Journal ArticleDOI
Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathways.
Ben Lehner,Ben Lehner,Ben Lehner,Catriona Crombie,Julia Tischler,Angelo Fortunato,Angelo Fortunato,Angelo Fortunato,Andrew G. Fraser +8 more
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TLDR
It is proposed that these genes function as general buffers of genetic variation and that these hub genes may act as modifier genes in multiple, mechanistically unrelated genetic diseases in humans.Abstract:
Most heritable traits, including disease susceptibility, are affected by interactions between multiple genes. However, we understand little about how genes interact because very few possible genetic interactions have been explored experimentally. We have used RNA interference in Caenorhabditis elegans to systematically test ∼65,000 pairs of genes for their ability to interact genetically. We identify ∼350 genetic interactions between genes functioning in signaling pathways that are mutated in human diseases, including components of the EGF/Ras, Notch and Wnt pathways. Most notably, we identify a class of highly connected 'hub' genes: inactivation of these genes can enhance the phenotypic consequences of mutation of many different genes. These hub genes all encode chromatin regulators, and their activity as genetic hubs seems to be conserved across animals. We propose that these genes function as general buffers of genetic variation and that these hub genes may act as modifier genes in multiple, mechanistically unrelated genetic diseases in humans.read more
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The genetic landscape of a cell.
Michael Costanzo,Anastasia Baryshnikova,Jeremy Bellay,Yungil Kim,Eric D. Spear,Carolyn S. Sevier,Huiming Ding,Judice L. Y. Koh,Kiana Toufighi,Sara Mostafavi,Jeany Prinz,Robert P. St.Onge,Benjamin VanderSluis,Taras Makhnevych,Franco J. Vizeacoumar,Solmaz Alizadeh,Sondra Bahr,Renee L. Brost,Yiqun Chen,Murat Cokol,Raamesh Deshpande,Zhijian Li,Zhen Yuan Lin,Wendy Liang,Michaela Marback,Jadine Paw,Bryan Joseph San Luis,Ermira Shuteriqi,Amy Hin Yan Tong,Nydia Van Dyk,Iain M. Wallace,Joseph Whitney,Matthew T. Weirauch,Guoqing Zhong,Hongwei Zhu,Walid A. Houry,Michael Brudno,Sasan Ragibizadeh,Balázs Papp,Csaba Pál,Frederick P. Roth,Guri Giaever,Corey Nislow,Olga G. Troyanskaya,Howard Bussey,Gary D. Bader,Anne-Claude Gingras,Quaid Morris,Philip M. Kim,Chris A. Kaiser,Chad L. Myers,Brenda J. Andrews,Charles Boone +52 more
TL;DR: A network based on genetic interaction profiles reveals a functional map of the cell in which genes of similar biological processes cluster together in coherent subsets, and highly correlated profiles delineate specific pathways to define gene function.
Journal ArticleDOI
Function and information content of DNA methylation
TL;DR: These observations indicate that the underlying DNA sequence largely accounts for local patterns of methylation, which is highly informative when studying gene regulation in normal and diseased cells, and it can potentially function as a biomarker.
Journal ArticleDOI
Phenotypic plasticity and the epigenetics of human disease
TL;DR: This model proposes that hereditary disorders of the epigenetic apparatus lead to developmental defects, that cancer epigenetics involves disruption of the stem-cell programme, and that common diseases with late-onset phenotypes involve interactions between the epigenome, the genome and the environment.
Journal ArticleDOI
Epistasis--the essential role of gene interactions in the structure and evolution of genetic systems.
TL;DR: There is a renewed appreciation both for the importance of studying gene interactions and for addressing these questions in a unified, quantitative manner with the advent of high-throughput functional genomics.
Journal ArticleDOI
Rare and common variants: twenty arguments
TL;DR: 20 arguments for and against each of these models of the genetic basis of complex traits are reviewed and it is concluded that both classes of effect can be readily reconciled.
References
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A genetic model for colorectal tumorigenesis
Eric R. Fearon,Bert Vogelstein +1 more
TL;DR: A model for the genetic basis of colorectal neoplasia that includes the following salient features is presented, which may be applicable to other common epithelial neoplasms, in which tumors of varying stage are more difficult to study.
Journal ArticleDOI
Systematic functional analysis of the Caenorhabditis elegans genome using RNAi
Ravi S. Kamath,Andrew G. Fraser,Andrew G. Fraser,Yan Dong,Gino B. Poulin,Richard Durbin,Monica Gotta,Alexander Kanapin,Nathalie Le Bot,Sergio Moreno,Sergio Moreno,Marc Sohrmann,David P. Welchman,Peder Zipperlen,Julie Ahringer +14 more
TL;DR: It is found that genes of similar functions are clustered in distinct, multi-megabase regions of individual chromosomes; genes in these regions tend to share transcriptional profiles.
Journal ArticleDOI
Systematic Genetic Analysis with Ordered Arrays of Yeast Deletion Mutants
Amy Hin Yan Tong,Marie Evangelista,Ainslie B. Parsons,Hong Xu,Gary D. Bader,Gary D. Bader,Nicholas Pagé,Mark D. Robinson,Sasan Raghibizadeh,Christopher W. V. Hogue,Christopher W. V. Hogue,Howard Bussey,Brenda J. Andrews,Mike Tyers,Mike Tyers,Charles Boone,Charles Boone +16 more
TL;DR: A method for systematic construction of double mutants, termed synthetic genetic array (SGA) analysis, in which a query mutation is crossed to an array of ∼4700 deletion mutants is developed, which should produce a global map of gene function.
Journal ArticleDOI
Hsp90 as a capacitor for morphological evolution
TL;DR: It is reported that when Drosophila Hsp90 is mutant or pharmacologically impaired, phenotypic variation affecting nearly any adult structure is produced, with specific variants depending on the genetic background and occurring both in laboratory strains and in wild populations.
Journal ArticleDOI
Global Mapping of the Yeast Genetic Interaction Network
Amy Hin Yan Tong,Guillaume Lesage,Gary D. Bader,Huiming Ding,Hong Xu,Xiaofeng Xin,James D. Young,Gabriel F. Berriz,Renee L. Brost,Michael Chang,Yiqun Chen,Xin Cheng,Gordon Chua,Helena Friesen,Debra S. Goldberg,Jennifer Haynes,Christine Humphries,Grace He,Shamiza Hussein,Lizhu Ke,Nevan J. Krogan,Zhijian Li,Joshua N. Levinson,Hong Lu,Patrice Menard,Christella Munyana,Ainslie B. Parsons,Owen Ryan,Raffi Tonikian,Tania Michelle Roberts,Anne-Marie Sdicu,Jesse Shapiro,Bilal N. Sheikh,Bernhard Suter,Sharyl L. Wong,Lan V. Zhang,Hongwei Zhu,Christopher G. Burd,Sean Munro,Chris Sander,Jasper Rine,Jack Greenblatt,Matthias Peter,Anthony Bretscher,Graham Bell,Frederick P. Roth,Grant W. Brown,Brenda J. Andrews,Howard Bussey,Charles Boone +49 more
TL;DR: Because digenic interactions are common in yeast, similar networks may underlie the complex genetics associated with inherited phenotypes in other organisms.
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The genetic landscape of a cell.
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