scholarly journals Cosi2 : An efficient simulator of exact and approximate coalescent with selection

2014 ◽  
Author(s):  
Ilya Shlyakhter ◽  
Pardis C. Sabeti ◽  
Stephen F. Schaffner
Keyword(s):  
Gene Conversion ◽  
Genetic Material ◽  
Small Subset ◽  
Demographic Model ◽  
Coalescent Simulation ◽  
Recombination Rates ◽  
Wide Range ◽  
Selection Gene ◽  
And Migration ◽  
Recombination Hot Spots

Motivation: Efficient simulation of population genetic samples under a given demographic model is a prerequisite for many analyses. Coalescent theory provides an efficient framework for such simulations, but simulating longer regions and higher recombination rates remains challenging. Simulators based on a Markovian approximation to the coalescent scale well, but do not support simulation of selection. Gene conversion is not supported by any published coalescent simulators that support selection. Results: We describe cosi2 , an efficient simulator that supports both exact and approximate coalescent simulation with positive selection. cosi2 improves on the speed of existing exact simulators, and permits further speedup in approximate mode while retaining support for selection. cosi2 supports a wide range of demographic scenarios including recombination hot spots, gene conversion, population size changes, population structure and migration. cosi2 implements coalescent machinery efficiently by tracking only a small subset of the Ancestral Recombination Graph, sampling only relevant recombination events, and using augmented skip lists to represent tracked genetic segments. To preserve support for selection in approximate mode, the Markov approximation is implemented not by moving along the chromosome but by performing a standard backwards-in-time coalescent simulation while restricting coalescence to node pairs with overlapping or near-overlapping genetic material. We describe the algorithms used by cosi2 and present comparisons with existing selection simulators.

scholarly journals Low-Energy Electron Damage to Condensed-Phase DNA and Its Constituents

2021 ◽  
Vol 22 (15) ◽  
pp. 7879
Author(s):  
Yingxia Gao ◽  
Yi Zheng ◽  
Léon Sanche
Keyword(s):  
Condensed Phase ◽  
Genetic Material ◽  
High Energy ◽  
Dna Lesions ◽  
Low Energy ◽  
Experimental Investigations ◽  
Experimental Conditions ◽  
Strand Breaks ◽  
Sequence Of Events ◽  
Wide Range

The complex physical and chemical reactions between the large number of low-energy (0–30 eV) electrons (LEEs) released by high energy radiation interacting with genetic material can lead to the formation of various DNA lesions such as crosslinks, single strand breaks, base modifications, and cleavage, as well as double strand breaks and other cluster damages. When crosslinks and cluster damages cannot be repaired by the cell, they can cause genetic loss of information, mutations, apoptosis, and promote genomic instability. Through the efforts of many research groups in the past two decades, the study of the interaction between LEEs and DNA under different experimental conditions has unveiled some of the main mechanisms responsible for these damages. In the present review, we focus on experimental investigations in the condensed phase that range from fundamental DNA constituents to oligonucleotides, synthetic duplex DNA, and bacterial (i.e., plasmid) DNA. These targets were irradiated either with LEEs from a monoenergetic-electron or photoelectron source, as sub-monolayer, monolayer, or multilayer films and within clusters or water solutions. Each type of experiment is briefly described, and the observed DNA damages are reported, along with the proposed mechanisms. Defining the role of LEEs within the sequence of events leading to radiobiological lesions contributes to our understanding of the action of radiation on living organisms, over a wide range of initial radiation energies. Applications of the interaction of LEEs with DNA to radiotherapy are briefly summarized.

scholarly journals The PI3K/Akt Pathway: Emerging Roles in Skin Homeostasis and a Group of Non-Malignant Skin Disorders

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1219
Author(s):  
Yan Teng ◽  
Yibin Fan ◽  
Jingwen Ma ◽  
Wei Lu ◽  
Na Liu ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Akt Pathway ◽  
Skin Disorders ◽  
Phosphatidylinositol 3 Kinase ◽  
Skin Development ◽  
Wide Range ◽  
Malignant Skin ◽  
Solid Foundation ◽  
And Migration ◽  
Poor Outcomes

