scholarly journals Genetic variation in human NPY expression affects stress response and emotion

Nature ◽  
2008 ◽  
Vol 452 (7190) ◽  
pp. 997-1001 ◽  
Author(s):  
Zhifeng Zhou ◽  
Guanshan Zhu ◽  
Ahmad R. Hariri ◽  
Mary-Anne Enoch ◽  
David Scott ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Stress Response

scholarly journals The dynamic effect of regulatory genetic variation on the in vivo ER stress transcriptional response

2021 ◽  
Author(s):  
Nikki D. Russell ◽  
Clement Y. Chow
Keyword(s):  
Genetic Variation ◽  
Stress Response ◽  
Er Stress ◽  
Transcriptional Response ◽  
Mouse Strains ◽  
Transcriptional Responses ◽  
Er Stress Response ◽  
Multiple Environments ◽  
Context Specific

AbstractGenotype x Environment (GxE) interactions occur when environmental conditions drastically change the effect of a genetic variant. In order to truly understand the effect of genetic variation, we need to incorporate multiple environments into our analyses. Many variants, under steady state conditions, may be silent or even have the opposite effect under stress conditions. This study uses an in vivo mouse model to investigate how the effect of genetic variation changes with tissue type and cellular stress. Endoplasmic reticulum (ER) stress occurs when misfolded proteins accumulate in the ER. This triggers the unfolded protein response (UPR), a large transcriptional response which attempts to return the cell to homeostasis. This transcriptional response, despite being a well conserved, basic cellular process, is highly variable across different genetic backgrounds, making it an ideal system to study GxE effects. In this study, we sought to better understand how genetic variation alters expression across tissues, in the presence and absence of ER stress. The use of different mouse strains and their F1s allow us to also identify context specific cis- and trans-regulatory mechanisms underlying variable transcriptional responses. We found hundreds of genes that respond to ER stress in a tissue- and/or genotype-dependent manner. Genotype-dependent ER stress-responsive genes are enriched for processes such as protein folding, apoptosis, and protein transport, indicating that some of the variability occurs in canonical ER stress factors. The majority of regulatory mechanisms underlying these variable transcriptional responses derive from cis-regulatory variation and are unique to a given tissue or ER stress state. This study demonstrates the need for incorporating multiple environments in future studies to better elucidate the effect of any particular genetic factor in basic biological pathways, like the ER stress response.Author SummaryThe effect of genetic variation is dependent on environmental context. Here we use genetically diverse mouse strains to understand how genetic variation interacts with stress state to produce variable transcriptional profiles. In this study, we take advantage of the endoplasmic reticulum (ER) stress response which is a large transcriptional response to misfolded proteins. Using this system, we uncovered tissue- and ER stress-specific effects of genetic variation on gene expression. Genes with genotype-dependent variable expression levels in response to ER stress were enriched for canonical ER stress functions, such as protein folding and transport. These variable effects of genetic variation are driven by unique sets of regulatory variation that are only active under context-specific circumstances. The results of this study highlight the importance of including multiple environments and genetic backgrounds when studying the ER stress response and other cellular pathways.

scholarly journals Evolutionary genetic integration of behavioural and endocrine components of the stress response

2019 ◽  
Author(s):  
T.M. Houslay ◽  
R.L. Earley ◽  
S.J. White ◽  
W. Lammers ◽  
A.J. Grimmer ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Stress Response ◽  
Response Selection ◽  
Animal Health ◽  
Functional Integration ◽  
Major Axis ◽  
Physiological Traits ◽  
Animal Populations ◽  
Stress Responsiveness ◽  
Genetic Integration

AbstractThe vertebrate stress response comprises a suite of behavioural and physiological traits that must be functionally integrated to ensure organisms cope adaptively with acute stressors. The expectation that natural selection has favoured functional integration leads to a prediction of genetic integration: genetic variation in the stress response should include covariation between its component behavioural and physiological traits. Despite the implications of such genetic integration for our understanding of human and animal health, as well as evolutionary responses to natural and anthropogenic stressors, formal quantitative genetic tests of this prediction are lacking. Here we demonstrate that Trinidadian guppies (Poecilia reticulata) show genetic variation in a suite of behavioural and physiological components of the acute stress response, and that these are indeed integrated into a single major axis of genetic variation. This axis appears to reflect continuous variation in the magnitude of integrated stress responsiveness, rather than variation in ‘coping style’ (a verbal model that postulates equal levels of stress responsiveness will manifest differently across individuals). The genetic integration we find here could either facilitate or constrain evolutionary responses to selection, depending upon the extent to which the direction of selection aligns with this single major axis of genetic covariation among stress response traits. Such integration also suggests that, while stress-related disease typically arises from physiological components of the stress response, selection on the genetically correlated behavioural responses to stress could offer a viable non-invasive route to the genetic improvement of health and welfare in captive animal populations.

scholarly journals A stress response that allows highly mutated eukaryotic cells to survive and proliferate

2019 ◽  
Author(s):  
Rebecca A. Zabinsky ◽  
Jonathan Mares ◽  
Richard She ◽  
Michelle K. Zeman ◽  
Thomas R. Silvers ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Stress Response ◽  
Genetic Variants ◽  
Transcriptional Response ◽  
Eukaryotic Cells ◽  
Mutation Burden ◽  
The Cost ◽  
Expression Program ◽  
Similar Gene

