively. Increased spontaneous mutation rates point to malfunctions in genes that normally act to reduce spontaneous mutation, whereas decreased rates are associated with defects in genes whose products are necessary for spontaneous mutagenesis. In this article, we survey and discuss the mutational specificities conferred by mutator and antimutator genes in the budding yeast Saccharomyces cerevisiae. The implications of selected aspects of the data are considered with respect to the mechanisms of spontaneous mutagenesis.

Nucleosome Positioning Signals in the DNA Sequence of the Human and Mouse H19 Imprinting Control Regions

2003 ◽  
Vol 325 (5) ◽  
pp. 873-887 ◽  
Author(s):  
C. Davey ◽  
R. Fraser ◽  
M. Smolle ◽  
M.W. Simmen ◽  
J. Allan
Keyword(s):  
Dna Sequence ◽  
Nucleosome Positioning ◽  
Human And Mouse ◽  
Control Regions

scholarly journals The Amyloid Structure of Mouse RIPK3 (Receptor Interacting Protein Kinase 3) in Cell Necroptosis

2020 ◽  
Author(s):  
Xia-lian Wu ◽  
Hong Hu ◽  
Xing-qi Dong ◽  
Jing Zhang ◽  
Jian Wang ◽  
...  
Keyword(s):  
Structural Transformation ◽  
Self Assembly ◽  
Structural Integrity ◽  
Immune Defense ◽  
Dynamics Simulation ◽  
Amyloid Formation ◽  
Interacting Protein ◽  
Functional Studies ◽  
First Time ◽  
Human And Mouse

ABSTRACTRIPK3 amyloid complex plays crucial roles in execution of TNF-induced necroptosis and in response to immune defense in both human and mouse. We have structurally characterized the mouse RIPK3 homogeneous self-assembly using solid-state NMR, illustrating a well-ordered N-shaped amyloid core structure featured with 3 parallel in-register β-sheets. The structure is different from previously published human RIPK1/RIPK3 hetero-amyloid complex. Functional studies indicate both RIPK1-RIPK3 binding and RIPK3 amyloid formation are essential but not sufficient for RIPK3-mediated necroptosis. The structural integrity of RIPK3 fibril with three β-strands is necessary for the signaling. Molecular dynamics simulation of the mouse RIPK1/RIPK3 model indicates less stable for the hetero-amyloid to adopt RIPK3 fibril conformation, suggesting a structural transformation of RIPK3 from RIPK1-RIPK3 binding to RIPK3 amyloid formation. This structural transformation is revealed for the first time, providing a missing link connecting RIPK1-RIPK3 binding to RIPK3 homo-oligomer formation in the signal transduction.

scholarly journals Selective depletion of a CD64-expressing phagocyte subset mediates protection against toxic kidney injury and failure

2021 ◽  
Vol 118 (39) ◽  
pp. e2022311118
Author(s):  
Natallia Salei ◽  
Xingqi Ji ◽  
Dalia Pakalniškytė ◽  
Vanessa Kuentzel ◽  
Stephan Rambichler ◽  
...  
Keyword(s):  
Mouse Model ◽  
Diphtheria Toxin ◽  
Kidney Injury ◽  
Immune Defense ◽  
Mononuclear Phagocytes ◽  
Specific Subset ◽  
Adult Kidney ◽  
Selective Depletion ◽  
Toxin Receptor ◽  
Injury And Repair

Dendritic cells (DC), macrophages, and monocytes, collectively known as mononuclear phagocytes (MPs), critically control tissue homeostasis and immune defense. However, there is a paucity of models allowing to selectively manipulate subsets of these cells in specific tissues. The steady-state adult kidney contains four MP subsets with Clec9a-expression history that include the main conventional DC1 (cDC1) and cDC2 subtypes as well as two subsets marked by CD64 but varying levels of F4/80. How each of these MP subsets contributes to the different phases of acute kidney injury and repair is unknown. We created a mouse model with a Cre-inducible lox-STOP-lox-diphtheria toxin receptor cassette under control of the endogenous CD64 locus that allows for diphtheria toxin–mediated depletion of CD64-expressing MPs without affecting cDC1, cDC2, or other leukocytes in the kidney. Combined with specific depletion of cDC1 and cDC2, we revisited the role of MPs in cisplatin-induced kidney injury. We found that the intrinsic potency reported for CD11c+ cells to limit cisplatin toxicity is specifically attributed to CD64+ MPs, while cDC1 and cDC2 were dispensable. Thus, we report a mouse model allowing for selective depletion of a specific subset of renal MPs. Our findings in cisplatin-induced injury underscore the value of dissecting the functions of individual MP subsets in kidney disease, which may enable therapeutic targeting of specific immune components in the absence of general immunosuppression.

