scholarly journals Chronos: a cell population dynamics model of CRISPR experiments that improves inference of gene fitness effects

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Joshua M. Dempster ◽  
Isabella Boyle ◽  
Francisca Vazquez ◽  
David E. Root ◽  
Jesse S. Boehm ◽  
...  
Keyword(s):  
Copy Number ◽  
Gene Knockout ◽  
Loss Of Function ◽  
Explicit Model ◽  
Dynamics Model ◽  
Fitness Effects ◽  
Population Dynamics Model ◽  
Crispr Screen ◽  
A Cell ◽  
Pan Cancer

AbstractCRISPR loss of function screens are powerful tools to interrogate biology but exhibit a number of biases and artifacts that can confound the results. Here, we introduce Chronos, an algorithm for inferring gene knockout fitness effects based on an explicit model of cell proliferation dynamics after CRISPR gene knockout. We test Chronos on two pan-cancer CRISPR datasets and one longitudinal CRISPR screen. Chronos generally outperforms competitors in separation of controls and strength of biomarker associations, particularly when longitudinal data is available. Additionally, Chronos exhibits the lowest copy number and screen quality bias of evaluated methods. Chronos is available at https://github.com/broadinstitute/chronos.

scholarly journals Chronos: a CRISPR cell population dynamics model

2021 ◽  
Author(s):  
Joshua M. Dempster ◽  
Isabella Boyle ◽  
Francisca Vazquez ◽  
David Root ◽  
Jesse S. Boehm ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Performance Metrics ◽  
Gene Knockout ◽  
Loss Of Function ◽  
Dynamics Model ◽  
Biological Experiment ◽  
Multiple Sources ◽  
Fitness Effects ◽  
Population Dynamics Model ◽  
Share Information

AbstractCRISPR loss of function screens are a powerful tool to interrogate cancer biology but are known to exhibit a number of biases and artifacts that can confound the results, such as DNA cutting toxicity, incomplete phenotype penetrance and screen quality bias. Computational methods that more faithfully model the CRISPR biological experiment could more effectively extract the biology of interest than typical current methods. Here we introduce Chronos, an algorithm for inferring gene knockout fitness effects based on an explicit model of the dynamics of cell proliferation after CRISPR gene knockout. Chronos is able to exploit longitudinal CRISPR data for improved inference. Additionally, it accounts for multiple sources of bias and can effectively share information across screens when jointly analyzing large datasets such as Project Achilles and Score. We show that Chronos outperforms competing methods across a range of performance metrics in multiple types of experiments.

scholarly journals Multiplex enCas12a screens detect functional buffering among paralogs otherwise masked in monogenic Cas9 knockout screens

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Merve Dede ◽  
Megan McLaughlin ◽  
Eiru Kim ◽  
Traver Hart
Keyword(s):  
Cell Lines ◽  
Protein Complexes ◽  
Gene Knockout ◽  
Essential Genes ◽  
Loss Of Function ◽  
Systematic Analysis ◽  
Synthetic Lethal ◽  
Synthetic Lethal Interactions ◽  
Crispr Screen ◽  
A Cell

Abstract Background Pooled library CRISPR/Cas9 knockout screening across hundreds of cell lines has identified genes whose disruption leads to fitness defects, a critical step in identifying candidate cancer targets. However, the number of essential genes detected from these monogenic knockout screens is low compared to the number of constitutively expressed genes in a cell. Results Through a systematic analysis of screen data in cancer cell lines generated by the Cancer Dependency Map, we observe that half of all constitutively expressed genes are never detected in any CRISPR screen and that these never-essentials are highly enriched for paralogs. We investigated functional buffering among approximately 400 candidate paralog pairs using CRISPR/enCas12a dual-gene knockout screening in three cell lines. We observe 24 synthetic lethal paralog pairs that have escaped detection by monogenic knockout screens at stringent thresholds. Nineteen of 24 (79%) synthetic lethal interactions are present in at least two out of three cell lines and 14 of 24 (58%) are present in all three cell lines tested, including alternate subunits of stable protein complexes as well as functionally redundant enzymes. Conclusions Together, these observations strongly suggest that functionally redundant paralogs represent a targetable set of genetic dependencies that are systematically under-represented among cell-essential genes in monogenic CRISPR-based loss of function screens.

