Effects Of Indels Research Articles

Deep molecular learning of transcriptional control of a synthetic CRE enhancer and its variants

Massively parallel reporter assay measures transcriptional activities of various cis-regulatory modules (CRMs) in a single experiment. We developed a thermodynamic computational model framework that calculates quantitative levels of gene expression directly from regulatory DNA sequences. Using the framework, we investigated the molecular mechanisms of cis-regulatory mutations of a synthetic enhancer that cause abnormal gene expression. We found that, in a human cell line, competitive binding between family transcription factors (TFs) with slightly different binding preferences significantly increases the accuracy of recapitulating the transcriptional effects of thousands of single- or multi-mutations. We also discovered that even if various harmful mutations occurred in an activator binding site, CRM could stably maintain or even increase gene expression through a certain form of competitive binding between family TFs. These findings enhance understanding the effect of SNPs and indels on CRMs and would help building robust custom-designed CRMs for biologics production and gene therapy.

Identification of polymorphisms in TYRP1, DCT and RAB38 genes and their association with coat color in alpacas

ObjectiveThe goal of this study was to characterize and investigate the effect of single nucleotide polymorphisms (SNPs) or InDels in tyrosinase related protein 1 (TYRP1), dopachrome tautomerase (DCT), and Ras-related protein 38 (RAB38) genes on coat color in South American camelids. TYRP1 is among one of the major regulators of pigmentation in mammals. DCT is a pigment cell-specific gene that plays an important role in the melanin synthesis pathway and the expression of skin color. RAB38 is involved in the transport of tyrosinase (TYR) and TYRP1, which are key enzymes in melanin production.MethodsFive fleece color tones from 327 alpacas (white, black, brown, gray and light fawn) were investigated to characterize and identify polymorphisms that play a role in coat color. Among the SNPs and Indels identified in the coding region, statistical analysis was performed to determine the association between the polymorphisms and fleece color in camelids, as well as the determination of allelic frequencies.ResultsTwenty two polymorphisms in the coding region, seven of them were nonsynonymous, eleven were synonymous, three located in the 5’UTR region and one deletion in the 3’UTR region were identified in the TYRP1 gene; in the DCT gene were identified twenty two polymorphisms, where five of them were non-synonymous, twelve were synonymous, one polymorphism in the 5’UTR region and four in the 3’UTR region; in adition, in the RAB38 gene six polymorphisms were identified, one was nonsynonymous, two were synonymous, in addition to three polymorphisms in the 3’UTR region were found in the RAB38 gene. There were low to moderate polymorphisms in the populations. Significant differences (P<0.001) were found with color fiber in the alpaca populations studied for TYRP1 and DCT genes.

Impact of COVID‐19 on Bangladesh's agriculture sector and the ways forward to recovery: An overview

The COVID‐19 outbreak has left an indelible effect on Bangladesh's agriculture sector, like that of most developing countries. Considering that agriculture is the cornerstone of Bangladesh's economy, we made an effort to compile a detailed scenario of COVID‐19's effect on it through a relevant literature review. Since no significant studies outlined a complete picture of the pandemic's impact on agriculture, our study ventured to reveal the circumstances of each sub‐sector of agriculture. During the early phases of the pandemic, farmers engaged in agriculture production got poor prices, with the majority of them incurring losses. Labor shortages and input scarcity were the most prevailing hindrances across all the sub‐sectors. The export volume seemed to shrink hugely, hurting the country's GDP. The supply chain for agricultural commodities was disrupted as a result of the lockdown and mobility restrictions, which resulted in the elimination of the majority of intermediaries. Unprecedented challenges occurred in the input and output markets, as well as in the agro‐industries, exacerbating the situation. However, while the vegetables and poultry sub‐sectors recovered utterly and the dairy sub‐sector somehow managed to stabilize, other sub‐sectors are still grieving. This study highlighted some policies that can mitigate the miseries of the agriculture sector and overcome further potential threats in Bangladesh and other agriculture‐led developing countries.

Functional genomic effects of indels using Bayesian genome-phenome wide association studies in sorghum.

