Network Hubs Buffer Environmental Variation in Saccharomyces cerevisiae

Regulatory and developmental systems produce phenotypes that are robust to environmental and genetic variation. A gene product that normally contributes to this robustness is termed a phenotypic capacitor. When a phenotypic capacitor fails, for example when challenged by a harsh environment or mutation, the system becomes less robust and thus produces greater phenotypic variation. A functional phenotypic capacitor provides a mechanism by which hidden polymorphism can accumulate, whereas its failure provides a mechanism by which evolutionary change might be promoted. The primary example to date of a phenotypic capacitor is Hsp90, a molecular chaperone that targets a large set of signal transduction proteins. In both Drosophila and Arabidopsis, compromised Hsp90 function results in pleiotropic phenotypic effects dependent on the underlying genotype. For some traits, Hsp90 also appears to buffer stochastic variation, yet the relationship between environmental and genetic buffering remains an important unresolved question. We previously used simulations of knockout mutations in transcriptional networks to predict that many gene products would act as phenotypic capacitors. To test this prediction, we use high-throughput morphological phenotyping of individual yeast cells from single-gene deletion strains to identify gene products that buffer environmental variation in Saccharomyces cerevisiae. We find more than 300 gene products that, when absent, increase morphological variation. Overrepresented among these capacitors are gene products that control chromosome organization and DNA integrity, RNA elongation, protein modification, cell cycle, and response to stimuli such as stress. Capacitors have a high number of synthetic-lethal interactions but knockouts of these genes do not tend to cause severe decreases in growth rate. Each capacitor can be classified based on whether or not it is encoded by a gene with a paralog in the genome. Capacitors with a duplicate are highly connected in the protein–protein interaction network and show considerable divergence in expression from their paralogs. In contrast, capacitors encoded by singleton genes are part of highly interconnected protein clusters whose other members also tend to affect phenotypic variability or fitness. These results suggest that buffering and release of variation is a widespread phenomenon that is caused by incomplete functional redundancy at multiple levels in the genetic architecture

Sibling Genes as Environment: Sibling Dopamine Genotypes and Adolescent Health Support Frequency Dependent Selection

While research consistently suggests siblings matter for individual outcomes, it remains unclear why. At the same time, studies of genetic effects on health typically correlate variants of a gene with the average level of behavioral or health measures, ignoring more complicated genetic dynamics. Using National Longitudinal Study of Adolescent Health data, we investigate whether sibling genes moderate individual genetic expression. We compare twin variation in health-related absences and self-rated health by genetic differences at three locations related to dopamine regulation and transport to test sibship-level cross-person gene–gene interactions. Results suggest effects of variation at these genetic locations are moderated by sibling genes. Although the mechanism remains unclear, this evidence is consistent with frequency dependent selection and suggests much genetic research may violate the stable unit treatment value assumption

Reexamining microRNA Site Accessibility in Drosophila: A Population Genomics Study

Kertesz et al. (Nature Genetics 2008) described PITA, a miRNA target prediction algorithm based on hybridization energy and site accessibility. In this note, we used a population genomics approach to reexamine their data and found that the PITA algorithm had lower specificity than methods based on evolutionary conservation at comparable levels of sensitivity

Feed-forward regulation adaptively evolves via dynamics rather than topology when there is intrinsic noise

In transcriptional regulatory networks (TRNs), a canonical 3-node feed-forward loop (FFL) is hypothesized to evolve to filter out short spurious signals. We test this adaptive hypothesis against a novel null evolutionary model. Our mutational model captures the intrinsically high prevalence of weak affinity transcription factor binding sites. We also capture stochasticity and delays in gene expression that distort external signals and intrinsically generate noise. Functional FFLs evolve readily under selection for the hypothesized function but not in negative controls. Interestingly, a 4-node "diamond" motif also emerges as a short spurious signal filter. The diamond uses expression dynamics rather than path length to provide fast and slow pathways. When there is no idealized external spurious signal to filter out, but only internally generated noise, only the diamond and not the FFL evolves. While our results support the adaptive hypothesis, we also show that non-adaptive factors, including the intrinsic expression dynamics, matter.University of Arizona; Pew Scholarship; John Templeton Foundation [39667]; National Institutes of Health [R35GM118170, R01GM076041]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Laboratory Measurement of the Anticoagulant Activity of the Non–Vitamin K Oral Anticoagulants

