scholarly journals Population-level survey of loss-of-function mutations revealed that background dependent fitness genes are rare and functionally related in yeast

2021 ◽  
Author(s):  
Elodie Caudal ◽  
Anne Friedrich ◽  
Marion Garin ◽  
Jing Hou ◽  
Joseph Schacherer
Keyword(s):  
Genetic Background ◽  
Genetic Interaction ◽  
Natural Populations ◽  
Interaction Network ◽  
Population Level ◽  
Continuous Variation ◽  
Loss Of Function ◽  
Individual Level ◽  
Cytoplasmic Transport ◽  
Natural Isolates

AbstractIn natural populations, the same mutation can lead to different phenotypic outcomes due to the genetic variation that exists among individuals. Such genetic background effects are commonly observed, including in the context of many human diseases. However, systematic characterization of these effects at the species level is still lacking to date. Here, we sought to comprehensively survey background-dependent traits associated with gene loss-of-function (LoF) mutations in 39 natural isolates of Saccharomyces cerevisiae using a transposon saturation strategy. By analyzing the modeled fitness variability of a total of 4,469 genes, we found that 15% of them, when impacted by a LoF mutation, exhibited a significant gain- or loss-of-fitness phenotype in certain natural isolates compared to the reference strain S288C. Out of these 632 genetic background-dependent fitness genes identified, a total of 2/3 show a continuous variation across the population while 1/3 are specific to a single genetic background. Genes related to mitochondrial function are significantly overrepresented in the set of genes showing a continuous variation and display a potential functional rewiring with other genes involved in transcription and chromatin remodeling as well as in nuclear-cytoplasmic transport. Such rewiring effects are likely modulated by both the genetic background and the environment. While background-specific cases are rare and span diverse cellular processes, they can be functionally related at the individual level. All background-dependent fitness genes tend to have an intermediate connectivity in the global genetic interaction network and have shown relaxed selection pressure at the population level, highlighting their potential evolutionary characteristics.

scholarly journals Age-specific reproduction in a long-lived species: the combined effects of senescence and individual quality

2008 ◽  
Vol 275 (1637) ◽  
pp. 963-970 ◽  
Author(s):  
R.H McCleery ◽  
C.M Perrins ◽  
B.C Sheldon ◽  
A Charmantier
Keyword(s):  
Life Histories ◽  
Age Groups ◽  
Natural Populations ◽  
Population Level ◽  
Individual Performance ◽  
Laying Date ◽  
Loss Of Function ◽  
Breeding Performance ◽  
Differential Survival ◽  
Mute Swans

Apparent changes in breeding performance with age measured at the population level can be due to changes in individual capacity at different ages, or to the differential survival of individuals with different capabilities. Estimating the relative importance of the two is important for understanding ageing patterns in natural populations, but there are few studies of such populations in which these effects have been disentangled. We analysed laying date and clutch size as measures of individual performance in a population of mute swans ( Cygnus olor ) studied over 25 years at Abbotsbury, UK. On both measures of breeding performance, individuals tended to improve up to the age of 6 or 7, and to decline after about the age of 12. Individuals with longer lifespans performed better at all ages (earlier laying, larger clutches) than animals that ceased breeding earlier. We conclude that the apparent mean increase in performance with age in mute swans is due to both individual improvement and differential survival of individuals who perform well, while the decline in older age groups is due to individual loss of function. Our results underline the need to take individual differences into account when testing hypotheses about life histories in wild populations.

scholarly journals Integrative analysis of large-scale loss-of-function screens identifies robust cancer-associated genetic interactions

2019 ◽  
Author(s):  
Christopher J. Lord ◽  
Niall Quinn ◽  
Colm J. Ryan
Keyword(s):  
Protein Interactions ◽  
Large Scale ◽  
Genetic Interaction ◽  
Interaction Network ◽  
Genetic Interactions ◽  
Molecular Heterogeneity ◽  
Loss Of Function ◽  
Driver Genes ◽  
Lethal Effects ◽  
Synthetic Lethal