High-throughput genomic and phenomic data have enhanced the ability to detect genotype-to-phenotype associations that can resolve broad pleiotropic effects of mutations on plant phenotypes. As the scale of genotyping and phenotyping has advanced, rigorous methodologies have been developed to accommodate larger datasets and maintain statistical precision. However, determining the functional effects of associated genes/loci is expensive and limited due to the complexity associated with cloning and subsequent characterization. Here, we utilized phenomic imputation of a multi-year, multi-environment dataset using PHENIX which imputes missing data using kinship and correlated traits, and we screened insertions and deletions (InDels) from the recently whole-genome sequenced Sorghum Association Panel for putative loss-of-function effects. Candidate loci from genome-wide association results were screened for potential loss of function using a Bayesian Genome-Phenome Wide Association Study (BGPWAS) model across both functionally characterized and uncharacterized loci. Our approach is designed to facilitate in silico validation of associations beyond traditional candidate gene and literature-search approaches and to facilitate the identification of putative variants for functional analysis and reduce the incidence of false-positive candidates in current functional validation methods. Using this Bayesian GPWAS model, we identified associations for previously characterized genes with known loss-of-function alleles, specific genes falling within known quantitative trait loci, and genes without any previous genome-wide associations while additionally detecting putative pleiotropic effects. In particular, we were able to identify the major tannin haplotypes at the Tan1 locus and effects of InDels on the protein folding. Depending on the haplotype present, heterodimer formation with Tan2 was significantly affected. We also identified major effect InDels in Dw2 and Ma1, where proteins were truncated due to frameshift mutations that resulted in early stop codons. These truncated proteins also lost most of their functional domains, suggesting that these indels likely result in loss of function. Here, we show that the Bayesian GPWAS model is able to identify loss-of-function alleles that can have significant effects upon protein structure and folding as well as multimer formation. Our approach to characterize loss-of-function mutations and their functional repercussions will facilitate precision genomics and breeding by identifying key targets for gene editing and trait integration.

The Victimized Personas in Jean Rhys’s Wide Sargasso Sea and Charlotte Bronte’s Jane Eyre, Feminism Perspectives

The Wide Sargasso Sea - (1966). After years of contemplating Charlotte Bronte's Creole madwoman Bertha Mason, Jean Rhys set out to give voice to what is mute in Bronte’s Jane Eyre. Rhys lets Antoinette narrate her tale, revealing the "other side" of Bronte's story: what occurred in the years before and after Mr. Rochester's first marriage in Jamaica. As a twentieth-century West Indian writer, Rhys was able to expose implicit assumptions and ideals in Bronte's writing, such as imperialist England's attitude toward her colonies. The natural environment is a mirror of interior states of being and emotion, a remark on the novel's characterization and action. Even though the two books seem to be identical, they are not. Rhys flips Bronte's Victorian Romantic symbols, Wide Sargasso Sea appears more contemporary and realistic. This paper aims to highlight the victimized characters in both novels and gives a real comparison of the most victimized ones. Both works, respectively, show women fighting patriarchy and injustice at any historical time. From a feminist standpoint, this study compares, Bertha Mason, in the two narratives. Even though Wide Sargasso Sea is a forerunner to Jane Eyre, Rhys expressed a more progressive and revolutionary feminist viewpoint. Bertha Mason is a more victimized female than Jane of the patriarchal system and colonization. These feminist works have left an indelible effect on literature. Most literary commentators have concentrated on Jane, the protagonist of Charlotte Bronte's narrative, on the other hand, there is Bertha Mason, the insane lady on the upper floor imprisoned, as just Jane's evil twin. Bertha has received much less attention than Jane, not as an evil side of Jane, but as a stand-alone figure. This study compares Bertha Mason's representation in Jane Eyre and Wide Sargasso Sea. Bertha, who acts as an impediment to Jane's pleasure in Jane Eyre, is recognized as a victim of society.

