@article{12238, abstract = {Upon the initiation of collective cell migration, the cells at the free edge are specified as leader cells; however, the mechanism underlying the leader cell specification remains elusive. Here, we show that lamellipodial extension after the release from mechanical confinement causes sustained extracellular signal-regulated kinase (ERK) activation and underlies the leader cell specification. Live-imaging of Madin-Darby canine kidney (MDCK) cells and mouse epidermis through the use of Förster resonance energy transfer (FRET)-based biosensors showed that leader cells exhibit sustained ERK activation in a hepatocyte growth factor (HGF)-dependent manner. Meanwhile, follower cells exhibit oscillatory ERK activation waves in an epidermal growth factor (EGF) signaling-dependent manner. Lamellipodial extension at the free edge increases the cellular sensitivity to HGF. The HGF-dependent ERK activation, in turn, promotes lamellipodial extension, thereby forming a positive feedback loop between cell extension and ERK activation and specifying the cells at the free edge as the leader cells. Our findings show that the integration of physical and biochemical cues underlies the leader cell specification during collective cell migration.}, author = {Hino, Naoya and Matsuda, Kimiya and Jikko, Yuya and Maryu, Gembu and Sakai, Katsuya and Imamura, Ryu and Tsukiji, Shinya and Aoki, Kazuhiro and Terai, Kenta and Hirashima, Tsuyoshi and Trepat, Xavier and Matsuda, Michiyuki}, issn = {1534-5807}, journal = {Developmental Cell}, keywords = {Developmental Biology, Cell Biology, General Biochemistry, Genetics and Molecular Biology, Molecular Biology}, number = {19}, pages = {2290--2304.e7}, publisher = {Elsevier}, title = {{A feedback loop between lamellipodial extension and HGF-ERK signaling specifies leader cells during collective cell migration}}, doi = {10.1016/j.devcel.2022.09.003}, volume = {57}, year = {2022}, } @article{12247, abstract = {Chromosomal inversions have been shown to play a major role in a local adaptation by suppressing recombination between alternative arrangements and maintaining beneficial allele combinations. However, so far, their importance relative to the remaining genome remains largely unknown. Understanding the genetic architecture of adaptation requires better estimates of how loci of different effect sizes contribute to phenotypic variation. Here, we used three Swedish islands where the marine snail Littorina saxatilis has repeatedly evolved into two distinct ecotypes along a habitat transition. We estimated the contribution of inversion polymorphisms to phenotypic divergence while controlling for polygenic effects in the remaining genome using a quantitative genetics framework. We confirmed the importance of inversions but showed that contributions of loci outside inversions are of similar magnitude, with variable proportions dependent on the trait and the population. Some inversions showed consistent effects across all sites, whereas others exhibited site-specific effects, indicating that the genomic basis for replicated phenotypic divergence is only partly shared. The contributions of sexual dimorphism as well as environmental factors to phenotypic variation were significant but minor compared to inversions and polygenic background. Overall, this integrated approach provides insight into the multiple mechanisms contributing to parallel phenotypic divergence.}, author = {Koch, Eva L. and Ravinet, Mark and Westram, Anja M and Johannesson, Kerstin and Butlin, Roger K.}, issn = {1558-5646}, journal = {Evolution}, keywords = {General Agricultural and Biological Sciences, Genetics, Ecology, Evolution, Behavior and Systematics}, number = {10}, pages = {2332--2346}, publisher = {Wiley}, title = {{Genetic architecture of repeated phenotypic divergence in Littorina saxatilis evolution}}, doi = {10.1111/evo.14602}, volume = {76}, year = {2022}, } @article{12248, abstract = {Eurasian brine shrimp (genus Artemia) have closely related sexual and asexual lineages of parthenogenetic females, which produce rare males at low frequencies. Although they are known to have ZW chromosomes, these are not well characterized, and it is unclear whether they are shared across the clade. Furthermore, the underlying genetic architecture of the transmission of asexuality, which can occur when rare males mate with closely related sexual females, is not well understood. We produced