genetic discovery
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2022 ◽  
Author(s):  
Dolly Reyes‐Dumeyer ◽  
Kelley Faber ◽  
Badri Vardarajan ◽  
Alison Goate ◽  
Alan Renton ◽  
...  

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Asli Azizoglu ◽  
Roger Brent ◽  
Fabian Rudolf

Conditional expression of genes and observation of phenotype remain central to biological discovery. Current methods enable either on/off or imprecisely controlled graded gene expression. We developed a 'well-tempered' controller, WTC846, for precisely adjustable, graded, growth condition independent expression of genes in Saccharomyces cerevisiae. Controlled genes are expressed from a strong semisynthetic promoter repressed by the prokaryotic TetR, which also represses its own synthesis; with basal expression abolished by a second, 'zeroing' repressor. The autorepression loop lowers cell-to-cell variation while enabling precise adjustment of protein expression by a chemical inducer. WTC846 allelic strains in which the controller replaced the native promoters recapitulated known null phenotypes (CDC42, TPI1), exhibited novel overexpression phenotypes (IPL1), showed protein dosage-dependent growth rates and morphological phenotypes (CDC28, TOR2, PMA1 and the hitherto uncharacterized PBR1), and enabled cell cycle synchronization (CDC20). WTC846 defines an 'expression clamp' allowing protein dosage to be adjusted by the experimenter across the range of cellular protein abundances, with limited variation around the setpoint.


2021 ◽  
Vol 2 (2) ◽  
pp. 100029
Author(s):  
Linda M. Polfus ◽  
Burcu F. Darst ◽  
Heather Highland ◽  
Xin Sheng ◽  
Maggie C.Y. Ng ◽  
...  

Sensors ◽  
2021 ◽  
Vol 21 (4) ◽  
pp. 1059
Author(s):  
Gilles Vandewiele ◽  
Femke Ongenae ◽  
Filip De Turck

In the time series classification domain, shapelets are subsequences that are discriminative of a certain class. It has been shown that classifiers are able to achieve state-of-the-art results by taking the distances from the input time series to different discriminative shapelets as the input. Additionally, these shapelets can be visualized and thus possess an interpretable characteristic, making them appealing in critical domains, where longitudinal data are ubiquitous. In this study, a new paradigm for shapelet discovery is proposed, which is based on evolutionary computation. The advantages of the proposed approach are that: (i) it is gradient-free, which could allow escaping from local optima more easily and supports non-differentiable objectives; (ii) no brute-force search is required, making the algorithm scalable; (iii) the total amount of shapelets and the length of each of these shapelets are evolved jointly with the shapelets themselves, alleviating the need to specify this beforehand; (iv) entire sets are evaluated at once as opposed to single shapelets, which results in smaller final sets with fewer similar shapelets that result in similar predictive performances; and (v) the discovered shapelets do not need to be a subsequence of the input time series. We present the results of the experiments, which validate the enumerated advantages.


2021 ◽  
pp. 699-708
Author(s):  
Rodrigo Bonazzola ◽  
Nishant Ravikumar ◽  
Rahman Attar ◽  
Enzo Ferrante ◽  
Tanveer Syeda-Mahmood ◽  
...  

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Maik Pietzner ◽  
Eleanor Wheeler ◽  
Julia Carrasco-Zanini ◽  
Johannes Raffler ◽  
Nicola D. Kerrison ◽  
...  

AbstractUnderstanding the genetic architecture of host proteins interacting with SARS-CoV-2 or mediating the maladaptive host response to COVID-19 can help to identify new or repurpose existing drugs targeting those proteins. We present a genetic discovery study of 179 such host proteins among 10,708 individuals using an aptamer-based technique. We identify 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links and evidence that putative viral interaction partners such as MARK3 affect immune response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and detailed interrogation of results is facilitated through an interactive webserver (https://omicscience.org/apps/covidpgwas/).


Nature ◽  
2020 ◽  
Vol 588 (7837) ◽  
pp. 296-302
Author(s):  
Tetsuya Takano ◽  
John T. Wallace ◽  
Katherine T. Baldwin ◽  
Alicia M. Purkey ◽  
Akiyoshi Uezu ◽  
...  
Keyword(s):  

2020 ◽  
Author(s):  
Xikun Han ◽  
Kaiah Steven ◽  
Ayub Qassim ◽  
Henry N Marshall ◽  
Cameron Bean ◽  
...  

AbstractCupping of the optic nerve head, a highly heritable trait, is a hallmark of glaucomatous optic neuropathy. Two key parameters are vertical cup-to-disc ratio (VCDR) and vertical disc diameter (VDD). However, manual assessment often suffers from poor accuracy and is time-intensive. Here, we show convolutional neural network models can accurately estimate VCDR and VDD for 282,100 images from both UK Biobank and an independent study (Canadian Longitudinal Study on Aging), enabling cross-ancestry epidemiological studies and new genetic discovery for these optic nerve head parameters. Using the AI approach we perform a systematic comparison of the distribution of VCDR and VDD, and compare these with intraocular pressure and glaucoma diagnoses across various genetically determined ancestries, which provides an explanation for the high rates of normal tension glaucoma in East Asia. We then used the large number of AI gradings to conduct a more powerful genome-wide association study (GWAS) of optic nerve head parameters. Using the AI based gradings increased estimates of heritability by ~50% for VCDR and VDD. Our GWAS identified more than 200 loci for both VCDR and VDD (double the number of loci from previous studies), uncovers dozens of novel biological pathways, with many of the novel loci also conferring risk for glaucoma.


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