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway regulates cell proliferation, differentiation, and migration, along with angiogenesis and metabolism. Additionally, it could mediate skin development and homeostasis. There is much evidence to suggest that dysregulation of PI3K/Akt pathway is frequently associated with several human cutaneous malignancies like malignant melanoma (MM), basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (SCC), as well as their poor outcomes. Nevertheless, emerging roles of PI3K/Akt pathway cascade in a group of common non-malignant skin disorders including acne and psoriasis, among others, have been recognized. The enhanced understanding of dysfunction of PI3K/Akt pathway in patients with these non-malignant disorders has offered a solid foundation for the progress of updated therapeutic targets. This article reviews the latest advances in the roles of PI3K/Akt pathway and their targets in the skin homeostasis and progression of a wide range of non-malignant skin disorders and describes the current progress in preclinical and clinical researches on the involvement of PI3K/Akt pathway targeted therapies.

scholarly journals Insights into mammalian biology from the wild house mouse Mus musculus

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Megan Phifer-Rixey ◽  
Michael W Nachman
Keyword(s):  
House Mouse ◽  
Mus Musculus ◽  
Genetic Model ◽  
Inbred Strains ◽  
Mendelian Inheritance ◽  
Model Organisms ◽  
House Mice ◽  
Small Subset ◽  
Wild Mice ◽  
Wide Range

The house mouse, Mus musculus, was established in the early 1900s as one of the first genetic model organisms owing to its short generation time, comparatively large litters, ease of husbandry, and visible phenotypic variants. For these reasons and because they are mammals, house mice are well suited to serve as models for human phenotypes and disease. House mice in the wild consist of at least three distinct subspecies and harbor extensive genetic and phenotypic variation both within and between these subspecies. Wild mice have been used to study a wide range of biological processes, including immunity, cancer, male sterility, adaptive evolution, and non-Mendelian inheritance. Despite the extensive variation that exists among wild mice, classical laboratory strains are derived from a limited set of founders and thus contain only a small subset of this variation. Continued efforts to study wild house mice and to create new inbred strains from wild populations have the potential to strengthen house mice as a model system.

More than just a pressure relief valve: physiological roles of volume-regulated LRRC8 anion channels

2019 ◽  
Vol 400 (11) ◽  
pp. 1481-1496 ◽  
Author(s):  
Lingye Chen ◽  
Benjamin König ◽  
Tianbao Liu ◽  
Sumaira Pervaiz ◽  
Yasmin S. Razzaque ◽  
...  
Keyword(s):  
Volume Regulation ◽  
Regulatory Volume Decrease ◽  
Anion Channel ◽  
Therapy Resistance ◽  
Cell Swelling ◽  
Organic Osmolytes ◽  
Anion Channels ◽  
Relief Valve ◽  
Wide Range ◽  
And Migration

Abstract The volume-regulated anion channel (VRAC) is a key player in the volume regulation of vertebrate cells. This ubiquitously expressed channel opens upon osmotic cell swelling and potentially other cues and releases chloride and organic osmolytes, which contributes to regulatory volume decrease (RVD). A plethora of studies have proposed a wide range of physiological roles for VRAC beyond volume regulation including cell proliferation, differentiation and migration, apoptosis, intercellular communication by direct release of signaling molecules and by supporting the exocytosis of insulin. VRAC was additionally implicated in pathological states such as cancer therapy resistance and excitotoxicity under ischemic conditions. Following extensive investigations, 5 years ago leucine-rich repeat-containing family 8 (LRRC8) heteromers containing LRRC8A were identified as the pore-forming components of VRAC. Since then, molecular biological approaches have allowed further insight into the biophysical properties and structure of VRAC. Heterologous expression, siRNA-mediated downregulation and genome editing in cells, as well as the use of animal models have enabled the assessment of the proposed physiological roles, together with the identification of new functions including spermatogenesis and the uptake of antibiotics and platinum-based cancer drugs. This review discusses the recent molecular biological insights into the physiology of VRAC in relation to its previously proposed roles.

scholarly journals Effects of Temperature on the Meiotic Recombination Landscape of the Yeast Saccharomyces cerevisiae

mBio ◽  
2017 ◽  
Vol 8 (6) ◽  
Author(s):  
Ke Zhang ◽  
Xue-Chang Wu ◽  
Dao-Qiong Zheng ◽  
Thomas D. Petes
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Gene Conversion ◽  
Meiotic Recombination ◽  
Hot Spots ◽  
Genetic Maps ◽  
Dna Breaks ◽  
Low Levels ◽  
C 30 ◽  
Recombination Hot Spots ◽  
In Cells