ABSTRACTRapid mutation fuels the evolution of many cancers and pathogens. Much of the ensuing genetic variation is detrimental, but cells can survive by limiting the cost of accumulating mutation burden. We investigated this behavior by propagating hypermutating yeast lineages to create independent populations harboring thousands of distinct genetic variants. Mutation rate and spectrum remained unchanged throughout the experiment, yet lesions that arose early were more deleterious than those that arose later. Although the lineages shared no mutations in common, each mounted a similar transcriptional response to mutation burden. The proteins involved in this response formed a highly connected network that has not previously been identified. Inhibiting this response increased the cost of accumulated mutations, selectively killing highly mutated cells. A similar gene expression program exists in hypermutating human cancers and is linked to survival. Our data thus define a conserved stress response that buffers the cost of accumulating genetic lesions and further suggest that this network could be targeted therapeutically.

scholarly journals Sex enhances survival in Paramecium

2019 ◽  
Author(s):  
Amarinder Singh Thind ◽  
Valerio Vitali ◽  
Mario R. Guarracino ◽  
Francesco Catania
Keyword(s):  
Genetic Variation ◽  
Stress Response ◽  
Sexual Reproduction ◽  
Stress Resistance ◽  
Evolutionary Biology ◽  
Molecular Mechanisms ◽  
Adaptive Significance ◽  
Paramecium Tetraurelia ◽  
Self Fertilization

AbstractThe pervasiveness of sex despite its well-known costs is a long-standing puzzle in evolutionary biology. Current explanations for the success of sex in nature largely rely on the adaptive significance of the new or rare genotypes that sex may generate. Less explored is the possibility that sex-underlying molecular mechanisms can enhance fitness and convey benefits to the individuals that bear the immediate costs of sex. Here we show that self-fertilization can increase stress resistance in the ciliate Paramecium tetraurelia. This advantage is independent of new genetic variation, coupled with a reduced nutritional input, and offers fresh insights into the mechanistic origin of sex. In addition to providing evidence that the molecular underpinnings of sexual reproduction and the stress response are linked in P. tetraurelia, these findings supply an explanation for the persistence of self-fertilization in this ciliate.

scholarly journals What’s Genetic Variation Got to Do with It? Starvation-Induced Self-Fertilization Enhances Survival in Paramecium

2020 ◽  
Vol 12 (5) ◽  
pp. 626-638 ◽  
Author(s):  
Amarinder Singh Thind ◽  
Valerio Vitali ◽  
Mario Rosario Guarracino ◽  
Francesco Catania
Keyword(s):  
Genetic Variation ◽  
Stress Response ◽  
Sexual Reproduction ◽  
Stress Resistance ◽  
Evolutionary Biology ◽  
Molecular Mechanisms ◽  
Adaptive Significance ◽  
Paramecium Tetraurelia ◽  
Self Fertilization

Abstract The pervasiveness of sex despite its well-known costs is a long-standing puzzle in evolutionary biology. Current explanations for the success of sex in nature largely rely on the adaptive significance of the new or rare genotypes that sex may generate. Less explored is the possibility that sex-underlying molecular mechanisms can enhance fitness and convey benefits to the individuals that bear the immediate costs of sex. Here, we show that the molecular environment associated with self-fertilization can increase stress resistance in the ciliate Paramecium tetraurelia. This advantage is independent of new genetic variation, coupled with a reduced nutritional input, and offers fresh insights into the mechanistic origin of sex. In addition to providing evidence that the molecular underpinnings of sexual reproduction and the stress response are linked in P. tetraurelia, these findings supply an integrative explanation for the persistence of self-fertilization in this ciliate.

scholarly journals Baldspot/ELOVL6 is a conserved modifier of disease and the ER stress response ELOVL6 modifies ER stress

2018 ◽  
Author(s):  
Rebecca A. S. Palu ◽  
Clement Y. Chow
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Genetic Variation ◽  
Stress Response ◽  
Er Stress ◽  
Chain Fatty Acid ◽  
Long Chain Fatty Acid ◽  
Fatty Acid Elongase ◽  
Er Stress Response ◽  
Long Chain

ABSTRACTEndoplasmic reticulum (ER) stress is an important modifier of human disease. Genetic variation in genes involved in the ER stress response has been linked to inter-individual differences in this response. However, the mechanisms and pathways by which genetic modifiers are acting on the ER stress response remain unclear. In this study, we characterize the role of the long chain fatty acid elongase Baldspot (ELOVL6) in modifying the ER stress response and disease. We demonstrate that loss of Baldspot rescues degeneration and reduces IRE1 and PERK signaling and cell death in a Drosophila model of retinitis pigmentosa and ER stress (Rh1G69D). Dietary supplementation of stearate bypasses the need for Baldspot activity. Finally, we demonstrate that Baldspot regulates the ER stress response across different tissues and induction methods. Our findings suggest that ELOVL6 is a promising target in the treatment of not only retinitis pigmentosa, but a number of different ER stress-related disorders.AUTHOR SUMMARYDifferences in genetic background drives disease variability, even among individuals with identical, causative mutations. Identifying and understanding how genetic variation impacts disease expression could improve diagnosis and treatment of patients. Previous work has linked the endoplasmic reticulum (ER) stress response pathway to disease variability. When misfolded proteins accumulate in the ER, the ER stress response returns the cell to its normal state. Chronic ER stress leads to massive amounts of cell death and tissue degeneration. Limiting tissue loss by regulating the ER stress response has been a major focus of therapeutic development. In this study, we characterize a novel regulator of the ER stress response, the long chain fatty acid elongase Baldspot/ELOVL6. In the absence of this enzyme, cells undergoing ER stress display reduced cell death, and degeneration in a Drosophila disease model. Feeding of excess fatty acids increases degeneration to original disease levels, linking the regulatory activity of Baldspot to its enzymatic activity. Finally, we demonstrate that Baldspot can alter the ER stress response under a variety of other ER stress conditions. Our studies demonstrate that Baldspot/ELOVL6 is a ubiquitous regulator of the ER stress response and is a good candidate therapeutic target.

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