a chromosome-level assembly for the sexual Eurasian species Artemia sinica and characterized in detail the pair of sex chromosomes of this species. We combined this new assembly with short-read genomic data for the sexual species Artemia sp. Kazakhstan and several asexual lineages of Artemia parthenogenetica, allowing us to perform an in-depth characterization of sex-chromosome evolution across the genus. We identified a small differentiated region of the ZW pair that is shared by all sexual and asexual lineages, supporting the shared ancestry of the sex chromosomes. We also inferred that recombination suppression has spread to larger sections of the chromosome independently in the American and Eurasian lineages. Finally, we took advantage of a rare male, which we backcrossed to sexual females, to explore the genetic basis of asexuality. Our results suggest that parthenogenesis is likely partly controlled by a locus on the Z chromosome, highlighting the interplay between sex determination and asexuality.}, author = {Elkrewi, Marwan N and Khauratovich, Uladzislava and Toups, Melissa A and Bett, Vincent K and Mrnjavac, Andrea and Macon, Ariana and Fraisse, Christelle and Sax, Luca and Huylmans, Ann K and Hontoria, Francisco and Vicoso, Beatriz}, issn = {1943-2631}, journal = {Genetics}, keywords = {Genetics}, number = {2}, publisher = {Oxford University Press}, title = {{ZW sex-chromosome evolution and contagious parthenogenesis in Artemia brine shrimp}}, doi = {10.1093/genetics/iyac123}, volume = {222}, year = {2022}, } @article{12261, abstract = {Dose–response relationships are a general concept for quantitatively describing biological systems across multiple scales, from the molecular to the whole-cell level. A clinically relevant example is the bacterial growth response to antibiotics, which is routinely characterized by dose–response curves. The shape of the dose–response curve varies drastically between antibiotics and plays a key role in treatment, drug interactions, and resistance evolution. However, the mechanisms shaping the dose–response curve remain largely unclear. Here, we show in Escherichia coli that the distinctively shallow dose–response curve of the antibiotic trimethoprim is caused by a negative growth-mediated feedback loop: Trimethoprim slows growth, which in turn weakens the effect of this antibiotic. At the molecular level, this feedback is caused by the upregulation of the drug target dihydrofolate reductase (FolA/DHFR). We show that this upregulation is not a specific response to trimethoprim but follows a universal trend line that depends primarily on the growth rate, irrespective of its cause. Rewiring the feedback loop alters the dose–response curve in a predictable manner, which we corroborate using a mathematical model of cellular resource allocation and growth. Our results indicate that growth-mediated feedback loops may shape drug responses more generally and could be exploited to design evolutionary traps that enable selection against drug resistance.}, author = {Angermayr, Andreas and Pang, Tin Yau and Chevereau, Guillaume and Mitosch, Karin and Lercher, Martin J and Bollenbach, Mark Tobias}, issn = {1744-4292}, journal = {Molecular Systems Biology}, keywords = {Applied Mathematics, Computational Theory and Mathematics, General Agricultural and Biological Sciences, General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, Information Systems}, number = {9}, publisher = {Embo Press}, title = {{Growth‐mediated negative feedback shapes quantitative antibiotic response}}, doi = {10.15252/msb.202110490}, volume = {18}, year = {2022}, } @article{12275, abstract = {N-glycans are molecularly diverse sugars borne by over 70% of proteins transiting the secretory pathway and have been implicated in protein folding, stability, and localization. Mutations in genes important for N-glycosylation result in congenital disorders of glycosylation that are often associated with intellectual disability. Here, we show that structurally distinct N-glycans regulate an extracellular protein complex involved in the patterning of somatosensory dendrites in Caenorhabditis elegans. Specifically, aman-2/Golgi alpha-mannosidase II, a conserved key enzyme in the biosynthesis of specific N-glycans, regulates the activity of the Menorin adhesion complex without obviously affecting the protein stability and localization of its components. AMAN-2 functions cell-autonomously to allow for decoration of the neuronal transmembrane receptor DMA-1/LRR-TM with the correct set of high-mannose/hybrid/paucimannose N-glycans. Moreover, distinct types of N-glycans on specific N-glycosylation sites regulate DMA-1/LRR-TM receptor function, which, together with three other extracellular proteins, forms the Menorin adhesion complex. In summary, specific N-glycan structures regulate dendrite patterning by coordinating the activity of an extracellular adhesion complex, suggesting that the molecular diversity of N-glycans can contribute to developmental specificity in the nervous system.