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When loss-of-function is loss of function: assessing mutational signatures and impact of loss-of-function genetic variants

Kymberleigh A Pagel, Vikas Pejaver, Guan Ning Lin, Hyun-Jun Nam, Matthew Mort, David N Cooper, Jonathan Sebat, Lilia M Iakoucheva, Sean D Mooney, Predrag Radivojac
2017 Bioinformatics  
The available methods to assess the impact of these variants rely primarily upon evolutionary conservation with little to no consideration of the structural and functional implications for the protein.  ...  Motivation: Loss-of-function genetic variants are frequently associated with severe clinical phenotypes, yet many are present in the genomes of healthy individuals.  ...  Funding This work has been supported by the National Institutes of Health through the awards R01LM009722 (SDM), R01MH105524 (LMI and PR), R21MH104766 (LMI), R01MH109885 (LMI), RO1MH076431 (JS) and the  ... 
doi:10.1093/bioinformatics/btx272 pmid:28882004 pmcid:PMC5870554 fatcat:tdqfes4pffchdavwl2dz6jtph4

The population genomics of adaptive loss of function

J. Grey Monroe, John K. McKay, Detlef Weigel, Pádraic J. Flood
2021 Heredity  
Here we examine the evolutionary dynamics of adaptive loss of function through the lens of population genomics and consider the challenges and opportunities of studying adaptive loss-of-function alleles  ...  AbstractDiscoveries of adaptive gene knockouts and widespread losses of complete genes have in recent years led to a major rethink of the early view that loss-of-function alleles are almost always deleterious  ...  This work was supported by NSF Awards 1556262 to JKM and 1701918 to JGM, DFG ERA-CAPS 1001 G + to DW, and the Max Planck Society.  ... 
doi:10.1038/s41437-021-00403-2 pmid:33574599 pmcid:PMC7878030 fatcat:n5gmqktr5rayhowqolpm3mcrxy

Non-Coding Loss-of-Function Variation in Human Genomes

Zachary Zappala, Stephen B. Montgomery
2016 Human Heredity  
In this review, we investigate recent studies of loss-of-function variation and emerging approaches for interpreting whole genome sequencing data to identify rare and impactful non-coding loss-of-function  ...  To date, the vast majority of surveyed loss-of-function variants are in protein-coding regions of the genome mainly due to the focus on these regions by exome-based sequencing projects and their relative  ...  S.B.M. is supported by the National Institutes of Health through R01HG008150, R01MH101814 and U01HG007436.  ... 
doi:10.1159/000447453 pmid:28076858 pmcid:PMC5499665 fatcat:ab72c7hv3bcdpjtkuk35h35ck4

Functional Genomic Characterization of Cancer Genomes

Thomas P. Howard, Francisca Vazquez, Aviad Tsherniak, Andrew L. Hong, Mik Rinne, Andrew J. Aguirre, Jesse S. Boehm, William C. Hahn
2016 Cold Spring Harbor Symposia on Quantitative Biology  
These studies have identified many highly recurrent alterations in specific cancer subtypes but have also identified mutations that occur at lower frequency and unstudied variants of known cancer-associated  ...  International efforts to sequence cancer genomes now provide an overview of the major genetic alterations that occur in most human cancers.  ...  Whereas mutation or loss of expression of a single gene has no impact, loss of both genes is lethal.  ... 
doi:10.1101/sqb.2016.81.031070 pmid:27815544 fatcat:e3f3f6umlvgoxiqcvh4dfsiy2e

Risk alleles of genes with monoallelic expression are enriched in gain-of-function variants and depleted in loss-of-function variants for neurodevelopmental disorders

V Savova, S Vinogradova, D Pruss, A A Gimelbrant, L A Weiss
2017 Molecular Psychiatry  
Artem Artemov, Rahul Deo, Aditi Deshpande, Ophir Klein, Andrey Mironov, Ludmila Pawlikowska, Jonathan Pritchard, Erika Yeh, and Noah Zaitlen.  ...  Both CNVs and loss-of-function variants are likely to act via haploinsufficiency.  ...  We defined likely loss-of-function genes as those showing a de novo loss-of-function mutation (LoF: frameshift, nonsense, donor/acceptor splice site mutations) in at least one case and no LoF mutations  ... 
doi:10.1038/mp.2017.13 pmid:28265118 pmcid:PMC5589474 fatcat:z4x2slkagfaopiedvbc6kks3fy

