Higher order genetic interactions switch cancer genes from two-hit to one-hit drivers.
Ontology highlight
ABSTRACT:
SUBMITTER: Park S
PROVIDER: S-EPMC8642467 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Disruption of certain genes can reveal cryptic genetic variants that do not typically show phenotypic effects. Because this phenomenon, which is referred to as 'phenotypic capacitance', is a potential source of trait variation and disease risk, it is important to understand how it arises at the genetic and molecular levels. Here, we use a cryptic colony morphology trait that segregates in a yeast cross to explore the mechanisms underlying phenotypic capacitance. We find that the colony trait is expressed when a mutation in IRA2, a negative regulator of the Ras pathway, co-occurs with specific combinations of cryptic variants in six genes. Four of these genes encode transcription factors that act downstream of the Ras pathway, indicating that the phenotype involves genetically complex changes in the transcriptional regulation of Ras targets. We provide evidence that the IRA2 mutation reveals the phenotypic effects of the cryptic variants by disrupting the transcriptional silencing of one or more genes that contribute to the trait. Supporting this role for the IRA2 mutation, deletion of SFL1, a repressor that acts downstream of the Ras pathway, also reveals the phenotype, largely due to the same cryptic variants that were detected in the IRA2 mutant cross. Our results illustrate how higher-order genetic interactions among mutations and cryptic variants can result in phenotypic capacitance in specific genetic backgrounds, and suggests these interactions might reflect genetically complex changes in gene expression that are usually suppressed by negative regulation.
| S-EPMC4618523 | biostudies-literature
Project description:A central question in genetics and evolution is the extent to which mutations have outcomes that change depending on the genetic context in which they occur. Pairwise interactions between mutations have been systematically mapped within and between genes, and contribute substantially to phenotypic variation amongst individuals. However, the extent to which genetic interactions themselves are stable or dynamic across genotypes is unclear. Here we quantify >45,000 genetic interactions between the same 87 pairs of mutations across >500 closely related genotypes of a yeast tRNA. Strikingly, all pairs of mutations interacted in at least 9% of genetic backgrounds and all pairs switched from interacting positively to interacting negatively in different genotypes (FDR<0.1). Higher order interactions are also abundant and dynamic across genotypes. The epistasis in this molecule means that all individual mutations switch from detrimental to beneficial in even closely-related genotypes. As a consequence, accurate genetic prediction requires mutation effects to be measured across different genetic backgrounds and the use of higher order epistatic terms.
2018-03-06 | GSE99418 | GEO
Project description:A central question in genetics and evolution is the extent to which the outcomes of mutations change depending on the genetic context in which they occur1-3. Pairwise interactions between mutations have been systematically mapped within4-18 and between 19 genes, and have been shown to contribute substantially to phenotypic variation among individuals 20 . However, the extent to which genetic interactions themselves are stable or dynamic across genotypes is unclear21, 22. Here we quantify more than 45,000 genetic interactions between the same 87 pairs of mutations across more than 500 closely related genotypes of a yeast tRNA. Notably, all pairs of mutations interacted in at least 9% of genetic backgrounds and all pairs switched from interacting positively to interacting negatively in different genotypes (false discovery rate?<?0.1). Higher-order interactions are also abundant and dynamic across genotypes. The epistasis in this tRNA means that all individual mutations switch from detrimental to beneficial, even in closely related genotypes. As a consequence, accurate genetic prediction requires mutation effects to be measured across different genetic backgrounds and the use of higher-order epistatic terms.
| S-EPMC6193533 | biostudies-literature
Project description:Gaussian process (GP)-based automatic relevance determination (ARD) is known to be an efficient technique for identifying determinants of gene-by-gene interactions important to trait variation. However, the estimation of GP models is feasible only for low-dimensional datasets (∼200 variables), which severely limits application of the GP-based ARD method for high-throughput sequencing data. In this paper, we provide a nonparametric prescreening method that preserves virtually all the major benefits of the GP-based ARD method and extends its scalability to the typical high-dimensional datasets used in practice. In several simulated test scenarios, the proposed method compared favorably with existing nonparametric dimension reduction/prescreening methods suitable for higher-order interaction searches. As a real-data example, the proposed method was applied to a high-throughput dataset downloaded from the cancer genome atlas (TCGA) with measured expression levels of 16,976 genes (after preprocessing) from patients diagnosed with acute myeloid leukemia.
| S-EPMC6893368 | biostudies-literature
Project description:The detailed principles of the hierarchical folding of eukaryotic chromosomes have been revealed during the last two decades. Along with structures composing three-dimensional (3D) genome organization (chromatin compartments, topologically associating domains, chromatin loops, etc.), the molecular mechanisms that are involved in their establishment and maintenance have been characterized. Generally, protein-protein and protein-DNA interactions underlie the spatial genome organization in eukaryotes. However, it is becoming increasingly evident that weak interactions, which exist in biological systems, also contribute to the 3D genome. Here, we provide a snapshot of our current understanding of the role of the weak interactions in the establishment and maintenance of the 3D genome organization. We discuss how weak biological forces, such as entropic forces operating in crowded solutions, electrostatic interactions of the biomolecules, liquid-liquid phase separation, DNA supercoiling, and RNA environment participate in chromosome segregation into structural and functional units and drive intranuclear functional compartmentalization.
