| 41. |
- Pentz, Jennifer T., et al.
(author)
-
Forecasting of phenotypic and genetic outcomes of experimental evolution in Pseudomonas protegens
- 2021
-
In: PLOS Genetics. - : Public Library of Science. - 1553-7390 .- 1553-7404. ; 17:8
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Journal article (peer-reviewed)abstract
- Experimental evolution with microbes is often highly repeatable under identical conditions, suggesting the possibility to predict short-term evolution. However, it is not clear to what degree evolutionary forecasts can be extended to related species in non-identical environments, which would allow testing of general predictive models and fundamental biological assumptions. To develop an extended model system for evolutionary forecasting, we used previous data and models of the genotype-to-phenotype map from the wrinkly spreader system in Pseudomonas fluorescens SBW25 to make predictions of evolutionary outcomes on different biological levels for Pseudomonas protegens Pf-5. In addition to sequence divergence (78% amino acid and 81% nucleotide identity) for the genes targeted by mutations, these species also differ in the inability of Pf-5 to make cellulose, which is the main structural basis for the adaptive phenotype in SBW25. The experimental conditions were changed compared to the SBW25 system to test if forecasts were extendable to a non-identical environment. Forty-three mutants with increased ability to colonize the air-liquid interface were isolated, and the majority had reduced motility and was partly dependent on the Pel exopolysaccharide as a structural component. Most (38/43) mutations are expected to disrupt negative regulation of the same three diguanylate cyclases as in SBW25, with a smaller number of mutations in promoter regions, including an uncharacterized polysaccharide synthase operon. A mathematical model developed for SBW25 predicted the order of the three main pathways and the genes targeted by mutations, but differences in fitness between mutants and mutational biases also appear to influence outcomes. Mutated regions in proteins could be predicted in most cases (16/22), but parallelism at the nucleotide level was low and mutational hot spot sites were not conserved. This study demonstrates the potential of short-term evolutionary forecasting in experimental populations and provides testable predictions for evolutionary outcomes in other Pseudomonas species.
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| 42. |
- Poom, Leo, et al.
(author)
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Priming and reversals of the perceived ambiguous orientation of a structure-from-motion shape and relation to personality traits
- 2022
-
In: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 17:8
-
Journal article (peer-reviewed)abstract
- We demonstrate contributions of top-down and bottom-up influences in perception as explored by priming and counts of perceived reversals and mixed percepts, as probed by an ambiguously slanted structure-from-motion (SFM) test-cylinder. We included three different disambiguated primes: a SFM cylinder, a still image of a cylinder, and an imagined cylinder. In Experiment 1 where the prime and test sequentially occupied the same location, we also administered questionnaires with the Big-5 trait openness and vividness of visual imagery to probe possible relations to top-down driven priming. Since influences of gaze or position in the prime conditions in Experiment 1 could not be ruled out completely, Experiment 2 was conducted where the test cylinder appeared at a randomly chosen position after the prime. In Experiment 2 we also measured the number of perceptual reversals and mixed percepts during prolonged viewing of our ambiguous SFM-cylinder, and administered questionnaires to measure all Big-5 traits, autism, spatial and object imagery, and rational or experiential cognitive styles, associated with bottom-up and top-down processes. The results revealed contributions of position-invariant and cue-invariant priming. In addition, residual contributions of low-level priming was found when the prime and test were both defined by SFM, and were presented at the same location, and the correlation between the SFM priming and the other two priming conditions were weaker than between the pictorial and imagery priming. As previously found with ambiguous binocular rivalry stimuli, we found positive correlations between mixed percepts and the Big-5 dimension openness to experience, and between reversals, mixed percepts and neuroticism. Surprisingly, no correlations between the scores from the vividness of imagery questionnaires and influence from any of the primes were obtained. An intriguing finding was the significant differences between the positive correlation from the experiential cognitive style scores, and the negative correlation between rational style and the cue invariant priming. Among other results, negative correlations between agreeableness and all priming conditions were obtained. These results not only support the notion of multiple processes involved in the perception of ambiguous SFM, but also link these processes in perception to specific personality traits.
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| 43. |
- Poveda-Huertes, Daniel, et al.