A look at the global impact of COVID-19 pandemic on neurosurgical services and residency training

BackgroundThe COVID-19 pandemic has left an indelible effect on healthcare delivery and education system, including residency training. Particularly, neurosurgical departments worldwide had to adapt their operating model to the constantly changing pandemic landscape. This review aimed to quantify the reduction in neurosurgical operative volume and describe the impact of these trends on neurosurgical residency training. MethodsWe performed a comprehensive search of PubMed and EMBASE between December 2019 and October 2022 to identify studies comparing pre-pandemic and pandemic neurosurgical caseloads as well as articles detailing the impact of COVID-19 on neurosurgery residency training. Statistical analysis of quantitative data was presented as pooled odds ratio (OR) and 95% confidence intervals (CI). ResultsA total of 49 studies met the inclusion criteria, of which 12 (24.5%) were survey-based. The case volume of elective surgeries and non-elective procedures decreased by 70.4% (OR=0.296, 95%CI 0.210–0.418) and 68.2% (OR=0.318, 95%CI 0.193–0.525), respectively. A significant decrease was also observed in functional (OR=0.542, 95%CI 0.394–0.746), spine (OR=0.545, 95%CI 0.409–0.725), and skull base surgery (OR=0.545, 95%CI 0.409–0.725), whereas the caseloads for tumor (OR=1.029, 95%CI 0.838–1.263), trauma (OR=1.021, 95%CI 0.846–1.232), vascular (OR=1.001, 95%CI 0.870–1.152), and pediatric neurosurgery (OR=0.589, 95%CI 0.344–1.010) remained relatively the same between pre-pandemic and pandemic periods. The reduction in caseloads had caused concerns among residents and program directors in regard to the diminished clinical exposure, financial constraints, and mental well-being. Some positives highlighted were rapid adaptation to virtual educational platforms and increasing time for self-learning and research activities. ConclusionWhile COVID-19 has brought about significant disruptions in neurosurgical practice and training, this unprecedented challenge has opened the door for technological advances and collaboration that broaden the accessibility of resources and reduce the worldwide gap in neurosurgical education.

Elucidating the Structural Impacts of Protein InDels.

The effects of amino acid insertions and deletions (InDels) remain a rather under-explored area of structural biology. These variations oftentimes are the cause of numerous disease phenotypes. In spite of this, research to study InDels and their structural significance remains limited, primarily due to a lack of experimental information and computational methods. In this work, we fill this gap by modeling InDels computationally; we investigate the rigidity differences between the wildtype and a mutant variant with one or more InDels. Further, we compare how structural effects due to InDels differ from the effects of amino acid substitutions, which are another type of amino acid mutation. We finish by performing a correlation analysis between our rigidity-based metrics and wet lab data for their ability to infer the effects of InDels on protein fitness.

Building Blocks of Society: History, Information Ecosystems, and Infrastructures

Building Blocks of Society: History, Information Ecosystems, and Infrastructures

Insertions and Deletions (Indels): A Missing Piece of the Protein Engineering Jigsaw.

Over the years, protein engineers have studied nature and borrowed its tricks to accelerate protein evolution in the test tube. While there have been considerable advances, our ability to generate new proteins in the laboratory is seemingly limited. One explanation for these shortcomings may be that insertions and deletions (indels), which frequently arise in nature, are largely overlooked during protein engineering campaigns. The profound effect of indels on protein structures, by way of drastic backbone alterations, could be perceived as "saltation" events that bring about significant phenotypic changes in a single mutational step. Should we leverage these effects to accelerate protein engineering and gain access to unexplored regions of adaptive landscapes? In this Perspective, we describe the role played by indels in the functional diversification of proteins in nature and discuss their untapped potential for protein engineering, despite their often-destabilizing nature. We hope to spark a renewed interest in indels, emphasizing that their wider study and use may prove insightful and shape the future of protein engineering by unlocking unique functional changes that substitutions alone could never achieve.

A Population-Genetic Lens into the Process of Gene Loss Following Whole-Genome Duplication.