| S-EPMC7229822 | biostudies-literature
Project description:A central assumption in most ecological models is that the interactions in a community operate only between pairs of species. However, two species may interactively affect the growth of a focal species. Although interactions among three or more species, called higher-order interactions, have the potential to modify our theoretical understanding of coexistence, ecologists lack clear expectations for how these interactions shape community structure. Here we analytically predict and numerically confirm how the variability and strength of higher-order interactions affect species coexistence. We found that as higher-order interaction strengths became more variable across species, fewer species could coexist, echoing the behavior of pairwise models. If interspecific higher-order interactions became too harmful relative to self-regulation, coexistence in diverse communities was destabilized, but coexistence was also lost when these interactions were too weak and mutualistic higher-order effects became prevalent. This behavior depended on the functional form of the interactions as the destabilizing effects of the mutualistic higher-order interactions were ameliorated when their strength saturated with species' densities. Last, we showed that more species-rich communities structured by higher-order interactions lose species more readily than their species-poor counterparts, generalizing classic results for community stability. Our work provides needed theoretical expectations for how higher-order interactions impact species coexistence in diverse communities.
| S-EPMC9618036 | biostudies-literature
Project description:Non-pairwise interactions, or higher-order interactions (HOIs), in microbial communities have been described as significant drivers of emergent features in microbiomes. Yet, the re-organization of microbial interactions between pairwise cultures and larger communities remains largely unexplored from a molecular perspective but is central to our understanding and further manipulation of microbial communities. Here, we used a bottom-up approach to investigate microbial interaction mechanisms from pairwise cultures up to 4-species communities from a simple microbiome (Hafnia alvei, Geotrichum candidum, Pencillium camemberti and Escherichia coli). Specifically, we characterized the interaction landscape for each species combination involving E. coli by identifying E. coli's interaction-associated mutants using an RB-TnSeq-based interaction assay. We observed a deep reorganization of the interaction-associated mutants, with very few 2-species interactions conserved all the way up to a 4-species community and the emergence of multiple HOIs. We further used a quantitative genetics strategy to decipher how 2-species interactions were quantitatively conserved in higher community compositions. Epistasis-based analysis revealed that, of the interactions that are conserved at all levels of complexity, 82% follow an additive pattern. Altogether, we demonstrate the complex architecture of microbial interactions even within a simple microbiome, and provide a mechanistic and molecular explanation of HOIs.
| S-EPMC9805437 | biostudies-literature
Project description:Human social interactions in local settings can be experimentally detected by recording the physical proximity and orientation of people. Such interactions, approximating face-to-face communications, can be effectively represented as time varying social networks with links being unceasingly created and destroyed over time. Traditional analyses of temporal networks have addressed mostly pairwise interactions, where links describe dyadic connections among individuals. However, many network dynamics are hardly ascribable to pairwise settings but often comprise larger groups, which are better described by higher-order interactions. Here we investigate the higher-order organizations of temporal social networks by analyzing five publicly available datasets collected in different social settings. We find that higher-order interactions are ubiquitous and, similarly to their pairwise counterparts, characterized by heterogeneous dynamics, with bursty trains of rapidly recurring higher-order events separated by long periods of inactivity. We investigate the evolution and formation of groups by looking at the transition rates between different higher-order structures. We find that in more spontaneous social settings, group are characterized by slower formation and disaggregation, while in work settings these phenomena are more abrupt, possibly reflecting pre-organized social dynamics. Finally, we observe temporal reinforcement suggesting that the longer a group stays together the higher the probability that the same interaction pattern persist in the future. Our findings suggest the importance of considering the higher-order structure of social interactions when investigating human temporal dynamics.
| S-EPMC8007734 | biostudies-literature
Project description:Naturally occurring signals in audition and touch can be complex and marked by temporal variations in frequency and amplitude. Auditory frequency sweep processing has been studied extensively; however, much less is known about sweep processing in touch because studies have primarily focused on the perception of simple sinusoidal vibrations. Given the extensive interactions between audition and touch in the frequency processing of pure tone signals, we reasoned that these senses might also interact in the processing of higher-order frequency representations like sweeps. In a series of psychophysical experiments, we characterized the influence of auditory distractors on the ability of participants to discriminate tactile frequency sweeps. Auditory frequency sweeps systematically biased the tactile perception of sweep direction. Importantly, auditory cues exerted little influence on tactile sweep direction perception when the sounds and vibrations occupied different absolute frequency ranges or when the sounds consisted of intensity sweeps. Thus, audition and touch interact in frequency sweep perception in a frequency- and feature-specific manner. Our results demonstrate that audio-tactile interactions are not constrained to the processing of simple sinusoids. Because higher-order frequency representations may be synthesized from simpler representations, our findings imply that multisensory interactions in the temporal frequency domain span multiple hierarchical levels in sensory processing. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
| S-EPMC6472995 | biostudies-literature
Project description:Transition-metal interfaces and multilayers are a promising class of systems to realize nanometer-sized, stable magnetic skyrmions for future spintronic devices. For room temperature applications, it is crucial to understand the interactions which control the stability of isolated skyrmions. Typically, skyrmion properties are explained by the interplay of pair-wise exchange interactions, the Dzyaloshinskii-Moriya interaction and the magnetocrystalline anisotropy energy. Here, we demonstrate that higher-order exchange interactions - which have so far been neglected - can play a key role for the stability of skyrmions. We use an atomistic spin model parametrized from first-principles and compare three different ultrathin film systems. We consider all fourth-order exchange interactions and show that, in particular, the four-site four spin interaction has a large effect on the energy barrier preventing skyrmion and antiskyrmion collapse into the ferromagnetic state. Our work opens perspectives to stabilize topological spin structures even in the absence of Dzyaloshinskii-Moriya interaction.
| S-EPMC7506016 | biostudies-literature