The Loss and Gain of Functional Amino Acid Residues Is a Common Mechanism Causing Human Inherited Disease

Jose Lugo-Martinez, Vikas Pejaver, Kymberleigh A. Pagel, Shantanu Jain, Matthew Mort, David N. Cooper, Sean D. Mooney, Predrag Radivojac, Yana Bromberg
2016 PLoS Computational Biology  
We first propose a formal model to assess probabilistically function-impacting variants.  ...  In this study, we analyzed data sets of disease-causing and putatively neutral human variants mapped to protein 3D structures as part of a systematic study of the loss and gain of various types of functional  ...  We mention that when either a loss or a gain of function event is found to be statistically significant, the mutation of this type of functional residue is considered to be an active mechanism of genetic  ... 
doi:10.1371/journal.pcbi.1005091 pmid:27564311 pmcid:PMC5001644 fatcat:owqlybtdezh33opy3xrhg2wrca

Strength of functional signature correlates with effect size in autism

Sara Ballouz, Jesse Gillis
2017 Genome Medicine  
Conclusions: We see a convergent functional signal for a subset of known and novel functions in ASD from all sources of genetic variation.  ...  Disagreements over genetic signatures associated with disease have been particularly prominent in the field of psychiatric genetics, creating a sharp divide between disease burdens attributed to common  ...  Availability of data and materials The datasets supporting the conclusions of this article are included within the article and in the additional files.  ... 
doi:10.1186/s13073-017-0455-8 pmid:28687074 pmcid:PMC5501949 fatcat:khszo5cgtrfutky74msehcuony

Strategies for Functional Interrogation of Big Cancer Data Using Drosophila Cancer Models

Erdem Bangi
2020 International Journal of Molecular Sciences  
Given the daunting scale and complexity of the big data available, experimental systems like Drosophila that allow large-scale functional studies and complex genetic manipulations in a rapid, cost-effective  ...  Functional exploration of these datasets and testing predictions from computational approaches using experimental models to interrogate their biological relevance is a key step towards achieving this goal  ...  Functional studies are required to determine whether these variants are deleterious and how they impact protein function (e.g., gain of function, loss of function, neomorphic).  ... 
doi:10.3390/ijms21113754 pmid:32466549 pmcid:PMC7312059 fatcat:lrv24h4tvvc6tc2egji2ck6eni

A guide for functional analysis ofBRCA1variants of uncertain significance

Gaël A. Millot, Marcelo A. Carvalho, Sandrine M. Caputo, Maaike P.G. Vreeswijk, Melissa A. Brown, Michelle Webb, Etienne Rouleau, Susan L. Neuhausen, Thomas v. O. Hansen, Alvaro Galli, Rita D. Brandão, Marinus J. Blok (+3 others)
2012 Human Mutation  
However, for a significant number of these variants, the effect on protein function is unknown making it difficult to infer the consequences on risks of breast and ovarian cancers.  ...  Thus, many individuals undergoing genetic testing for BRCA1 mutations receive test results reporting a variant of uncertain clinical significance (VUS), leading to issues in risk assessment, counseling  ...  of breast and ovarian cancer.  ... 
doi:10.1002/humu.22150 pmid:22753008 pmcid:PMC3470782 fatcat:7ulklk4tjvae7ayj6ixpzr4yrq

Passenger mutations in 2500 cancer genomes: Overall molecular functional impact and consequences [article]

Sushant Kumar, Jonathan Warrell, Shantao Li, Patrick McGillivray, William Meyerson, Leonidas Salichos, Arif Harmanci, Alexander Martinez-Fundichely, Calvin Wing Yiu Chan, Morten Nielsen, Lucas Lochovsky, Yan Zhang (+6 others)
2018 bioRxiv   pre-print
The impact distribution of PCAWG mutations shows that, in addition to high- and low-impact mutations, there is a group of medium- impact putative passengers predicted to influence gene activity.  ...  In this study, we leveraged the comprehensive variant data from PCAWG to ascertain the molecular functional impact of each variant.  ...  We are thankful to the members of the PCAWG technical working group for generating the variant calls.  ... 
doi:10.1101/280446 fatcat:mnoke5tn2fgnxbxvtz3qbvgefi