Whole-genome duplications (WGDs) have occurred in many eukaryotic lineages. However, the underlying evolutionary forces and molecular mechanisms responsible for the long-term retention of gene duplicates created by WGDs are not well understood. We employ a population-genomic approach to understand the selective forces acting on paralogs and investigate ongoing duplicate-gene loss in multiple species of Paramecium that share an ancient WGD. We show that mutations that abolish protein function are more likely to be segregating in retained WGD paralogs than in single-copy genes, most likely because of ongoing nonfunctionalization post-WGD. This relaxation of purifying selection occurs in only one WGD paralog, accompanied by the gradual fixation of nonsynonymous mutations and reduction in levels of expression, and occurs over a long period of evolutionary time, “marking” one locus for future loss. Concordantly, the fitness effects of new nonsynonymous mutations and frameshift-causing indels are significantly more deleterious in the highly expressed copy compared with their paralogs with lower expression. Our results provide a novel mechanistic model of gene duplicate loss following WGDs, wherein selection acts on the sum of functional activity of both duplicate genes, allowing the two to wander in expression and functional space, until one duplicate locus eventually degenerates enough in functional efficiency or expression that its contribution to total activity is too insignificant to be retained by purifying selection. Retention of duplicates by such mechanisms predicts long times to duplicate-gene loss, which should not be falsely attributed to retention due to gain/change in function.

Building America: The Life of Benjamin Henry Latrobe

Benjamin Henry Latrobe was one of those early American figures whose talents, outsized personality, and rises and falls reveal much about the new United States. Jean H. Baker argues that he ought to be considered “a founder of the republic—not of political ideas but of the neoclassical buildings and substantial internal improvements that expressed those ideals” (p. 1). Latrobe's work as an architect and designer had an indelible effect on the nation. And because of Baker's painstaking reconstruction of his life, we now know much more about the character behind those visions. As the author demonstrates, understanding Latrobe requires unpacking the man's many contradictions. Raised in a Moravian community in Fulneck, northern England, and initially intended for the church, he ultimately became a deist. Whereas the Moravians in Fulneck had raised children communally rather than under the control of their birth parents, he embraced the nuclear family model as an...

In rice splice variants that restore the reading frame after frameshifting indel introduction are common, often induced by the indels and sometimes lead to organism-level rescue.

The introduction of frameshifting non-3n indels enables the identification of gene-trait associations. However, it has been hypothesised that recovery of the original reading frame owing to usage of non-canonical splice forms could cause rescue. To date there is very little evidence for organism-level rescue by such a mechanism and it is unknown how commonly indels induce, or are otherwise associated with, frame-restoring splice forms. We perform CRISPR/Cas9 editing of randomly selected loci in rice to investigate these issues. We find that the majority of loci have a frame-restoring isoform. Importantly, three quarters of these isoforms are not seen in the absence of the indels, consistent with indels commonly inducing novel isoforms. This is supported by analysis in the context of NMD knockdowns. We consider in detail the two top rescue candidates, in wax deficient anther 1 (wda1) and brittle culm (bc10), finding that organismal-level rescue in both cases is strong but owing to different splice modification routes. More generally, however, as frame-restoring isoforms are low abundance and possibly too disruptive, such rescue we suggest to be the rare exception, not the rule. Nonetheless, assuming that indels commonly induce frame-restoring isoforms, these results emphasize the need to examine RNA level effects of non-3n indels and suggest that multiple non-3n indels in any given gene are advisable to probe a gene’s trait associations.

Protein design and variant prediction using autoregressive generative models

The ability to design functional sequences and predict effects of variation is central to protein engineering and biotherapeutics. State-of-art computational methods rely on models that leverage evolutionary information but are inadequate for important applications where multiple sequence alignments are not robust. Such applications include the prediction of variant effects of indels, disordered proteins, and the design of proteins such as antibodies due to the highly variable complementarity determining regions. We introduce a deep generative model adapted from natural language processing for prediction and design of diverse functional sequences without the need for alignments. The model performs state-of-art prediction of missense and indel effects and we successfully design and test a diverse 105-nanobody library that shows better expression than a 1000-fold larger synthetic library. Our results demonstrate the power of the alignment-free autoregressive model in generalizing to regions of sequence space traditionally considered beyond the reach of prediction and design.

Research on the Mode of Urban Planning and Construction under the Concept of Green City

The history of urban planning in the world is also a history of the development of excellent planning ideas. Planning ideas have been continuously improved in urban evolution and historical baptism. Good planning has an indelible effect on the development of cities, the solution of urban problems, and the shaping of urban beauty. This article discusses the significance of planning and building a green city, analyzes the current basic conditions of urban construction, management and development, as well as existing contradictions and problems, and proposes countermeasures to solve the problems.