}, author = {Rahman, Maisha and Ramirez, Nelson and Diaz‐Balzac, Carlos A and Bülow, Hannes E}, issn = {1469-3178}, journal = {EMBO Reports}, keywords = {Genetics, Molecular Biology, Biochemistry}, number = {7}, publisher = {Embo Press}, title = {{Specific N-glycans regulate an extracellular adhesion complex during somatosensory dendrite patterning}}, doi = {10.15252/embr.202154163}, volume = {23}, year = {2022}, } @article{12280, abstract = {In repeated interactions, players can use strategies that respond to the outcome of previous rounds. Much of the existing literature on direct reciprocity assumes that all competing individuals use the same strategy space. Here, we study both learning and evolutionary dynamics of players that differ in the strategy space they explore. We focus on the infinitely repeated donation game and compare three natural strategy spaces: memory-1 strategies, which consider the last moves of both players, reactive strategies, which respond to the last move of the co-player, and unconditional strategies. These three strategy spaces differ in the memory capacity that is needed. We compute the long term average payoff that is achieved in a pairwise learning process. We find that smaller strategy spaces can dominate larger ones. For weak selection, unconditional players dominate both reactive and memory-1 players. For intermediate selection, reactive players dominate memory-1 players. Only for strong selection and low cost-to-benefit ratio, memory-1 players dominate the others. We observe that the supergame between strategy spaces can be a social dilemma: maximum payoff is achieved if both players explore a larger strategy space, but smaller strategy spaces dominate.}, author = {Schmid, Laura and Hilbe, Christian and Chatterjee, Krishnendu and Nowak, Martin}, issn = {1553-7358}, journal = {PLOS Computational Biology}, keywords = {Computational Theory and Mathematics, Cellular and Molecular Neuroscience, Genetics, Molecular Biology, Ecology, Modeling and Simulation, Ecology, Evolution, Behavior and Systematics}, number = {6}, publisher = {Public Library of Science}, title = {{Direct reciprocity between individuals that use different strategy spaces}}, doi = {10.1371/journal.pcbi.1010149}, volume = {18}, year = {2022}, } @article{12288, abstract = {To understand the function of neuronal circuits, it is crucial to disentangle the connectivity patterns within the network. However, most tools currently used to explore connectivity have low throughput, low selectivity, or limited accessibility. Here, we report the development of an improved packaging system for the production of the highly neurotropic RVdGenvA-CVS-N2c rabies viral vectors, yielding titers orders of magnitude higher with no background contamination, at a fraction of the production time, while preserving the efficiency of transsynaptic labeling. Along with the production pipeline, we developed suites of ‘starter’ AAV and bicistronic RVdG-CVS-N2c vectors, enabling retrograde labeling from a wide range of neuronal populations, tailored for diverse experimental requirements. We demonstrate the power and flexibility of the new system by uncovering hidden local and distal inhibitory connections in the mouse hippocampal formation and by imaging the functional properties of a cortical microcircuit across weeks. Our novel production pipeline provides a convenient approach to generate new rabies vectors, while our toolkit flexibly and efficiently expands the current capacity to label, manipulate and image the neuronal activity of interconnected neuronal circuits in vitro and in vivo.