Global Constraints within the Developmental Program of the Drosophila Wing

Organismal development is a complex process, involving a vast number of molecular constituents interacting on multiple spatio-temporal scales in the formation of intricate body structures. Despite this complexity, development is remarkably reproducible and displays tolerance to both genetic and environmental perturbations. This robustness implies the existence of hidden simplicities in developmental programs. Here, using the Drosophila wing as a model system, we develop a new quantitative strategy that enables a robust description of biologically salient phenotypic variation. Analyzing natural phenotypic variation across a highly outbred population, and variation generated by weak perturbations in genetic and environmental conditions, we observe a highly constrained set of wing phenotypes. Remarkably, the phenotypic variants can be described by a single integrated mode that corresponds to a non-intuitive combination of structural variations across the wing. This work demonstrates the presence of constraints that funnel environmental inputs and genetic variation into phenotypes stretched along a single axis in morphological space. Our results provide quantitative insights into the nature of robustness in complex forms while yet accommodating the potential for evolutionary variations. Methodologically, we introduce a general strategy for finding such invariances in other developmental contexts.

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Requirements Engineering

Requirements Engineering for Sociotechnical Systems ◽

10.4018/978-1-59140-506-1.ch001 ◽

2011 ◽

pp. 1-20 ◽

Cited By ~ 9

Author(s):

Päivi Parviainen ◽

Maarit Tihinen ◽

Marco Lormanms ◽

Rini van Solingen

Keyword(s):

Requirements Engineering ◽

Sociotechnical Systems ◽

Software Requirements ◽

Main Process ◽

Vast Number ◽

Complex Process ◽

System Requirements ◽

Systems Requirements ◽

Continuous Activities ◽

Requirements Development

This chapter introduces requirements engineering for sociotechnical systems. Requirements engineering for sociotechnical systems is a complex process that considers product demands from a vast number of viewpoints, roles, responsibilities, and objectives. This chapter explains the requirements engineering terminology and describes the requirements engineering process in detail, with examples of available methods for the main process activities. The main activities described include system requirements development, requirements allocation and flow-down, software requirements development, and continuous activities, including requirements documentation, requirements validation and verification, and requirements management. As requirements engineering is the process with the largest impact on the end product, it is recommended to invest more effort in both industrial application as well as research to increase understanding and deployment of the concepts presented in this chapter.

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Environmental perturbations lead to extensive directional shifts in RNA processing

10.1101/119974 ◽

2017 ◽

Author(s):

A. L. Richards ◽

D. Watza ◽

A. Findley ◽

A. Alazizi ◽

X. Wen ◽

...

Keyword(s):

Gene Expression ◽

Genetic Variation ◽

Rna Processing ◽

Complex Traits ◽

Intron Retention ◽

Vast Number ◽

Factor Binding ◽

Environmental Perturbations ◽

Exon Usage ◽

The Impact

AbstractEnvironmental perturbations have large effects on both organismal and cellular traits, including gene expression, but the extent to which the environment affects RNA processing remains largely uncharacterized. Recent studies have identified a large number of genetic variants associated with variation in RNA processing that also have an important role in complex traits; yet we do not know in which contexts the different underlying isoforms are used. Here, we comprehensively characterized changes in RNA processing events across 89 environments in five human cell types and identified 15,300 event shifts (FDR = 15%) comprised of eight event types in over 4,000 genes. Many of these changes occur consistently in the same direction across conditions, indicative of global regulation by trans factors. Accordingly, we demonstrate that environmental modulation of splicing factor binding predicts shifts in intron retention, and that binding of transcription factors predicts shifts in AFE usage in response to specific treatments. We validated the mechanism hypothesized for AFE in two independent datasets. Using ATAC-seq, we found altered binding of 64 factors in response to selenium at sites of AFE shift, including ELF2 and other factors in the ETS family. We also performed AFE QTL mapping in 373 individuals and found an enrichment for SNPs predicted to disrupt binding of the ELF2 factor. Together, these results demonstrate that RNA processing is dramatically changed in response to environmental perturbations through specific mechanisms regulated by trans factors.Author SummaryChanges in a cell’s environment and genetic variation have been shown to impact gene expression. Here, we demonstrate that environmental perturbations also lead to extensive changes in alternative RNA processing across a large number of cellular environments that we investigated. These changes often occur in a non-random manner. For example, many treatments lead to increased intron retention and usage of the downstream first exon. We also show that the changes to first exon usage are likely dependent on changes in transcription factor binding. We provide support for this hypothesis by considering how first exon usage is affected by disruption of binding due to treatment with selenium. We further validate the role of a specific factor by considering the effect of genetic variation in its binding sites on first exon usage. These results help to shed light on the vast number of changes that occur in response to environmental stimuli and will likely aid in understanding the impact of compounds to which we are daily exposed.