AbstractGenetic interactions, such as synthetic lethal effects, can now be systematically identified in cancer cell lines using high-throughput genetic perturbation screens. Despite this advance, few genetic interactions have been reproduced across multiple studies and many appear highly context-specific. Understanding which genetic interactions are robust in the face of the molecular heterogeneity observed in tumours and what factors influence this robustness could streamline the identification of therapeutic targets. Here, we develop a computational approach to identify robust genetic interactions that can be reproduced across independent experiments and across non-overlapping cell line panels. We used this approach to evaluate >140,000 potential genetic interactions involving cancer driver genes and identified 1,520 that are significant in at least one study but only 220 that reproduce across multiple studies. Analysis of these interactions demonstrated that: (i) oncogene addiction effects are more robust than oncogene-related synthetic lethal effects; and (ii) robust genetic interactions in cancer are enriched for gene pairs whose protein products physically interact. This suggests that protein-protein interactions can be used not only to understand the mechanistic basis of genetic interaction effects, but also to prioritise robust targets for further development. To explore the utility of this approach, we used a protein-protein interaction network to guide the search for robust synthetic lethal interactions associated with passenger gene alterations and validated two novel robust synthetic lethalities.

scholarly journals Climate change as a catalyst of social evolution

2020 ◽  
Author(s):  
Jeanette Moss ◽  
Geoffrey While
Keyword(s):  
Climate Change ◽  
Social Group ◽  
Social Evolution ◽  
Social Complexity ◽  
Group Formation ◽  
Natural Populations ◽  
Population Level ◽  
Biodiversity Loss ◽  
Individual Level ◽  
Animal Societies

Anthropogenic climatic change will be a major factor shaping natural populations over the foreseeable future. The scope of this issue has spawned the integrative field of global change biology, which is chiefly concerned with identifying vulnerabilities of natural systems to climate change and integrating these into models of biodiversity loss. Meanwhile, there remains considerable latitude for investigating the multiple indirect and nuanced ways that broad-scale shifts in the abiotic environment will impact biological systems. One major unexplored category of effects is on social organisation. While climate has consistently been implicated as a major source of natural selection responsible for facilitating the evolution of complex animal societies, studies directed at testing these links on contemporary climatic time scales have thus far been limited to a select few higher-order, eusocial, taxa. Here, we present the case for how climate change, and specifically rising global temperatures, could catalyze social change at multiple stages of social evolution. We argue that these effects will manifest themselves through a range of subtle, climate-mediated pathways affecting the opportunities, nature, and context of interactions between individuals. We propose a broad conceptual framework for considering these pathways first at the individual level, and then discuss how feedbacks between bottom-up and top-down processes could mediate population-level shifts. We then implement this framework to explore the capacity for climate-mediated shifts in social evolution within three broad categories of social complexity: social group formation, social group maintenance, and social elaboration. For each category, we leverage social evolutionary theory and phylogenetic work spanning diverse systems to describe the pivotal traits that underpin transitions from each level of social complexity. In doing so, we aim to build a case for how short-term individual responses to climate could scale to impart constructive and/or destructive effects on the origins, maintenance, and diversification of animal societies.

scholarly journals Long-term social dynamics drive loss of function in pathogenic bacteria

2015 ◽  
Vol 112 (34) ◽  
pp. 10756-10761 ◽  
Author(s):  
Sandra Breum Andersen ◽  
Rasmus Lykke Marvig ◽  
Søren Molin ◽  
Helle Krogh Johansen ◽  
Ashleigh S. Griffin
Keyword(s):  
Social Interactions ◽  
Pathogenic Bacteria ◽  
Social Dynamics ◽  
Natural Populations ◽  
Population Level ◽  
Evolutionary Change ◽  
Bacterial Cells ◽  
Loss Of Function

Laboratory experiments show that social interactions between bacterial cells can drive evolutionary change at the population level, but significant challenges limit attempts to assess the relevance of these findings to natural populations, where selection pressures are unknown. We have increasingly sophisticated methods for monitoring phenotypic and genotypic dynamics in bacteria causing infectious disease, but in contrast, we lack evidence-based adaptive explanations for those changes. Evolutionary change during infection is often interpreted as host adaptation, but this assumption neglects to consider social dynamics shown to drive evolutionary change in vitro. We provide evidence to show that long-term behavioral dynamics observed in a pathogen are driven by selection to outcompete neighboring conspecific cells through social interactions. We find thatPseudomonas aeruginosabacteria, causing lung infections in patients with cystic fibrosis, lose cooperative iron acquisition by siderophore production during infection. This loss could be caused by changes in iron availability in the lung, but surprisingly, we find that cells retain the ability to take up siderophores produced by conspecifics, even after they have lost the ability to synthesize siderophores. Only when cooperative producers are lost from the population is the receptor for uptake lost. This finding highlights the potential pitfalls of interpreting loss of function in pathogenic bacterial populations as evidence for trait redundancy in the host environment. More generally, we provide an example of how sequence analysis can be used to generate testable hypotheses about selection driving long-term phenotypic changes of pathogenic bacteria in situ.

scholarly journals Exploring a local genetic interaction network using evolutionary replay experiments