AbstractBackgroundNon–vitamin K oral anticoagulants (NOACs) do not require routine laboratory monitoring. However, laboratory measurement may be desirable in special situations and populations.ObjectivesThis study’s objective was to systematically review and summarize current evidence regarding laboratory measurement of the anticoagulant activity of dabigatran, rivaroxaban, and apixaban.MethodsWe searched PubMed and Web of Science for studies that reported a relationship between drug levels of dabigatran, rivaroxaban, and apixaban and coagulation assay results. Study quality was evaluated using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2).ResultsWe identified 17 eligible studies for dabigatran, 15 for rivaroxaban, and 4 for apixaban. For dabigatran, a normal thrombin time excludes clinically relevant drug concentrations. The activated partial thromboplastin time (APTT) and prothrombin time (PT) are less sensitive and may be normal at trough drug levels. The dilute thrombin time (R2 = 0.92 to 0.99) and ecarin-based assays (R2 = 0.92 to 1.00) show excellent linearity across on-therapy drug concentrations and may be used for drug quantification. For rivaroxaban and apixaban, anti-Xa activity is linear (R2 = 0.89 to 1.00) over a wide range of drug levels and may be used for drug quantification. Undetectable anti-Xa activity likely excludes clinically relevant drug concentrations. The PT is less sensitive (especially for apixaban); a normal PT may not exclude clinically relevant levels. The APTT demonstrates insufficient sensitivity and linearity for quantification.ConclusionsDabigatran, rivaroxaban, and apixaban exhibit variable effects on coagulation assays. Understanding these effects facilitates interpretation of test results in NOAC-treated patients. More information on the relationship between drug levels and clinical outcomes is needed

Development of an Oral Health Survey: Columbus, Ohio

This article describes the method used to develop and implement a local oral health survey (Columbus, Ohio) conducted in 1986. With the shift in the national dental disease pattern in the past decade, local oral health information is essential for program planning purposes. A collaborative effort by a city health department, a state health department, a dental school, and a school of public health demonstrated how this group worked harmoniously in a relatively inexpensive venture to determine the oral status of various age groups (grades 1–2, grades 6–7, age 35–44, and age 65 +). This information provided part of the framework for a five-year dental plan at the Columbus Health Department. The survey design will serve as a basis for conducting a similar survey statewide. Modifications of existing oral health survey instruments are discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65714/1/j.1752-7325.1988.tb03177.x.pd

Dark Matter implications of the Fermi-LAT measurement of anisotropies in the diffuse gamma-ray background: status report

For the first time, the Fermi-LAT measured the angular power spectrum (APS) of anisotropies in the diffuse gamma-ray background. The data is found to be broadly compatible with a model with contributions from the point sources in the 1-year catalog, the galactic diffuse background, and the extragalactic isotropic emission; however deviations are present at both large and small angular scales. In this study, we complement the model with a contribution from Dark Matter (DM) whose distribution is modeled exploiting the results of the most recent N-body simulations, considering the contribution of extragalactic halos and subhalos (from Millennium-II) and of galactic substructures (from Aquarius). With the use of the Fermi Science Tools, these simulations serve as templates to produce mock gamma-ray count maps for DM gamma-ray emission, both in the case of an annihilating and a decaying DM candidate. The APS will then be computed and compared with the Fermi-LAT results to derive constraints on the DM particle physics properties. The possible systematic due to an imperfect model of the galactic foreground is also studied and taken into account properly. The present paper reports on the status of the project.Comment: Proceeding for the RICAP2011 conferenc

Heritability and the Equal Environments Assumption: Evidence from Multiple Samples of Misclassified Twins

The final publication is available at Springer via https://doi.org/10.1007/s10519-013-9602-1Classically derived estimates of heritability from twin models have been plagued by the possibility of genetic-environmental covariance. Survey questions that attempt to measure directly the extent to which more genetically similar kin (such as monozygotic twins) also share more similar environmental conditions represent poor attempts to gauge a complex underlying phenomenon of GE-covariance. The present study exploits a natural experiment to address this issue: Self-misperception of twin zygosity in the National Longitudinal Survey of Adolescent Health (Add Health). Such twins were reared under one “environmental regime of similarity” while genetically belonging to another group, reversing the typical GE-covariance and allowing bounded estimates of heritability for a range of outcomes. In addition, we examine twins who were initially misclassified by survey assignment—a stricter standard—in three datasets: Add Health, the Minnesota Twin Family Study and the Child and Adolescent Twin Study in Sweden. Results are similar across approaches and datasets and largely support the validity of the equal environments assumption

Children's spontaneous correction of false beliefs in a conversation partner.

Preschool children were tested for their ability to vary the verbal information they offered regarding an object's location depending on whether the person searching for that object was likely to infer or misinfer its location. Older children (mean age: 5 years 3 months) offered information in a selective fashion: If the location of the hidden object could be readily inferred by their conversation partner, they indicated its location only when explicitly asked but if its location was likely to be misinferred, they often indicated that location prior to being explicitly asked. The response pattern of younger children (mean age: 3 years 6 months) was less conclusive. A relatively large number of younger children took matters "into their own hands" and immediately grasped for the concealed object, irrespective of whether its location could be readily inferred. However, the reactions of the remaining 3-year-olds suggest that even at this age children may be sensitive to the likely beliefs of their conversation partner. © 1999 The International Society for the Study of Behavioural Development