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Embryonic geometry underlies phenotypic variation in decanalized conditions

10.1101/579623 ◽

2019 ◽

Author(s):

A. Huang ◽

T. E. Saunders

Keyword(s):

Phenotypic Variation ◽

Regulatory Network ◽

Physical Space ◽

Model Organisms ◽

Wild Type ◽

Environmental Perturbations ◽

Key Factor ◽

In The Wild ◽

Gene Regulatory ◽

Anterior Posterior

AbstractDuring development, many mutations cause increased variation in phenotypic outcomes, a phenomenon termed decanalization. Such variations can often be attributed to genetic and environmental perturbations. However, phenotypic discordance remains even in isogenic model organisms raised in homogeneous environments. To understand the mechanisms underlying phenotypic variation, we used as a model the highly precise anterior-posterior (AP) patterning of the early Drosophila embryo. We decanalized the system by depleting the maternal bcd product and found that in contrast to the highly scaled patterning in the wild-type, the segmentation gene boundaries shift away from the scaled positions according to the total embryonic length. Embryonic geometry is hence a key factor predetermining patterning outcomes in such decanalized conditions. Embryonic geometry was also found to predict individual patterning outcomes under bcd overexpression, another decanalizing condition. Further analysis of the gene regulatory network acting downstream of the morphogen identified vulnerable points in the networks due to limitations in the available physical space.

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A georeferenced dataset of drought and heat-induced tree mortality in Europe

One Ecosystem ◽

10.3897/oneeco.4.e37753 ◽

2019 ◽

Vol 4 ◽

Cited By ~ 3

Author(s):

Giovanni Caudullo ◽

José I Barredo

Keyword(s):

Tree Mortality ◽

Data File ◽

Ecosystem Functions ◽

Temporal Data ◽

Forest Dieback ◽

Complex Interactions ◽

Lack Of Information ◽

Complex Process ◽

Spatio Temporal ◽

Systematic Collection

Global warming is altering climate patterns and the frequency and magnitude of heat and drought events affecting ecosystems worldwide. One of the effects of these changes is tree mortality driven by heat and drought, which have effects in forest ecosystem functions, services and biodiversity. Therefore, systematic observations and georeferenced data on tree mortality is a fundamental prerequisite for a more comprehensive understanding of the complex interactions between climate and forests. Tree mortality is a complex process for which literature presents major knowledge gaps, making predictions on the fate of climate change challenging. Some of the gaps are due to limited spatio-temporal data on tree mortality. Despite extensive tree mortality and forest dieback, associated with drought and temperature stress, have been reported in Europe, a publicly available systematic collection of georeferenced data reporting tree mortality is lacking. The dataset presented in this paper is a contribution to mitigate the lack of information on tree mortality. Our dataset builds on scientific and peer-reviewed literature and provides a georeferenced set of documented tree mortality occurrences in the period 1970-2017 in Europe. The aim of this study is to describe the creation of the dataset and to provide the data file to interested users.

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The landscape of human mutually exclusive splicing

10.1101/133215 ◽

2017 ◽

Author(s):

Klas Hatje ◽

Ramon O. Vidal ◽

Raza-Ur Rahman ◽

Dominic Simm ◽

Björn Hammesfahr ◽

...

Keyword(s):

Strong Evidence ◽

Human Disease ◽

Biological Role ◽

Rna Seq ◽

Timothy Syndrome ◽

Temporal Expression ◽

Genome Wide ◽

Spatio Temporal ◽

Organismal Development

AbstractMutually exclusive splicing of exons is a mechanism of functional gene and protein diversification with pivotal roles in organismal development and diseases such as Timothy syndrome, cardiomyopathy and cancer in humans. In order to obtain a first genome-wide estimate of the extent and biological role of mutually exclusive splicing in humans we predicted and subsequently validated mutually exclusive exons (MXEs) using 515 publically available RNA-seq datasets. Here, we provide evidence for the expression of over 855 MXEs, 42% of which represent novel exons, increasing the annotated human mutually exclusive exome more than five-fold. The data provides strong evidence for the existence of large and multi-cluster MXEs in higher vertebrates and offers new insights into MXE splicing mechanics and evolution. Finally, MXEs are significantly enriched in pathogenic mutations and their spatio-temporal expression predicts human disease pathology.