A profile-based method for identifying functional divergence of orthologous genes in bacterial genomes [article]

Nicole E Wheeler, Lars Barquist, Robert A Kingsley, Paul P Gardner
2015 bioRxiv   pre-print
impact biological function.  ...  Motivation: Next generation sequencing technologies have provided us with a wealth of information on genetic variation, but predicting the functional significance of this variation is a difficult task.  ...  Acknowledgements We would like to thank Fatemeh Ashari Ghomi for her contributions, and Sean Eddy for his clarification of some technical aspects of the HMMER3 software.  ... 
doi:10.1101/022616 fatcat:cyu3ym2xtjhd5lgydm5eibp43a

Functional Impact of Chromatin Remodeling Gene Mutations and Predictive Signature for Therapeutic Response in Bladder Cancer

Jason E. Duex, Kalin E. Swain, Garrett M. Dancik, Richard D. Paucek, Charles Owens, Mair E.A. Churchill, Dan Theodorescu
2017 Molecular Cancer Research  
Finally, a gene expression signature was developed that associated with loss of HAT activity and that this signature was associated with more aggressive cancer in four patient datasets.  ...  Here, we examined the functional relevance of mutations in two chromatin-remodeling genes, EP300 and its paralog, CREBBP, which are mutated in almost one-third of patients.  ...  Acknowledgments The authors thank the Protein Production/Tissue Culture/MoAB Shared Resource (PPSR) of the University of Colorado Cancer Center for providing cell lines and cell line authentication.  ... 
doi:10.1158/1541-7786.mcr-17-0260 pmid:28970362 pmcid:PMC5951683 fatcat:ho4re5xmtbhnvj5h5xgu2lqhw4

A profile-based method for identifying functional divergence of orthologous genes in bacterial genomes

Nicole E. Wheeler, Lars Barquist, Robert A. Kingsley, Paul P. Gardner
2016 Bioinformatics  
impact biological function.  ...  Motivation: Next generation sequencing technologies have provided us with a wealth of information on genetic variation, but predi cting the functional significance of this variation is a difficult task  ...  PPG and NEW are supported by a Rutherford Discovery Fellowship administered by the Royal Society of New Zealand. Conflict of Interest: none declared.  ... 
doi:10.1093/bioinformatics/btw518 pmid:27503221 pmcid:PMC5181535 fatcat:efvahskdtrge3aidfgxy6jbkz4

A Comprehensive In Silico Analysis of the Functional and Structural Impact of Nonsynonymous SNPs in the ABCA1 Transporter Gene

Francisco R. Marín-Martín, Cristina Soler-Rivas, Roberto Martín-Hernández, Arantxa Rodriguez-Casado
2014 Cholesterol  
Identification of deleterious nsSNPs is crucial to characterize the genetic basis of diseases, assess individual susceptibility to disease, determinate molecular and therapeutic targets, and predict clinical  ...  In this study using PolyPhen2 and MutPred in silico algorithms, we analyzed the genetic variations that can alter the expression and function of the ABCA1 gene that causes the allelic disorders familial  ...  Conflict of Interests The authors declare that there is no conflict of interests regarding the publishing of this paper.  ... 
doi:10.1155/2014/639751 pmid:25215231 pmcid:PMC4156994 fatcat:riupuxr36ndrtfb2p6m6p6ircq

High-throughput functional analysis of natural variants in yeast [article]

Chiann-Ling C Yeh, Andreas Tsouris, Joseph Schacherer, Maitreya J. Dunham
2021 bioRxiv   pre-print
Integrating these results with a phylogenetic tree, we observe how often loss-of-function occurs and whether or not there is an evolutionary pattern to our observable phenotypic results.  ...  How natural variation affects phenotype is difficult to determine given our incomplete ability to deduce the functional impact of the polymorphisms detected in a population.  ...  Even for a single 41 locus, an exhaustive population-scale determination of genetic variants impacting phenotype 42 remains out of sight.  ... 
doi:10.1101/2021.02.26.433108 fatcat:xqlqtoqy2jfx7ielzvlzvkbtku
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