}, author = {Sumser, Anton L and Jösch, Maximilian A and Jonas, Peter M and Ben Simon, Yoav}, issn = {2050-084X}, journal = {eLife}, keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Medicine, General Neuroscience}, publisher = {eLife Sciences Publications}, title = {{Fast, high-throughput production of improved rabies viral vectors for specific, efficient and versatile transsynaptic retrograde labeling}}, doi = {10.7554/elife.79848}, volume = {11}, year = {2022}, } @article{12670, abstract = {DNA methylation plays essential homeostatic functions in eukaryotic genomes. In animals, DNA methylation is also developmentally regulated and, in turn, regulates development. In the past two decades, huge research effort has endorsed the understanding that DNA methylation plays a similar role in plant development, especially during sexual reproduction. The power of whole-genome sequencing and cell isolation techniques, as well as bioinformatics tools, have enabled recent studies to reveal dynamic changes in DNA methylation during germline development. Furthermore, the combination of these technological advances with genetics, developmental biology and cell biology tools has revealed functional methylation reprogramming events that control gene and transposon activities in flowering plant germlines. In this review, we discuss the major advances in our knowledge of DNA methylation dynamics during male and female germline development in flowering plants.}, author = {He, Shengbo and Feng, Xiaoqi}, issn = {1744-7909}, journal = {Journal of Integrative Plant Biology}, keywords = {Plant Science, General Biochemistry, Genetics and Molecular Biology, Biochemistry}, number = {12}, pages = {2240--2251}, publisher = {Wiley}, title = {{DNA methylation dynamics during germline development}}, doi = {10.1111/jipb.13422}, volume = {64}, year = {2022}, } @article{10834, abstract = {Hematopoietic-specific protein 1 (Hem1) is an essential subunit of the WAVE regulatory complex (WRC) in immune cells. WRC is crucial for Arp2/3 complex activation and the protrusion of branched actin filament networks. Moreover, Hem1 loss of function in immune cells causes autoimmune diseases in humans. Here, we show that genetic removal of Hem1 in macrophages diminishes frequency and efficacy of phagocytosis as well as phagocytic cup formation in addition to defects in lamellipodial protrusion and migration. Moreover, Hem1-null macrophages displayed strong defects in cell adhesion despite unaltered podosome formation and concomitant extracellular matrix degradation. Specifically, dynamics of both adhesion and de-adhesion as well as concomitant phosphorylation of paxillin and focal adhesion kinase (FAK) were significantly compromised. Accordingly, disruption of WRC function in non-hematopoietic cells coincided with both defects in adhesion turnover and altered FAK and paxillin phosphorylation. Consistently, platelets exhibited reduced adhesion and diminished integrin αIIbβ3 activation upon WRC removal. Interestingly, adhesion phenotypes, but not lamellipodia formation, were partially rescued by small molecule activation of FAK. A full rescue of the phenotype, including lamellipodia formation, required not only the presence of WRCs but also their binding to and activation by Rac. Collectively, our results uncover that WRC impacts on integrin-dependent processes in a FAK-dependent manner, controlling formation and dismantling of adhesions, relevant for properly grabbing onto extracellular surfaces and particles during cell edge expansion, like in migration or phagocytosis.}, author = {Stahnke, Stephanie and Döring, Hermann and Kusch, Charly and de Gorter, David J.J. and Dütting, Sebastian and Guledani, Aleks and Pleines, Irina and Schnoor, Michael and Sixt, Michael K and Geffers, Robert and Rohde, Manfred and Müsken, Mathias and Kage, Frieda and Steffen, Anika and Faix, Jan and Nieswandt, Bernhard and Rottner, Klemens and Stradal, Theresia E.B.}, issn = {0960-9822}, journal = {Current Biology}, keywords = {General Agricultural and Biological Sciences, General Biochemistry, Genetics and Molecular Biology}, number = {10}, pages = {2051--2064.e8}, publisher = {Elsevier}, title = {{Loss of Hem1 disrupts macrophage function and impacts migration, phagocytosis, and integrin-mediated adhesion}}, doi = {10.1016/j.cub.2021.02.043}, volume = {31}, year = {2021}, } @article{10838, abstract = {Combining hybrid zone analysis with genomic data is a promising approach to understanding the genomic basis of adaptive divergence. It allows for the identification of genomic regions underlying barriers to gene flow. It also provides insights into spatial patterns of allele frequency change, informing about