(author)
-
Increased mitochondrial protein import and cardiolipin remodelling upon early mtUPR
- 2021
-
In: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 17:7
-
Journal article (peer-reviewed)abstract
- Mitochondrial defects can cause a variety of human diseases and protective mechanisms exist to maintain mitochondrial functionality. Imbalances in mitochondrial proteostasis trigger a transcriptional program, termed mitochondrial unfolded protein response (mtUPR). However, the temporal sequence of events in mtUPR is unclear and the consequences on mitochondrial protein import are controversial. Here, we have quantitatively analyzed all main import pathways into mitochondria after different time spans of mtUPR induction. Kinetic analyses reveal that protein import into all mitochondrial subcompartments strongly increases early upon mtUPR and that this is accompanied by rapid remodelling of the mitochondrial signature lipid cardiolipin. Genetic inactivation of cardiolipin synthesis precluded stimulation of protein import and compromised cellular fitness. At late stages of mtUPR upon sustained stress, mitochondrial protein import efficiency declined. Our work clarifies the enigma of protein import upon mtUPR and identifies sequential mtUPR stages, in which an early increase in protein biogenesis to restore mitochondrial proteostasis is followed by late stages characterized by a decrease in import capacity upon prolonged stress induction.
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| 44. |
- Ramachandran, Sohini, et al.
(author)
-
Estimation of non-null SNP effect size distributions enables the detection of enriched genes underlying complex traits
- 2020
-
In: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 16:6
-
Journal article (peer-reviewed)abstract
- Traditional univariate genome-wide association studies generate false positives and nega-tives due to difficulties distinguishing associated variants from variants with spurious non-zero effects that do not directly influence the trait. Recent efforts have been directed atidentifying genes or signaling pathways enriched for mutations in quantitative traits or case-control studies, but these can be computationally costly and hampered by strict modelassumptions. Here, we present gene-ε, a new approach for identifying statistical associa-tions between sets of variants and quantitative traits. Our key insight is that enrichment stud-ies on the gene-level are improved when we reformulate the genome-wide SNP-level nullhypothesis to identify spurious small-to-intermediate SNP effects and classify them as non-causal. gene-ε efficiently identifies enriched genes under a variety of simulated geneticarchitectures, achieving greater than a 90% true positive rate at 1% false positive rate forpolygenic traits. Lastly, we apply gene-ε to summary statistics derived from six quantitativetraits using European-ancestry individuals in the UK Biobank, and identify enriched genesthat are in biologically relevant pathways.
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| 45. |
- Ryvkin, Julia, et al.
(author)
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Failure to mate enhances investment in behaviors that may promote mating reward and impairs the ability to cope with stressors via a subpopulation of Neuropeptide F receptor neurons
- 2024
-
In: PLOS Genetics. - 1553-7390 .- 1553-7404. ; 20:1
-
Journal article (peer-reviewed)abstract
- Living in dynamic environments such as the social domain, where interaction with others determines the reproductive success of individuals, requires the ability to recognize opportunities to obtain natural rewards and cope with challenges that are associated with achieving them. As such, actions that promote survival and reproduction are reinforced by the brain reward system, whereas coping with the challenges associated with obtaining these rewards is mediated by stress-response pathways, the activation of which can impair health and shorten lifespan. While much research has been devoted to understanding mechanisms underlying the way by which natural rewards are processed by the reward system, less attention has been given to the consequences of failure to obtain a desirable reward. As a model system to study the impact of failure to obtain a natural reward, we used the well-established courtship suppression paradigm in Drosophila melanogaster as means to induce repeated failures to obtain sexual reward in male flies. We discovered that beyond the known reduction in courtship actions caused by interaction with non-receptive females, repeated failures to mate induce a stress response characterized by persistent motivation to obtain the sexual reward, reduced male-male social interaction, and enhanced aggression. This frustrative-like state caused by the conflict between high motivation to obtain sexual reward and the inability to fulfill their mating drive impairs the capacity of rejected males to tolerate stressors such as starvation and oxidative stress. We further show that sensitivity to starvation and enhanced social arousal is mediated by the disinhibition of a small population of neurons that express receptors for the fly homologue of neuropeptide Y. Our findings demonstrate for the first time the existence of social stress in flies and offers a framework to study mechanisms underlying the crosstalk between reward, stress, and reproduction in a simple nervous system that is highly amenable to genetic manipulation. In this study we investigated the effects of failure to obtain reward on the behavioral actions and physiology of male flies. We exposed Drosophila males to repeated sexual encounters with non-receptive females that rejected their courtship efforts and tested the effect on their behavioral responses using a collection of behavioral paradigms. These responses encompass alterations in social behavior, increased aggression, heightened motivation to mate, and a reduced capacity to cope with stressors. We further show that the high motivational state and sensitivity to stress is mediated by the disinhibition of a small population of neurons that express receptors for the fly homologue of neuropeptide Y.
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| 46. |
- Silva, Willian T. A. F., 1987-, et al.