Comparative assessments of indel annotations in healthy and cancer genomes with next-generation sequencing data

BackgroundInsertion and deletion (indel) is one of the major variation types in human genomes. Accurate annotation of indels is of paramount importance in genetic variation analysis and investigation of their roles in human diseases. Previous studies revealed a high number of false positives from existing indel calling methods, which limits downstream analyses of the effects of indels on both healthy and disease genomes. In this study, we evaluated seven commonly used general indel calling programs for germline indels and four somatic indel calling programs through comparative analysis to investigate their common features and differences and to explore ways to improve indel annotation accuracy.MethodsIn our comparative analysis, we adopted a more stringent evaluation approach by considering both the indel positions and the indel types (insertion or deletion sequences) between the samples and the reference set. In addition, we applied an efficient way to use a benchmark for improved performance comparisons for the general indel calling programsResultsWe found that germline indels in healthy genomes derived by combining several indel calling tools could help remove a large number of false positive indels from individual programs without compromising the number of true positives. The performance comparisons of somatic indel calling programs are more complicated due to the lack of a reliable and comprehensive benchmark. Nevertheless our results revealed large variations among the programs and among cancer types.ConclusionsWhile more accurate indel calling programs are needed, we found that the performance for germline indel annotations can be improved by combining the results from several programs. In addition, well-designed benchmarks for both germline and somatic indels are key in program development and evaluations.

Novel InDels of GHR, GHRH, GHRHR and Their Association with Growth Traits in Seven Chinese Sheep Breeds.

Simple SummaryIt is advantageous to find the potential molecular markers which are associated with the growth and development of mutton sheep through molecular breeding. In this study, four molecular markers were selected from growth hormone receptor (GHR), one was found on growth hormone releasing hormone (GHRH) and growth hormone releasing hormone receptor (GHRHR), respectively. The purposes of this paper were to screen molecular makers in the related genes of the growth hormone (GH) axis and provide theoretical basis for molecular breeding and genetic selection of mutton sheep. In this study, six molecular markers were selected from the genes for growth hormone receptor (GHR), growth hormone releasing hormone (GHRH), and growth hormone releasing hormone receptor (GHRHR). The three molecular markers in GHR and one in GHRHR could potentially be used for marker assisted selection of growing-related traits in mutton sheep.The GH growth axis plays an important role in the growth and development of animals and runs through the whole life of animals. Many studies have shown that molecular mutations in key genes of the GH axis will affect the growth and development of animals. The purpose of this study was to explore the distribution characteristics of InDels of GHR, GHRH, and GHRHR in seven Chinese sheep populations, and to further explore the relationship between InDels and sheep growth traits. GHR showed high variation in Chinese sheep, and GHR-53 showed the highest minimum allele frequency (MAF). There was only one InDel mutation site in both GHRH and GHRHR. The genotype frequencies of Hu sheep (HS), Tong sheep (TS), and Lanzhou fat-tail sheep (LFTS) were quite different from other breeds. The association between GHR, GHRH, and GHRHR InDels and body size traits in seven varieties were analyzed. The results showed that there was no significant relationship between GHRH and body size traits in the seven sheep populations. There was a positive association between GHR-21 and hip height of LFSH (p < 0.05). GHR-43 reduced body height and chest depth of Small tail han sheep (STHS) and hip width of TS. GHR-44 significantly affected the body weight of HS, the body height of STHS and the head depth of TS. GHR-53 significantly reduced cannon girth of HS, chest of STHS and forehead width of TS. GHRHR-2 significantly reduced the body weight of LFHS. To sum up, this study revealed the effects of GHR, GHRH, and GHRHR InDels on sheep phenotypic traits, which indicated their potential application prospects in the genetic improvement of mutton sheep.