2021 ◽  
Author(s):  
Ryan C. Vignogna ◽  
Sean W. Buskirk ◽  
Gregory I. Lang
Keyword(s):  
Experimental Evolution ◽  
Gene Deletion ◽  
Genetic Interaction ◽  
Interaction Network ◽  
Genetic Interactions ◽  
Loss Of Function ◽  
Positive Allele ◽  
Genetic Interaction Network ◽  
Allele Specific ◽  
Yeast Genetic

ABSTRACTUnderstanding how genes interact is a central challenge in biology. Experimental evolution provides a useful, but underutilized, tool for identifying genetic interactions, particularly those that involve non-loss-of-function mutations or mutations in essential genes. We previously identified a strong positive genetic interaction between specific mutations in KEL1 (P344T) and HSL7 (A695fs) that arose in an experimentally-evolved Saccharomyces cerevisiae population. Because this genetic interaction is not phenocopied by gene deletion, it was previously unknown. Using “evolutionary replay” experiments we identified additional mutations that have positive genetic interactions with the kel1-P344T mutation. We replayed the evolution of this population 672 times from six timepoints. We identified 30 populations where the kel1-P344T mutation reached high frequency. We performed whole-genome sequencing on these populations to identify genes in which mutations arose specifically in the kel1-P344T background. We reconstructed mutations in the ancestral and kel1-P344T backgrounds to validate positive genetic interactions. We identify several genetic interactors with KEL1, we validate these interactions by reconstruction experiments, and we show these interactions are not recapitulated by loss-of-function mutations. Our results demonstrate the power of experimental evolution to identify genetic interactions that are positive, allele specific, and not readily detected by other methods, and sheds light on a previously under-explored region of the yeast genetic interaction network.

scholarly journals Predators inhibit brain cell proliferation in natural populations of electric fish, Brachyhypopomus occidentalis

2016 ◽  
Vol 283 (1824) ◽  
pp. 20152113 ◽  
Author(s):  
Kent D. Dunlap ◽  
Alex Tran ◽  
Michael A. Ragazzi ◽  
Rüdiger Krahe ◽  
Vielka L. Salazar
Keyword(s):  
Cell Proliferation ◽  
Electric Fish ◽  
Acute Stress ◽  
Natural Populations ◽  
Population Level ◽  
Brain Cell ◽  
Predation Pressure ◽  
Natural Environments ◽  
Individual Level ◽  
The Individual

Compared with laboratory environments, complex natural environments promote brain cell proliferation and neurogenesis. Predators are one important feature of many natural environments, but, in the laboratory, predatory stimuli tend to inhibit brain cell proliferation. Often, laboratory predatory stimuli also elevate plasma glucocorticoids, which can then reduce brain cell proliferation. However, it is unknown how natural predators affect cell proliferation or whether glucocorticoids mediate the neurogenic response to natural predators. We examined brain cell proliferation in six populations of the electric fish, Brachyhypopomus occidentalis , exposed to three forms of predator stimuli: (i) natural variation in the density of predatory catfish; (ii) tail injury, presumably from predation attempts; and (iii) the acute stress of capture. Populations with higher predation pressure had lower density of proliferating (PCNA+) cells, and fish with injured tails had lower proliferating cell density than those with intact tails. However, plasma cortisol did not vary at the population level according to predation pressure or at the individual level according to tail injury. Capture stress significantly increased cortisol, but only marginally decreased cell proliferation. Thus, it appears that the presence of natural predators inhibits brain cell proliferation, but not via mechanisms that depend on changes in basal cortisol levels. This study is the first demonstration of predator-induced alteration of brain cell proliferation in a free-living vertebrate.

scholarly journals Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons

2021 ◽  
pp. 1-16
Author(s):  
Alison Fellgett ◽  
C. Adam Middleton ◽  
Jack Munns ◽  
Chris Ugbode ◽  
David Jaciuch ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Genetic Interaction ◽  
In Vitro Assays ◽  
Rab Proteins ◽  
Circadian Activity ◽  
Loss Of Function ◽  
Lrrk2 G2019s

