"Genetics: More Than Merely a Mutated Gene" by Michigan State University (01 August 2013). The research findings appear in the journal PLoS Genetics (01 August 2013). ssg: The human body is a system that constantly strives for equilibrium but influences that cannot be balanced are traceable to an unreceptive regulatory context that cannot resolve conflict. It sounds like the human condition to me. East Lansing, MI, USA. If two women have the same genetic mutation that puts them at higher-than-average risk for a disease such as breast cancer, why does only one develop the disease? Genetic scientists have begun to understand how the rest of the genome interacts with such mutations to cause the differences we see among individuals. “It’s been known for a while that genetic mutations can modify each other’s effects,” said Ian Dworkin, MSU associate professor of zoology and co-author of the paper. “And we also know that the subtle differences in an individual’s genome — what scientists call wild type genetic background — also affects how mutations are manifested.” Dworkin and Sudarshan Chari, zoology doctoral student and the paper’s lead author, wanted to know how common it was for wild type genetic background to alter the way genetic mutations interact with each other. This is the first time that it’s been examined in a systematic manner, Dworkin added. Using the fruit fly genome, the researchers found that wild type genetic background affected the outcomes of interactions between genetic mutations about 75 percent of the time. This could have huge implications in how scientists construct genetic networks — maps of how genes interact with each other. Click on the article title to read the complete text at Michigan State University and review the research paper (cf. below). "The Conditional Nature of Genetic Interactions: The Consequences of Wild-Type Backgrounds on Mutational Interactions in a Genome-Wide Modifier Screen." Sudarshan Chari and Ian Dworkin. PLoS Genetics 2013; 9(8): e1003661. doi: 10.1371/journal.pgen.1003661 "Abstract" The phenotypic outcome of a mutation cannot be simply mapped onto the underlying DNA variant. Instead, the phenotype is a function of the allele, the genetic background in which it occurs and the environment where the mutational effects are expressed. While the influence of genetic background on the expressivity of individual mutations is recognized, its consequences on the interactions between genes, or the genetic network they form, is largely unknown. The description of genetic networks is essential for much of biology; yet if, and how, the topologies of such networks are influenced by background is unknown. Furthermore, a comprehensive examination of the background dependent nature of genetic interactions may lead to identification of novel modifiers of biological processes. Previous work in Drosophila melanogaster demonstrated that wild-type genetic background influences the effects of an allele of scalloped (sd), with respect to both its principal consequence on wing development and its interactions with a mutation in optomotor blind. In this study we address whether the background dependence of mutational interactions is a general property of genetic systems by performing a genome wide dominant modifier screen of the sd allele in two wild-type genetic backgrounds using molecularly defined deletions. We demonstrate that ~74% of all modifiers of the sd phenotype are background-dependent due in part to differential sensitivity to genetic perturbation. These background dependent interactions include some with qualitative differences in the phenotypic outcome, as well as instances of sign epistasis. This suggests that genetic interactions are often contingent on genetic background, with flexibility in genetic networks due to segregating variation in populations. Such background dependent effects can substantially alter conclusions about how genes influence biological processes, the potential for genetic screens in alternative wild-type backgrounds identifying new loci that contribute to trait expression, and the inferences of the topology of genetic networks. "Author Summary" Examining the consequences of how one mutation behaves when in the presence of a second mutation forms the basis of our understanding of genetic interactions, and is part of the fundamental toolbox of genetic analysis. Yet the logical interpretation of such mutational interactions depends on the generality of such findings. A small number of studies have demonstrated that factors such as the wild-type background in which the mutations are studied can have a profound impact on the observed phenotype of both specific effects of the mutation and the interactions between mutations. However, whether such findings are a common property of genetic interactions was unknown. We tested the generality of the background dependence of interactions between mutations and observed that the vast majority of the interactions were highly dependent on the wild-type background in which they are observed. We demonstrate that the same regions of the genome that contribute to the differences observed in the degree of severity of the mutational effect appear to also be responsible for the background dependence of the interaction. plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1003661 #news #history #culture #science #scienceeveryday #sciencesunday #biology #dna #genomics #genetics #phenotype #mutation #variation #allele #epistasis #topology #research #abstract #download #openaccess #sharongaughan
Posted on: Mon, 05 Aug 2013 12:43:24 +0000
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