the interplay between environmental factors, dispersal and selection. However, when only a single hybrid zone is analysed, it is difficult to separate patterns generated by selection from those resulting from chance. Therefore, it is beneficial to look for repeatable patterns across replicate hybrid zones in the same system. We applied this approach to the marine snail Littorina saxatilis, which contains two ecotypes, adapted to wave-exposed rocks vs. high-predation boulder fields. The existence of numerous hybrid zones between ecotypes offered the opportunity to test for the repeatability of genomic architectures and spatial patterns of divergence. We sampled and phenotyped snails from seven replicate hybrid zones on the Swedish west coast and genotyped them for thousands of single nucleotide polymorphisms. Shell shape and size showed parallel clines across all zones. Many genomic regions showing steep clines and/or high differentiation were shared among hybrid zones, consistent with a common evolutionary history and extensive gene flow between zones, and supporting the importance of these regions for divergence. In particular, we found that several large putative inversions contribute to divergence in all locations. Additionally, we found evidence for consistent displacement of clines from the boulder–rock transition. Our results demonstrate patterns of spatial variation that would not be accessible without continuous spatial sampling, a large genomic data set and replicate hybrid zones.}, author = {Westram, Anja M and Faria, Rui and Johannesson, Kerstin and Butlin, Roger}, issn = {1365-294X}, journal = {Molecular Ecology}, keywords = {Genetics, Ecology, Evolution, Behavior and Systematics}, number = {15}, pages = {3797--3814}, publisher = {Wiley}, title = {{Using replicate hybrid zones to understand the genomic basis of adaptive divergence}}, doi = {10.1111/mec.15861}, volume = {30}, year = {2021}, } @article{11052, abstract = {In order to combat molecular damage, most cellular proteins undergo rapid turnover. We have previously identified large nuclear protein assemblies that can persist for years in post-mitotic tissues and are subject to age-related decline. Here, we report that mitochondria can be long lived in the mouse brain and reveal that specific mitochondrial proteins have half-lives longer than the average proteome. These mitochondrial long-lived proteins (mitoLLPs) are core components of the electron transport chain (ETC) and display increased longevity in respiratory supercomplexes. We find that COX7C, a mitoLLP that forms a stable contact site between complexes I and IV, is required for complex IV and supercomplex assembly. Remarkably, even upon depletion of COX7C transcripts, ETC function is maintained for days, effectively uncoupling mitochondrial function from ongoing transcription of its mitoLLPs. Our results suggest that modulating protein longevity within the ETC is critical for mitochondrial proteome maintenance and the robustness of mitochondrial function.}, author = {Krishna, Shefali and Arrojo e Drigo, Rafael and Capitanio, Juliana S. and Ramachandra, Ranjan and Ellisman, Mark and HETZER, Martin W}, issn = {1534-5807}, journal = {Developmental Cell}, keywords = {Developmental Biology, Cell Biology, General Biochemistry, Genetics and Molecular Biology, Molecular Biology}, number = {21}, pages = {P2952--2965.e9}, publisher = {Elsevier}, title = {{Identification of long-lived proteins in the mitochondria reveals increased stability of the electron transport chain}}, doi = {10.1016/j.devcel.2021.10.008}, volume = {56}, year = {2021}, } @article{8931, abstract = {Auxin is a major plant growth regulator, but current models on auxin perception and signaling cannot explain the whole plethora of auxin effects, in particular those associated with rapid responses. A possible candidate for a component of additional auxin perception mechanisms is the AUXIN BINDING PROTEIN 1 (ABP1), whose function in planta remains unclear. Here we combined expression analysis with gain- and loss-of-function approaches to analyze the role of ABP1 in plant development. ABP1 shows a broad expression largely overlapping with, but not regulated by, transcriptional auxin response activity. Furthermore, ABP1 activity is not essential for the transcriptional auxin signaling. Genetic in planta analysis revealed that abp1 loss-of-function mutants show largely normal development with minor defects in bolting. On the other hand, ABP1 gain-of-function alleles show a broad range of growth and developmental defects, including root and hypocotyl growth and bending, lateral root and leaf development, bolting, as well as response to heat stress. At the cellular level, ABP1 gain-of-function leads to impaired auxin effect on PIN polar distribution and affects BFA-sensitive PIN intracellular aggregation. The gain-of-function analysis suggests a broad, but still mechanistically unclear involvement of ABP1 in plant development, possibly masked in abp1 loss-of-function mutants by a functional redundancy.