POPULATION DYNAMICS OF TRANSPOSABLE ELEMENTS: COPY NUMBER REGULATION AND SPECIES INVASION REQUIREMENTS

2005 ◽  
Vol 13 (04) ◽  
pp. 455-475 ◽  
Author(s):  
CLAUDIO J. STRUCHINER ◽  
MARGARET G. KIDWELL ◽  
JOSÉ M. C. RIBEIRO
Keyword(s):  
Population Dynamics ◽  
Transposable Elements ◽  
Parameter Space ◽  
Copy Number ◽  
Host Population ◽  
Reproductive Capacity ◽  
Dynamics Model ◽  
Population Extinction ◽  
Population Dynamics Model ◽  
Copy Number Regulation

A deterministic population dynamics model of the spread of transposable elements (TE) in sexually reproducing populations is presented. The population is modeled by a three-parameter equation describing host reproductive capacity, population size and the strength of the density dependence, while TE dynamics were modeled based also on three parameters, the maximum ability of the element to copy itself in the absence of regulation (T0), the regulatory effect of copy number decreasing transposition (C0.5), and the deleterious effect of each new transposition on host fitness (d). The mechanism of transposition control is therefore a function of the number of new TE copies. Our results indicate that non-regulated elements cannot fix in host populations, and that prediction of stable copy number following successful invasion is mainly a function of the combination of T0 and C0.5 values. Fitness reduction does not affect the final copy number after successful invasion of the element. Fitness reduction, however, will affect the surface of the {T0 × C0.5} parameter space leading to successful invasion of the TE. Invasion of host populations by eight or more individuals containing elements with appropriate parameters will lead to successful element fixation at any size of the host population. Host population extinction due to the invasion of TE's is observed in a small area of the {T0 × C0.5} parameter space. These results are qualitatively preserved under alternative choices for the shape of the functions defining regulation of transposition and distinct sets of parameters determining host population dynamics.

scholarly journals A random effects population dynamics model based on proportions-at-age and removal data for estimating total mortality

2012 ◽  
Vol 69 (11) ◽  
pp. 1881-1893 ◽  
Author(s):  
Verena M. Trenkel ◽  
Mark V. Bravington ◽  
Pascal Lorance
Keyword(s):  
Population Dynamics ◽  
Random Effects ◽  
Fixed Effects ◽  
Random Effect ◽  
Total Mortality ◽  
Estimation Bias ◽  
Effective Sample Size ◽  
Dynamics Model ◽  
Population Dynamics Model ◽  
Study Parameter

Catch curves are widely used to estimate total mortality for exploited marine populations. The usual population dynamics model assumes constant recruitment across years and constant total mortality. We extend this to include annual recruitment and annual total mortality. Recruitment is treated as an uncorrelated random effect, while total mortality is modelled by a random walk. Data requirements are minimal as only proportions-at-age and total catches are needed. We obtain the effective sample size for aggregated proportion-at-age data based on fitting Dirichlet-multinomial distributions to the raw sampling data. Parameter estimation is carried out by approximate likelihood. We use simulations to study parameter estimability and estimation bias of four model versions, including models treating mortality as fixed effects and misspecified models. All model versions were, in general, estimable, though for certain parameter values or replicate runs they were not. Relative estimation bias of final year total mortalities and depletion rates were lower for the proposed random effects model compared with the fixed effects version for total mortality. The model is demonstrated for the case of blue ling (Molva dypterygia) to the west of the British Isles for the period 1988 to 2011.

A microbial treatment population dynamics optimization approach

2021 ◽  
pp. 1-15
Author(s):  
Jinding Gao
Keyword(s):  
Population Dynamics ◽  
Information Exchange ◽  
Information Diffusion ◽  
Optimization Problems ◽  
Microbial Control ◽  
Function Optimization ◽  
Optimization Approach ◽  
Dynamics Model ◽  
Population Dynamics Model ◽  
Number Of Individuals