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Cortical visual prosthesis: a detailed large-scale simulation study

10.1101/610378 ◽

2019 ◽

Author(s):

Jan Antolik ◽

Quentin Sabatier ◽

Charlie Galle ◽

Yves Frègnac ◽

Ryad Benosman

Keyword(s):

Temporal Pattern ◽

Large Scale ◽

Spatial Configuration ◽

Visual Prosthesis ◽

Neural Network Modeling ◽

General Strategy ◽

Road Map ◽

Starting Point ◽

Vision Restoration ◽

Spatio Temporal

AbstractRecent advances in applying optogenetics in primates initiated the development of light based prosthetic implants for sensory restoration. Thanks to being the most well explored cortical area that is readily accessible at the surface of the brain, vision restoration via direct optogenetic activation of primary visual cortex is one of the most promising early targets for a optogenetics based prosthetic program. However, two fundamental elements of the cortical optogenetic prosthesis remain unclear. First, the exact mechanisms of neural dynamics under direct cortical stimulation, especially in the context of living, active and functionally specific intra-cortical neural circuitry, is poorly understood. Second, we lack protocols for transformation of arbitrary visual stimuli into light activation patterns that would induce perception of the said stimulus by the subject. In this study we address these issues using a large-scale spiking neural network modeling strategy of high biological fidelity. We examine the relationship between specific spatial configuration of light delivered to cortex and the resulting spatio-temporal pattern of activity evoked in the simulated cortical circuitry. Using such virtual experiments, we design a protocol for translation of a specific set of stimuli to activation pattern of a matrix of light emitting elements and provide a detailed assessment of the resulting cortical activations with respect to the natural vision control condition. In this study we restrict our focus to the grating stimulus class, which are an ideal starting point for exploration due to their thoroughly characterized representation in V1 and well-defined information content. However, we also provide an outline of a straight-forward road-map for transforming this grating centric stimulation protocol towards general strategy capable of transforming arbitrary spatio-temporal visual stimulus to a spatio-temporal pattern of light, thus enabling vision restoration via optogenetic V1 activation.

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The Power of Human Cancer Genetics as Revealed by Low-Grade Gliomas

Annual Review of Genetics ◽

10.1146/annurev-genet-120417-031642 ◽

2019 ◽

Vol 53 (1) ◽

pp. 483-503 ◽

Cited By ~ 3

Author(s):

David T.W. Jones ◽

Pratiti Bandopadhayay ◽

Nada Jabado

Keyword(s):

Large Scale ◽

Cancer Genetics ◽

Brain Size ◽

Human Cancer ◽

Low Grade ◽

Structural Variations ◽

Vast Number ◽

Low Grade Gliomas ◽

Molecular Alterations ◽

Age Related

The human brain contains a vast number of cells and shows extraordinary cellular diversity to facilitate the many cognitive and automatic commands governing our bodily functions. This complexity arises partly from large-scale structural variations in the genome, evolutionary processes to increase brain size, function, and cognition. Not surprisingly given recent technical advances, low-grade gliomas (LGGs), which arise from the glia (the most abundant cell type in the brain), have undergone a recent revolution in their classification and therapy, especially in the pediatric setting. Next-generation sequencing has uncovered previously unappreciated diverse LGG entities, unraveling genetic subgroups and multiple molecular alterations and altered pathways, including many amenable to therapeutic targeting. In this article we review these novel entities, in which oncogenic processes show striking age-related neuroanatomical specificity (highlighting their close interplay with development); the opportunities they provide for targeted therapies, some of which are already practiced at the bedside; and the challenges of implementing molecular pathology in the clinic.

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The mechanisms of gene regulatory networks constrain evolution: A lesson from synthetic circuits

10.1101/184325 ◽

2017 ◽

Author(s):

Yolanda Schaerli ◽

Alba Jiménez ◽

José M. Duarte ◽

Ljiljana Mihajlovic ◽

Julien Renggli ◽

...