(author)
-
Evolution of plasticity in production and transgenerational inheritance of small RNAs under dynamic environmental conditions
- 2021
-
In: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 17:5
-
Journal article (peer-reviewed)abstract
- In a changing environment, small RNAs (sRNAs) play an important role in the post-transcriptional regulation of gene expression and can vary in abundance depending on the conditions experienced by an individual (phenotypic plasticity) and its parents (non-genetic inheritance). Many sRNAs are unusual in that they can be produced in two ways, either using genomic DNA as the template (primary sRNAs) or existing sRNAs as the template (secondary sRNAs). Thus, organisms can evolve rapid plastic responses to their current environment by adjusting the amplification rate of sRNA templates. sRNA levels can also be transmitted transgenerationally by the direct transfer of either sRNAs or the proteins involved in amplification. Theory is needed to describe the selective forces acting on sRNA levels, accounting for the dual nature of sRNAs as regulatory elements and templates for amplification and for the potential to transmit sRNAs and their amplification agents to offspring. Here, we develop a model to study the dynamics of sRNA production and inheritance in a fluctuating environment. We tested the selective advantage of mutants capable of sRNA-mediated phenotypic plasticity within resident populations with fixed levels of sRNA transcription. Even when the resident was allowed to evolve an optimal constant rate of sRNA production, plastic amplification rates capable of responding to environmental conditions were favored. Mechanisms allowing sRNA transcripts or amplification agents to be inherited were favored primarily when parents and offspring face similar environments and when selection acts before the optimal level of sRNA can be reached within the organism. Our study provides a clear set of testable predictions for the evolution of sRNA-related mechanisms of phenotypic plasticity and transgenerational inheritance.Author summarySmall RNAs (sRNA) are produced by a wide range of organisms, from bacteria to plants and animals. These molecules are involved in the response to environmental stress (e.g., temperature, pathogens) and can be transmitted across generations. We developed a model to explore the dynamics of sRNA production (phenotypic plasticity) and inheritance in a fluctuating environment. We tested whether different sRNA mutants can invade a population where individuals produce sRNA at a constant optimal transcription rate. In our simulations, plastic amplification rates capable of responding to environmental conditions were favored and the transmission of sRNA transcripts or amplification agents across generations was particularly advantageous when parents and offspring faced similar environments. sRNA amplification alone is not favored except when optimal sRNA levels are not reached within a generation. Our model provides novel predictions for the molecular mechanisms of sRNA production and guidance for future empirical studies on mutations that impair the mechanisms of sRNA production and their fitness consequences.
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| 47. |
- Stårsta, Magnus, et al.
(author)
-
RHS-elements function as type II toxin-antitoxin modules that regulate intra-macrophage replication of Salmonella Typhimurium
- 2020
-
In: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 16:2
-
Journal article (peer-reviewed)abstract
- RHS elements are components of conserved toxin-delivery systems, wide-spread within the bacterial kingdom and some of the most positively selected genes known. However, very little is known about how Rhs toxins affect bacterial biology. Salmonella Typhimurium contains a full-length rhs gene and an adjacent orphan rhs gene, which lacks the conserved delivery part of the Rhs protein. Here we show that, in addition to the conventional delivery, Rhs toxin-antitoxin pairs encode for functional type-II toxin-antitoxin (TA) loci that regulate S. Typhimurium proliferation within macrophages. Mutant S. Typhimurium cells lacking both Rhs toxins proliferate 2-times better within macrophages, mainly because of an increased growth rate. Thus, in addition to providing strong positive selection for the rhs loci under conditions when there is little or no toxin delivery, internal expression of the toxin-antitoxin system regulates growth in the stressful environment found inside macrophages.
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| 48. |
- Sun, Bin, et al.
(author)
-
FIONA1-mediated methylation of the 3’UTR of FLC affects FLC transcript levels and flowering in Arabidopsis
- 2022
-
In: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 18:9
-
Journal article (other academic/artistic)abstract
- Adenosine bases of RNA can be transiently modified by the deposition of a methyl-group to form N6-methyladenosine (m6A). This adenosine-methylation is an ancient process and the enzymes involved are evolutionary highly conserved. A genetic screen designed to identify suppressors of late flowering transgenic Arabidopsis plants overexpressing the miP1a microProtein yielded a new allele of the FIONA1 (FIO1) m6A-methyltransferase. To characterize the early flowering phenotype of fio1 mutant plants we employed an integrative approach of mRNA-seq, Nanopore direct RNA-sequencing and meRIP-seq to identify differentially expressed transcripts as well as differentially methylated RNAs. We provide evidence that FIO1 is the elusive methyltransferase responsible for the 3’-end methylation of the FLOWERING LOCUS C (FLC) transcript. Furthermore, our genetic and biochemical data suggest that 3’-methylation stabilizes FLC mRNAs and non-methylated FLC is a target for rapid degradation.