scholarly journals Mutation bias shapes gene evolution in Arabidopsis thaliana

2020 ◽  
Author(s):  
J. Grey Monroe ◽  
Thanvi Srikant ◽  
Pablo Carbonell-Bejerano ◽  
Moises Exposito-Alonso ◽  
Mao-Lun Weng ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
De Novo ◽  
Gene Evolution ◽  
Gc Content ◽  
Mutation Rates ◽  
Rate Variation ◽  
Recent Theory ◽  
De Novo Mutations ◽  
Coding Region ◽  
Mutational Hotspots

Classical evolutionary theory maintains that mutation rate variation between genes should be random with respect to fitness 1–4 and evolutionary optimization of genic mutation rates remains controversial 3,5. However, it has now become known that cytogenetic (DNA sequence + epigenomic) features influence local mutation probabilities 6, which is predicted by more recent theory to be a prerequisite for beneficial mutation rates between different classes of genes to readily evolve 7. To test this possibility, we used de novo mutations in Arabidopsis thaliana to create a high resolution predictive model of mutation rates as a function of cytogenetic features across the genome. As expected, mutation rates are significantly predicted by features such as GC content, histone modifications, and chromatin accessibility. Deeper analyses of predicted mutation rates reveal effects of introns and untranslated exon regions in distancing coding sequences from mutational hotspots at the start and end of transcribed regions in A. thaliana. Finally, predicted coding region mutation rates are significantly lower in genes where mutations are more likely to be deleterious, supported by numerous estimates of evolutionary and functional constraint. These findings contradict neutral expectations that mutation probabilities are independent of fitness consequences. Instead they are consistent with the evolution of lower mutation rates in functionally constrained loci due to cytogenetic features, with important implications for evolutionary biology8.

scholarly journals The detailed 3D multi-loop aggregate/rosette chromatin architecture and functional dynamic organization of the human and mouse genomes

2016 ◽  
Vol 9 (1) ◽  
Author(s):  
Tobias A. Knoch ◽  
Malte Wachsmuth ◽  
Nick Kepper ◽  
Michael Lesnussa ◽  
Anis Abuseiris ◽  
...  
Keyword(s):  
Dna Sequence ◽  
Gene Expression Regulation ◽  
Three Dimensional ◽  
Cell Types ◽  
Scaling Analysis ◽  
Chromatin Architecture ◽  
Novel Approach ◽  
A Genome ◽  
3D Architecture ◽  
Human And Mouse

Abstract Background The dynamic three-dimensional chromatin architecture of genomes and its co-evolutionary connection to its function—the storage, expression, and replication of genetic information—is still one of the central issues in biology. Here, we describe the much debated 3D architecture of the human and mouse genomes from the nucleosomal to the megabase pair level by a novel approach combining selective high-throughput high-resolution chromosomal interaction capture (T2C), polymer simulations, and scaling analysis of the 3D architecture and the DNA sequence. Results The genome is compacted into a chromatin quasi-fibre with ~5 ± 1 nucleosomes/11 nm, folded into stable ~30–100 kbp loops forming stable loop aggregates/rosettes connected by similar sized linkers. Minor but significant variations in the architecture are seen between cell types and functional states. The architecture and the DNA sequence show very similar fine-structured multi-scaling behaviour confirming their co-evolution and the above. Conclusions This architecture, its dynamics, and accessibility, balance stability and flexibility ensuring genome integrity and variation enabling gene expression/regulation by self-organization of (in)active units already in proximity. Our results agree with the heuristics of the field and allow “architectural sequencing” at a genome mechanics level to understand the inseparable systems genomic properties.

scholarly journals The amyloid structure of mouse RIPK3 (receptor interacting protein kinase 3) in cell necroptosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xia-lian Wu ◽  
Hong Hu ◽  
Xing-qi Dong ◽  
Jing Zhang ◽  
Jian Wang ◽  
...  
Keyword(s):  
Structural Transformation ◽  
Self Assembly ◽  
Structural Integrity ◽  
Complex Structure ◽  
Immune Defense ◽  
Amyloid Formation ◽  
Interacting Protein ◽  
Functional Studies ◽  
Dynamics Simulations ◽  
Human And Mouse

AbstractRIPK3 amyloid complex plays crucial roles during TNF-induced necroptosis and in response to immune defense in both human and mouse. Here, we have structurally characterized mouse RIPK3 homogeneous self-assembly using solid-state NMR, revealing a well-ordered N-shaped amyloid core structure featured with 3 parallel in-register β-sheets. This structure differs from previously published human RIPK1/RIPK3 hetero-amyloid complex structure, which adopted a serpentine fold. Functional studies indicate both RIPK1-RIPK3 binding and RIPK3 amyloid formation are essential but not sufficient for TNF-induced necroptosis. The structural integrity of RIPK3 fibril with three β-strands is necessary for signaling. Molecular dynamics simulations with a mouse RIPK1/RIPK3 model indicate that the hetero-amyloid is less stable when adopting the RIPK3 fibril conformation, suggesting a structural transformation of RIPK3 from RIPK1-RIPK3 binding to RIPK3 amyloid formation. This structural transformation would provide the missing link connecting RIPK1-RIPK3 binding to RIPK3 homo-oligomer formation in the signal transduction.

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