In order to solve some function optimization problems, Population Dynamics Optimization Algorithm under Microbial Control in Contaminated Environment (PDO-MCCE) is proposed by adopting a population dynamics model with microbial treatment in a polluted environment. In this algorithm, individuals are automatically divided into normal populations and mutant populations. The number of individuals in each category is automatically calculated and adjusted according to the population dynamics model, it solves the problem of artificially determining the number of individuals. There are 7 operators in the algorithm, they realize the information exchange between individuals the information exchange within and between populations, the information diffusion of strong individuals and the transmission of environmental information are realized to individuals, the number of individuals are increased or decreased to ensure that the algorithm has global convergence. The periodic increase of the number of individuals in the mutant population can greatly increase the probability of the search jumping out of the local optimal solution trap. In the iterative calculation, the algorithm only deals with 3/500∼1/10 of the number of individual features at a time, the time complexity is reduced greatly. In order to assess the scalability, efficiency and robustness of the proposed algorithm, the experiments have been carried out on realistic, synthetic and random benchmarks with different dimensions. The test case shows that the PDO-MCCE algorithm has better performance and is suitable for solving some optimization problems with higher dimensions.

scholarly journals Maturation of the Na,K-ATPase in the Endoplasmic Reticulum in Health and Disease

2021 ◽  
Author(s):  
Vitalii Kryvenko ◽  
Olga Vagin ◽  
Laura A. Dada ◽  
Jacob I. Sznajder ◽  
István Vadász
Keyword(s):  
Endoplasmic Reticulum ◽  
Intracellular Signaling ◽  
Loss Of Function ◽  
Α Subunit ◽  
Rate Limiting Step ◽  
Atpase Subunits ◽  
A Cell ◽  
Health And Disease ◽  
And Function ◽  
Rate Limiting

Abstract The Na,K-ATPase establishes the electrochemical gradient of cells by driving an active exchange of Na+ and K+ ions while consuming ATP. The minimal functional transporter consists of a catalytic α-subunit and a β-subunit with chaperon activity. The Na,K-ATPase also functions as a cell adhesion molecule and participates in various intracellular signaling pathways. The maturation and trafficking of the Na,K-ATPase include co- and post-translational processing of the enzyme in the endoplasmic reticulum (ER) and the Golgi apparatus and subsequent delivery to the plasma membrane (PM). The ER folding of the enzyme is considered as the rate-limiting step in the membrane delivery of the protein. It has been demonstrated that only assembled Na,K-ATPase α:β-complexes may exit the organelle, whereas unassembled, misfolded or unfolded subunits are retained in the ER and are subsequently degraded. Loss of function of the Na,K-ATPase has been associated with lung, heart, kidney and neurological disorders. Recently, it has been shown that ER dysfunction, in particular, alterations in the homeostasis of the organelle, as well as impaired ER-resident chaperone activity may impede folding of Na,K-ATPase subunits, thus decreasing the abundance and function of the enzyme at the PM. Here, we summarize our current understanding on maturation and subsequent processing of the Na,K-ATPase in the ER under physiological and pathophysiological conditions. Graphic Abstract

scholarly journals Chromosomal copy number heterogeneity predicts survival rates across cancers

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Erik van Dijk ◽  
Tom van den Bosch ◽  
Kristiaan J. Lenos ◽  
Khalid El Makrini ◽  
Lisanne E. Nijman ◽  
...  
Keyword(s):  
Copy Number ◽  
Cancer Survival ◽  
Survival Rates ◽  
Cancer Prognosis ◽  
Disease Outcomes ◽  
Distinct Disease ◽  
Cancer Types ◽  
Chromosomal Copy Number ◽  
Chromosomal Copy ◽  
Pan Cancer

AbstractSurvival rates of cancer patients vary widely within and between malignancies. While genetic aberrations are at the root of all cancers, individual genomic features cannot explain these distinct disease outcomes. In contrast, intra-tumour heterogeneity (ITH) has the potential to elucidate pan-cancer survival rates and the biology that drives cancer prognosis. Unfortunately, a comprehensive and effective framework to measure ITH across cancers is missing. Here, we introduce a scalable measure of chromosomal copy number heterogeneity (CNH) that predicts patient survival across cancers. We show that the level of ITH can be derived from a single-sample copy number profile. Using gene-expression data and live cell imaging we demonstrate that ongoing chromosomal instability underlies the observed heterogeneity. Analysing 11,534 primary cancer samples from 37 different malignancies, we find that copy number heterogeneity can be accurately deduced and predicts cancer survival across tissues of origin and stages of disease. Our results provide a unifying molecular explanation for the different survival rates observed between cancer types.

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