Genetic Variability of Indels in the Prolactin and Dopamine Receptor D2 Genes and Their Association with the Yield of Allanto-Amniotic Fluid in Russian White Laying Hens

Currently, there is virtually no information on genetic factors affecting the yield of allanto-amniotic fluid, which is the raw material for the production of human and animal vaccines. Association studies including this trait are beneficial for increasing productivity of a biotechnological line of chickens used for the production of ‘Clean Eggs’. We examined here a population of the Russian White breed for the effects of indels in the prolactin (PRL) and dopamine receptor D2 (DRD2) genes on the yield of extraembryonic fluid (YEF) and embryo weight at 12.5 days of development. A 24-bp insertion in the 5' flanking region of the PRL gene significantly (P<0.01) increases YEF in the embryos. The heterozygous embryos contained the highest YEF (9.6 mL) than that of the homozygous insertion (9.4 mL) and deletion embryos (8.4 mL). We also found a significant association (P<0.001) between the PRL genotypes and egg weight (EW). The results of the present study suggest a significant association between the PRL gene variation and quantitative traits in the Russian White chickens, contributing to a long-term programme on the effective use of the genetic potential of Russian gene pool breeds and populations of chickens.

A 31-bp indel in the 5\u2032 UTR region of GNB1L is significantly associated with chicken body weight and carcass traits

BackgroundG-protein subunit beta 1 like (GNB1L) encodes a G-protein beta-subunit-like polypeptide. Chicken GNB1L is upregulated in the breast muscle of high feed efficiency chickens, and its expression is 1.52-fold that in low feed efficiency chickens. However, no report has described the effects of GNB1L indels on the chicken carcass and growth traits.ResultsThis study identified a 31-bp indel in the 5′ untranslated region (UTR) of GNB1L and elucidated the effect of this gene mutation on the carcass and growth traits in chickens. The 31-bp indel showed a highly significant association with the body weight at 8 different stages and was significantly correlated with daily gains at 0 to 4 weeks and 4 to 8 weeks. Similarly, the mutation was significantly associated with small intestine length, breast width, breast depth and breast muscle weight. Moreover, DD and ID were superior genotypes for chicken growth and carcass traits.ConclusionsThese results show that the 31-bp indel of GNB1L significantly affects chicken body weight and carcass traits and can serve as a candidate molecular marker for chicken genetics and breeding programs.

Sleep-Wake Disorders in Childhood.

The presentation of sleep issues in childhood differs from the presentation in adulthood and may be more subtle. Sleep issues may affect children differently than adults, and distinct treatment approaches are often used in children. Sodium oxybate was approved by the US Food and Drug Administration (FDA) in October 2018 for an expanded indication of treatment of sleepiness or cataplexy in patients with narcolepsy type 1 or narcolepsy type 2 aged 7 years or older, with side effect and safety profiles similar to those seen in adults. Restless sleep disorder is a recently proposed entity in which restless sleep, daytime sleepiness, and often iron deficiency are observed, but children do not meet the criteria for restless legs syndrome or periodic limb movement disorder. Children's sleep is discussed in this article, including normal sleep patterns and effects of insufficient sleep. Sleep disorders of childhood are reviewed, including insomnia, obstructive sleep apnea, restless legs syndrome, parasomnias, narcolepsy, and Kleine-Levin syndrome. Children with neurologic issues or neurodevelopmental disorders frequently have sleep disorders arising from an interaction of heterogeneous factors. Further attention to sleep may often be warranted through a polysomnogram or referral to a pediatric sleep specialist. Sleep disorders may cause indelible effects on children's cognitive functioning, general health, and well-being, and awareness of sleep disorders is imperative for neurologists who treat children.

From the Sunken Place to the Shitty Place: The Film Get Out, Psychic Emancipation and Modern Race Relations From a Psychodynamic Clinical Perspective

Increasingly, as analysts and psychotherapists, we engage in racial encounters that challenge concepts of empathy, neutrality, and anonymity. This paper attempts to enter this dynamic space to uncover the utility of working within racial tensions for its inherent therapeutic value. Part of this challenge for the clinician, who often identifies and is identified as liberal, is to acknowledge the ubiquity of race as unconsciously structuralizing along with our defenses against this recognition. The intransigence of racism, as formed intrapsychically and discovered in our working functions as analysts and psychotherapists, when not actively challenged and reflected on will be explored. Attempts to explicate the indelible effects of race in the American clinician will be provided that goes beyond countertransference or enactments. Clinical examples and connections to modern cinema are utilized to provide a framework to advance our knowledge in working with racial material.