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| 49. |
- Tomic, Tajana Tesan, et al.
(author)
-
MYO5B mutations in pheochromocytoma/paraganglioma promote cancer progression
- 2020
-
In: PLOS Genetics. - : Public Library of Science. - 1553-7390 .- 1553-7404. ; 16:6
-
Journal article (peer-reviewed)abstract
- Identification of additional cancer-associated genes and secondary mutations driving the metastatic progression in pheochromocytoma and paraganglioma (PPGL) is important for subtyping, and may provide optimization of therapeutic regimens. We recently reported novel recurrent nonsynonymous mutations in the MYO5B gene in metastatic PPGL. Here, we explored the functional impact of these MYO5B mutations, and analyzed MYO5B expression in primary PPGL tumor cases in relation to mutation status. Immunohistochemistry and mRNA expression analysis in 30 PPGL tumors revealed an increased MYO5B expression in metastatic compared to non-metastatic cases. In addition, subcellular localization of MYO5B protein was altered from cytoplasmic to membranous in some metastatic tumors, and the strongest and most abnormal expression pattern was observed in a paraganglioma harboring a somatic MYO5B:p.G1611S mutation. In addition to five previously discovered MYO5B mutations, the present study of 30 PPGL (8 previous and 22 new samples) also revealed two, and hence recurrent, mutations in the gene paralog MYO5A. The three MYO5B missense mutations with the highest prediction scores (p.L587P, p.G1611S and p.R1641C) were selected and functionally validated using site directed mutagenesis and stable transfection into human neuroblastoma cells (SK-N-AS) and embryonic kidney cells (HEK293). In vitro analysis showed a significant increased proliferation rate in all three MYO5B mutated clones. The two somatically derived mutations, p.L587P and p.G1611S, were also found to increase the migration rate. Expression analysis of MYO5B mutants compared to wild type clones, demonstrated a significant enrichment of genes involved in migration, proliferation, cell adhesion, glucose metabolism, and cellular homeostasis. Our study validates the functional role of novel MYO5B mutations in proliferation and migration, and suggest the MYO5-pathway to be involved in the malignant progression in some PPGL tumors. © 2020 Tomic et al.
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| 50. |
- Wang, Dandan, et al.
(author)
-
Porcine ZBED6 regulates growth of skeletal muscle and internal organs via multiple targets
- 2021
-
In: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 17:10
-
Journal article (peer-reviewed)abstract
- ZBED6 (zinc finger BED domain containing protein 6) is a transcription factor unique to placental mammals and its interaction with the IGF2 (insulin-like growth factor 2) locus plays a prominent role in the regulation of postnatal skeletal muscle growth. Here, we generated lean Bama miniature pigs by generating ZBED6-knockout (ZBED6(-/-)) and investigated the mechanism underlying ZBED6 in growth of muscle and internal organs of placental mammals. ZBED6(-/-) pigs show markedly higher lean mass, lean mass rate, larger muscle fiber area and heavier internal organs (heart and liver) than wild-type (WT) pigs. The striking phenotypic changes of ZBED6(-/-) pigs coincided with remarkable upregulation of IGF2 mRNA and protein expression across three tissues (gastrocnemius muscle, longissimus dorsi, heart). Despite a significant increase in liver weight, ZBED6(-/-) pigs show comparable levels of IGF2 expression to those of WT controls. A mechanistic study revealed that elevated methylation in the liver abrogates ZBED6 binding at the IGF2 locus, explaining the unaltered hepatic IGF2 expression in ZBED6(-/-) pigs. These results indicate that a ZBED6-IGF2-independent regulatory pathway exists in the liver. Transcriptome analysis and ChIP-PCR revealed new ZBED6 target genes other than IGF2, including cyclin dependent kinase inhibitor 1A (CDKN1A) and tsukushi, small leucine rich proteoglycan (TSKU), that regulates growth of muscle and liver, respectively. Author summary The lean meat rate is an important economic trait for the swine industry and it is determined by muscle growth and development. A single base change in intron 3 of the insulin-like growth factor 2 (IGF2) gene increases meat production in pigs by disrupting a binding site for zinc finger BED domain containing protein 6 (ZBED6). Chinese indigenous pig breeds carrying the homozygous IGF2 wild-type allele produce low lean meat. We thus generate a lean pig model in Chinese Bama pig by knocking out ZBED6. In this model, we demonstrate that ZBED6 KO increases muscle and internal organ growth through ZBED6-IGF2 axis and other target genes. These results not only open new strategies for lean meat breeding in Chinese indigenous pigs, but also provide new insights to the global function of ZBED6 in organ growth and development.
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