Keyword(s):

Gene Expression ◽

Gene Regulatory Networks ◽

Phenotypic Variation ◽

Regulatory Networks ◽

Molecular Mechanisms ◽

Raw Material ◽

Darwinian Evolution ◽

Regulatory Mechanisms ◽

Gene Regulatory ◽

Organismal Development

AbstractPhenotypic variation is the raw material of adaptive Darwinian evolution. The phenotypic variation found in organismal development is biased towards certain phenotypes, but the molecular mechanisms behind such restrictions are still poorly understood. Gene regulatory networks have been proposed as one cause of constrained phenotypic variation. However, most of the evidence for this is theoretical rather than experimental. Here, we study evolutionary biases in two synthetic gene regulatory circuits expressed inE. colithat produce a gene expression stripe - a pivotal pattern in embryonic development. The two parental circuits produce the same phenotype, but create it through different regulatory mechanisms. We show that mutations cause distinct novel phenotypes in the two networks and use a combination of experimental measurements, mathematical modelling and DNA sequencing to understand why mutations bring forth only some but not other novel gene expression phenotypes. Our results reveal that the regulatory mechanisms of networks restrict the possible phenotypic variation upon mutation. Consequently, seemingly equivalent networks can indeed be distinct in how they constrain the outcome of further evolution.

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A Stochastic Model for Actin Waves in Eukaryotic Cells

10.1101/2019.12.31.892034 ◽

2019 ◽

Cited By ~ 1

Author(s):

Jifeng Hu ◽

Varunyu Khamviwath ◽

Hans G. Othmer

Keyword(s):

Stochastic Model ◽

Mechanical Response ◽

Dynamical Behavior ◽

Eukaryotic Cells ◽

Actin Network ◽

Produce Cell ◽

Complex Process ◽

Propagating Waves ◽

Spatio Temporal ◽

Actin Waves

AbstractA stochastic model of spontaneous actin wave formation in eukaryotic cells that includes positive feedback between the actin network and filament nucleating factors on the membrane is developed and analyzed. Simulation results show that the model can produce a variety of actin network behavior depending on the conditions. Actin spots of diameter about 0.5 µm can be formed and persist for tens of seconds at low actin concentrations, and these spots may either shrink and die or grow and develop into fully-developed propagating waves. The model correctly captures the vertical profile of actin waves along line scans through wave fronts, as well as the separation between the region enclosed by circular actin waves and the external area. Our results show how the complicated actin behavior depends on the amounts and state of various membrane molecules.Author SummaryLocomotion of eukaryotic cells is a complex process that involves the spatio-temporal control and integration of a number of sub-processes, including the transduction of chemical or mechanical signals from the environment, local and global modification of the cytoskeleton, and translation of the intra- and extracellular signals into a mechanical response. In view of the complexity of the processes, understanding how force generation and mechanical interactions with the surroundings are controlled in space and time to produce cell-level movement is a major challenge. Recent experimental work has shown that a variety of actin waves propagate within cells, both under normal conditions and during re-building of the cytoskeleton following its disruption. Controlled disruption and re-building of the actin network has led to new insights into the key components involved in actin waves, and here we develop a stochastic model that can qualitatively and quantitatively describe the dynamical behavior of such waves.

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Crystalloid Inclusions in Hepatocyte Mitochondria and Their Similarity to Cytoplasmic Crystalloids

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100051001 ◽

1974 ◽

Vol 32 ◽

pp. 198-199

Author(s):

Odell T. Minick ◽

Hidejiro Yokoo

Keyword(s):

Liver Disease ◽

Alcoholic Liver Disease ◽

Special Interest ◽

Structural Variations ◽

Mitochondrial Alterations ◽

The Matrix ◽

Crystalloid Inclusions ◽

Liver Biopsies

Mitochondrial alterations were studied in 25 liver biopsies from patients with alcoholic liver disease. Of special interest were the morphologic resemblance of certain fine structural variations in mitochondria and crystalloid inclusions. Four types of alterations within mitochondria were found that seemed to relate to cytoplasmic crystalloids.Type 1 alteration consisted of localized groups of cristae, usually oriented in the long direction of the organelle (Fig. 1A). In this plane they appeared serrated at the periphery with blind endings in the matrix. Other sections revealed a system of equally-spaced diagonal lines lengthwise in the mitochondrion with cristae protruding from both ends (Fig. 1B). Profiles of this inclusion were not unlike tangential cuts of a crystalloid structure frequently seen in enlarged mitochondria described below.

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