Recent research suggests that genetic interactions involving more than two loci may influence a number of complex traits. How these ‘higher-order’ interactions arise at the genetic and molecular levels remains an open question. To provide insights into this problem, we dissected a colony morphology phenotype that segregates in a yeast cross and results from synthetic higher-order interactions. Using backcrossing and selective sequencing of progeny, we found five loci that collectively produce the trait. We fine-mapped these loci to 22 genes in total and identified a single gene at each locus that caused loss of the phenotype when deleted. Complementation tests or allele replacements provided support for functional variation in these genes, and revealed that pre-existing genetic variants and a spontaneous mutation interact to cause the trait. The causal genes have diverse functions in endocytosis (END3), oxidative stress response (TRR1), RAS-cAMP signalling (IRA2), and transcriptional regulation of multicellular growth (FLO8 and MSS11), and for the most part have not previously been shown to exhibit functional relationships. Further efforts uncovered two additional loci that together can complement the non-causal allele of END3, suggesting that multiple genotypes in the cross can specify the same phenotype. Our work sheds light on the complex genetic and molecular architecture of higher-order interactions, and raises questions about the broader contribution of such interactions to heritable trait variation.
The contribution of genetic interactions involving three or more loci to complex traits is poorly understood. Because these higher-order genetic interactions (HGIs) are difficult to detect in genetic mapping studies, very few examples of them have been described. However, the lack of data on HGIs should not be misconstrued as proof that this class of genetic effect is unimportant. To the contrary, evidence from model organisms suggests that HGIs frequently influence genetic studies and contribute to many complex traits. Here, we review the growing literature on HGIs and discuss the future of research on this topic.
Among the available metal oxide nanostructures, tungsten oxide has remained, at times, troublesome to fabricate, with many synthetic methods often requiring exotic equipment and or reagents. In this work, we present a systematic investigation demonstrating a new method for the deposition of anhydrous and hydrated nanostructured tungsten oxide thin films via spin coating. The attributes of these materials include the following: high surface area, controllable deposition, and compatibility with existing semiconductor fabrication infrastructure making this method a suitable candidate for application in the manufacture of gas sensors and dye sensitized solar cells. We will show that it is possible to form micrometer thick highly crystalline nanostructured thin films and, using Raman, SEM, XRD, XPS, and TEM analysis, will prove that these nanostructures can be rendered into anhydrous or partially or fully hydrated tungsten oxides. We further demonstrate the application of these materials in the fabrication of an inexpensive NO2 gas sensor, capable of sensing sub-ppm levels of NO2 concentrations at a modest operating temperature of 175 °C.
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.
Cryptic genetic variants that do not typically influence traits can interact epistatically with each other and mutations to cause unexpected phenotypes. To improve understanding of the genetic architectures and molecular mechanisms that underlie these interactions, we comprehensively dissected the genetic bases of 17 independent instances of the same cryptic colony phenotype in a yeast cross. In eight cases, the phenotype resulted from a genetic interaction between a de novo mutation and one or more cryptic variants. The number and identities of detected cryptic variants depended on the mutated gene. In the nine remaining cases, the phenotype arose without a de novo mutation due to two different classes of higher-order genetic interactions that only involve cryptic variants. Our results may be relevant to other species and disease, as most of the mutations and cryptic variants identified in our study reside in components of a partially conserved and oncogenic signalling pathway.
Determining how genetic variation alters the expression of heritable phenotypes across conditions is important for agriculture, evolution, and medicine. Central to this problem is the concept of genotype-by-environment interaction (or ‘GxE’), which occurs when segregating genetic variation causes individuals to show different phenotypic responses to the environment. While many studies have sought to identify individual loci that contribute to GxE, obtaining a deeper understanding of this phenomenon may require defining how sets of loci collectively alter the relationship between genotype, environment, and phenotype. Here, we identify combinations of alleles at seven loci that control how a mutationally induced colony phenotype is expressed across a range of temperatures (21, 30, and 37°C) in a panel of yeast recombinants. We show that five predominant multi-locus genotypes involving the detected loci result in trait expression with varying degrees of temperature sensitivity. By comparing these genotypes and their patterns of trait expression across temperatures, we demonstrate that the involved alleles contribute to temperature sensitivity in different ways. While alleles of the transcription factor MSS11 specify the potential temperatures at which the trait can occur, alleles at the other loci modify temperature sensitivity within the range established by MSS11 in a genetic background- and/or temperature-dependent manner. Our results not only represent one of the first characterizations of GxE at the resolution of multi-locus genotypes, but also provide an example of the different roles that genetic variants can play in altering trait expression across conditions.
We demonstrate that when, and only when, the biaxial stress is increased above a critical value of 6+/-1 GPa during the growth of a carbon film at room temperature, tetrahedral amorphous carbon is formed. This confirms that the stress present during the formation of an amorphous carbon film determines its sp;{3} bonding fraction. In the vicinity of the critical stress, a highly oriented graphitelike material is formed which exhibits low electrical resistance and provides Ohmic contacts to silicon. Atomistic simulations reveal that the structural transitions are thermodynamically driven and not the result of dynamical effects.
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