Background: Inherited mutations in the LRRK2 protein are the common causes of Parkinson’s disease, but the mechanisms by which increased kinase activity of mutant LRRK2 leads to pathological events remain to be determined. In vitro assays (heterologous cell culture, phospho-protein mass spectrometry) suggest that several Rab proteins might be directly phosphorylated by LRRK2-G2019S. An in vivo screen of Rab expression in dopaminergic neurons in young adult Drosophila demonstrated a strong genetic interaction between LRRK2-G2019S and Rab10. Objective: To determine if Rab10 is necessary for LRRK2-induced pathophysiological responses in the neurons that control movement, vision, circadian activity, and memory. These four systems were chosen because they are modulated by dopaminergic neurons in both humans and flies. Methods: LRRK2-G2019S was expressed in Drosophila dopaminergic neurons and the effects of Rab10 depletion on Proboscis Extension, retinal neurophysiology, circadian activity pattern (‘sleep’), and courtship memory determined in aged flies. Results: Rab10 loss-of-function rescued LRRK2-G2019S induced bradykinesia and retinal signaling deficits. Rab10 knock-down, however, did not rescue the marked sleep phenotype which results from dopaminergic LRRK2-G2019S. Courtship memory is not affected by LRRK2, but is markedly improved by Rab10 depletion. Anatomically, both LRRK2-G2019S and Rab10 are seen in the cytoplasm and at the synaptic endings of dopaminergic neurons. Conclusion: We conclude that, in Drosophila dopaminergic neurons, Rab10 is involved in some, but not all, LRRK2-induced behavioral deficits. Therefore, variations in Rab expression may contribute to susceptibility of different dopaminergic nuclei to neurodegeneration seen in people with Parkinson’s disease.

scholarly journals Blood Pressure Trajectories Across the Life Course

2021 ◽  
Vol 34 (3) ◽  
pp. 234-241
Author(s):  
Norrina B Allen ◽  
Sadiya S Khan
Keyword(s):  
Blood Pressure ◽  
Measurement Errors ◽  
Clinical Care ◽  
Population Level ◽  
Cumulative Exposure ◽  
Older Adulthood ◽  
Individual Level ◽  
The Life Course ◽  
Level Group ◽  
Improve Health

Abstract High blood pressure (BP) is a strong modifiable risk factor for cardiovascular disease (CVD). Longitudinal BP patterns themselves may reflect the burden of risk and vascular damage due to prolonged cumulative exposure to high BP levels. Current studies have begun to characterize BP patterns as a trajectory over an individual’s lifetime. These BP trajectories take into account the absolute BP levels as well as the slope of BP changes throughout the lifetime thus incorporating longitudinal BP patterns into a single metric. Methodologic issues that need to be considered when examining BP trajectories include individual-level vs. population-level group-based modeling, use of distinct but complementary BP metrics (systolic, diastolic, mean arterial, mid, and pulse pressure), and potential for measurement errors related to varied settings, devices, and number of readings utilized. There appear to be very specific developmental periods during which divergent BP trajectories may emerge, specifically adolescence, the pregnancy period, and older adulthood. Lifetime BP trajectories are impacted by both individual-level and community-level factors and have been associated with incident hypertension, multimorbidity (CVD, renal disease, cognitive impairment), and overall life expectancy. Key unanswered questions remain around the additive predictive value of BP trajectories, intergenerational contributions to BP patterns (in utero BP exposure), and potential genetic drivers of BP patterns. The next phase in understanding BP trajectories needs to focus on how best to incorporate this knowledge into clinical care to reduce the burden of hypertensive-related outcomes and improve health equity.

scholarly journals Examining the Effects of the Sacramento Dockless E-Bike Share on Bicycling and Driving

2021 ◽  
Vol 13 (1) ◽  
pp. 368
Author(s):  
Dillon T. Fitch ◽  
Hossain Mohiuddin ◽  
Susan L. Handy
Keyword(s):  
Travel Behavior ◽  
Regression Models ◽  
Population Level ◽  
Panel Survey ◽  
Multilevel Regression ◽  
Combine Data ◽  
Cross Sectional ◽  
Individual Level ◽  
Before And After ◽  
Bike Share

One way cities are looking to promote bicycling is by providing publicly or privately operated bike-share services, which enable individuals to rent bicycles for one-way trips. Although many studies have examined the use of bike-share services, little is known about how these services influence individual-level travel behavior more generally. In this study, we examine the behavior of users and non-users of a dockless, electric-assisted bike-share service in the Sacramento region of California. This service, operated by Jump until suspended due to the coronavirus pandemic, was one of the largest of its kind in the U.S., and spanned three California cities: Sacramento, West Sacramento, and Davis. We combine data from a repeat cross-sectional before-and-after survey of residents and a longitudinal panel survey of bike-share users with the goal of examining how the service influenced individual-level bicycling and driving. Results from multilevel regression models suggest that the effect of bike-share on average bicycling and driving at the population level is likely small. However, our results indicate that people who have used-bike share are likely to have increased their bicycling because of bike-share.

Sign in / Sign up

Export Citation Format

Share Document