ABSTRACT Although meiosis in warm-blooded organisms takes place in a narrow temperature range, meiosis in many organisms occurs over a wide variety of temperatures. We analyzed the properties of meiosis in the yeast Saccharomyces cerevisiae in cells sporulated at 14°C, 30°C, or 37°C. Using comparative-genomic-hybridization microarrays, we examined the distribution of Spo11-generated meiosis-specific double-stranded DNA breaks throughout the genome. Although there were between 300 and 400 regions of the genome with high levels of recombination (hot spots) observed at each temperature, only about 20% of these hot spots were found to have occurred independently of the temperature. In S. cerevisiae , regions near the telomeres and centromeres tend to have low levels of meiotic recombination. This tendency was observed in cells sporulated at 14°C and 30°C, but not at 37°C. Thus, the temperature of sporulation in yeast affects some global property of chromosome structure relevant to meiotic recombination. Using single-nucleotide polymorphism (SNP)-specific whole-genome microarrays, we also examined crossovers and their associated gene conversion events as well as gene conversion events that were unassociated with crossovers in all four spores of tetrads obtained by sporulation of diploids at 14°C, 30°C, or 37°C. Although tetrads from cells sporulated at 30°C had slightly (20%) more crossovers than those derived from cells sporulated at the other two temperatures, spore viability was good at all three temperatures. Thus, despite temperature-induced variation in the genetic maps, yeast cells produce viable haploid products at a wide variety of sporulation temperatures. IMPORTANCE In the yeast Saccharomyces cerevisiae , recombination is usually studied in cells that undergo meiosis at 25°C or 30°C. In a genome-wide analysis, we showed that the locations of genomic regions with high and low levels of meiotic recombination (hot spots and cold spots, respectively) differed dramatically in cells sporulated at 14°C, 30°C, and 37°C. Thus, in yeast, and likely in other non-warm-blooded organisms, genetic maps are strongly affected by the environment.

scholarly journals HMBG1 as a Driver of Inflammatory and Immune Processes in the Pathogenesis of Ocular Diseases

2018 ◽  
Vol 2018 ◽  
pp. 1-8
Author(s):  
Yi Liu ◽  
Guo-Bin Zhuang ◽  
Xue-Zhi Zhou
Keyword(s):  
Current Knowledge ◽  
High Mobility ◽  
Retinal Cell ◽  
Ocular Diseases ◽  
Wide Range ◽  
Glycation End Products ◽  
Cell Layers ◽  
Proinflammatory Activity ◽  
And Migration ◽  
Proliferation And Migration

High-mobility group box 1 (HMGB1) is a nuclear protein that can also act as an extracellular trigger of inflammation, proliferation, and migration in eye diseases. It induces signaling pathways by binding to the receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs) 2, 4, and 9. This proinflammatory activity is considered to be important in the pathogenesis of a wide range of ocular diseases resulting from hemodynamic changes, presence of neovascular endothelial cells, secretion of intraocular immune factors or inflammation, and apoptosis of retinal cell layers. Further work is needed to elucidate in detail how HMGB1 contributes to ocular disease and how its damaging activity can be modulated. In this review, we summarize current knowledge on HMGB1 as a ligand that can evoke inflammation and immune responses in ocular diseases.

scholarly journals Possible role of natural selection in the formation of tandem-repetitive noncoding DNA.

Genetics ◽  
1994 ◽  
Vol 136 (1) ◽  
pp. 333-341
Author(s):  
W Stephan ◽  
S Cho
Keyword(s):  
Natural Selection ◽  
Satellite Dna ◽  
Repeat Length ◽  
Crossing Over ◽  
Recombination Rates ◽  
Noncoding Dna ◽  
Satellite Dnas ◽  
Unequal Crossing Over ◽  
Wide Range ◽  
Long Range Ordering

Abstract A simulation model of sequence-dependent amplification, unequal crossing over and mutation is analyzed. This model predicts the spontaneous formation of tandem-repetitive patterns of noncoding DNA from arbitrary sequences for a wide range of parameter values. Natural selection is found to play an essential role in this self-organizing process. Natural selection which is modeled as a mechanism for controlling the length of a nucleotide string but not the sequence itself favors the formation of tandem-repetitive structures. Two measures of sequence heterogeneity, inter-repeat variability and repeat length, are analyzed in detail. For fixed mutation rate, both inter-repeat variability and repeat length are found to increase with decreasing rates of (unequal) crossing over. The results are compared with data on micro-, mini- and satellite DNAs. The properties of minisatellites and satellite DNAs resemble the simulated structures very closely. This suggests that unequal crossing over is a dominant long-range ordering force which keeps these arrays homogeneous even in regions of very low recombination rates, such as at satellite DNA loci. Our analysis also indicates that in regions of low rates of (unequal) crossing over, inter-repeat variability is maintained at a low level at the expense of much larger repeat units (multimeric repeats), which are characteristic of satellite DNA. In contrast, the microsatellite data do not fit the proposed model well, suggesting that unequal crossing over does not act on these very short tandem arrays.

scholarly journals Some patterns and social impacts of external migration on a below-replacement population: Denmark by the turn of the millennium

1996 ◽  
pp. 136-149
Author(s):  
Hans O Hansen ◽  
Paul S. Maxim
Keyword(s):  
Population Growth ◽  
Social Impacts ◽  
Turn Of The Millennium ◽  
Differential Fertility ◽  
The Past ◽  
Naturalized Citizens ◽  
Wide Range ◽  
And Migration ◽  
The Impact ◽  
External Migration

As with many other nations in Europe, Denmark has experienced below-replacement fertility over the past three decades. The impact on population growth of the recent fertility decline to a large extent has been offset by a positive net balance of external migration. To provide a factual basis for a wide range of policy issues and social and cultural impacts we start by studying external migration, differential fertility, naturalization of foreign nationals, and population growth in the framework of multidimensional life models. Migrants and naturalized citizens tend to have reproductive behavior and sex/age profiles that differ significantly from those of the remaining population. To study some concerted demographic and social impacts of such differentials, we construct a number of midterm projections based on existing and expected development of fertility, mortality, and migration.

Decolonization and Migration

2014 ◽  
Author(s):  
Maud S. Mandel
Keyword(s):  
North Africa ◽  
North African ◽  
Social Actors ◽  
The North ◽  
Wide Range ◽  
French Colonial ◽  
Colonial Policies ◽  
And Migration ◽  
Jewish Populations ◽  
The Way

This chapter builds on the link between French colonial policies and Muslim–Jewish relations in the metropole by tracing how decolonization throughout North Africa changed the way a diverse set of social actors, including French colonial administrators, international Jewish spokesmen, and a wide range of indigenous nationalist groups conceptualized Jewish belonging throughout the region. It argues that the process led to the emergence of the “North African Jew,” a category to which no individual ascribed but that worked rhetorically to unite the diverse Moroccan, Tunisian, and Algerian Jewish populations into a collective often understood to be in conflict with “North Africans,” “Muslims,” or “Arabs.”

scholarly journals The Theory and Applications of Measuring Broad-Range and Chromosome-Wide Recombination Rate from Allele Frequency Decay around a Selected Locus

2020 ◽  
Vol 37 (12) ◽  
pp. 3654-3671
Author(s):  
Kevin H -C Wei ◽  
Aditya Mantha ◽  
Doris Bachtrog
Keyword(s):  
Genetic Distance ◽  
Allele Frequency ◽  
Recombination Rate ◽  
High Throughput Sequencing ◽  
Genetic Material ◽  
Cost Effective ◽  
Genetic Distances ◽  
Recombination Rates ◽  
Marker Selection ◽  
Cost Effective Approach

Abstract Recombination is the exchange of genetic material between homologous chromosomes via physical crossovers. High-throughput sequencing approaches detect crossovers genome wide to produce recombination rate maps but are difficult to scale as they require large numbers of recombinants individually sequenced. We present a simple and scalable pooled-sequencing approach to experimentally infer near chromosome-wide recombination rates by taking advantage of non-Mendelian allele frequency generated from a fitness differential at a locus under selection. As more crossovers decouple the selected locus from distal loci, the distorted allele frequency attenuates distally toward Mendelian and can be used to estimate the genetic distance. Here, we use marker selection to generate distorted allele frequency and theoretically derive the mathematical relationships between allele frequency attenuation, genetic distance, and recombination rate in marker-selected pools. We implemented nonlinear curve-fitting methods that robustly estimate the allele frequency decay from batch sequencing of pooled individuals and derive chromosome-wide genetic distance and recombination rates. Empirically, we show that marker-selected pools closely recapitulate genetic distances inferred from scoring recombinants. Using this method, we generated novel recombination rate maps of three wild-derived strains of Drosophila melanogaster, which strongly correlate with previous measurements. Moreover, we show that this approach can be extended to estimate chromosome-wide crossover interference with reciprocal marker selection and discuss how it can be applied in the absence of visible markers. Altogether, we find that our method is a simple and cost-effective approach to generate chromosome-wide recombination rate maps requiring only one or two libraries.

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