}, author = {Gelová, Zuzana and Gallei, Michelle C and Pernisová, Markéta and Brunoud, Géraldine and Zhang, Xixi and Glanc, Matous and Li, Lanxin and Michalko, Jaroslav and Pavlovicova, Zlata and Verstraeten, Inge and Han, Huibin and Hajny, Jakub and Hauschild, Robert and Čovanová, Milada and Zwiewka, Marta and Hörmayer, Lukas and Fendrych, Matyas and Xu, Tongda and Vernoux, Teva and Friml, Jiří}, issn = {0168-9452}, journal = {Plant Science}, keywords = {Agronomy and Crop Science, Plant Science, Genetics, General Medicine}, publisher = {Elsevier}, title = {{Developmental roles of auxin binding protein 1 in Arabidopsis thaliana}}, doi = {10.1016/j.plantsci.2020.110750}, volume = {303}, year = {2021}, } @article{8997, abstract = {Phenomenological relations such as Ohm’s or Fourier’s law have a venerable history in physics but are still scarce in biology. This situation restrains predictive theory. Here, we build on bacterial “growth laws,” which capture physiological feedback between translation and cell growth, to construct a minimal biophysical model for the combined action of ribosome-targeting antibiotics. Our model predicts drug interactions like antagonism or synergy solely from responses to individual drugs. We provide analytical results for limiting cases, which agree well with numerical results. We systematically refine the model by including direct physical interactions of different antibiotics on the ribosome. In a limiting case, our model provides a mechanistic underpinning for recent predictions of higher-order interactions that were derived using entropy maximization. We further refine the model to include the effects of antibiotics that mimic starvation and the presence of resistance genes. We describe the impact of a starvation-mimicking antibiotic on drug interactions analytically and verify it experimentally. Our extended model suggests a change in the type of drug interaction that depends on the strength of resistance, which challenges established rescaling paradigms. We experimentally show that the presence of unregulated resistance genes can lead to altered drug interaction, which agrees with the prediction of the model. While minimal, the model is readily adaptable and opens the door to predicting interactions of second and higher-order in a broad range of biological systems.}, author = {Kavcic, Bor and Tkačik, Gašper and Bollenbach, Tobias}, issn = {1553-7358}, journal = {PLOS Computational Biology}, keywords = {Modelling and Simulation, Genetics, Molecular Biology, Antibiotics, Drug interactions}, publisher = {Public Library of Science}, title = {{Minimal biophysical model of combined antibiotic action}}, doi = {10.1371/journal.pcbi.1008529}, volume = {17}, year = {2021}, } @article{13356, abstract = {Self-assembly of nanoparticles can be mediated by polymers, but has so far led almost exclusively to nanoparticle aggregates that are amorphous. Here, we employed Coulombic interactions to generate a range of composite materials from mixtures of charged nanoparticles and oppositely charged polymers. The assembly behavior of these nanoparticle/polymer composites depends on their order of addition: polymers added to nanoparticles give rise to stable aggregates, but nanoparticles added to polymers disassemble the initially formed aggregates. The amorphous aggregates were transformed into crystalline ones by transiently increasing the ionic strength of the solution. The morphology of the resulting crystals depended on the length of the polymer: short polymer chains mediated the self-assembly of nanoparticles into strongly faceted crystals, whereas long chains led to pseudospherical nanoparticle/polymer assemblies, within which the crystalline order of nanoparticles was retained.}, author = {Bian, Tong and Klajn, Rafal}, issn = {1749-6632}, journal = {Annals of the New York Academy of Sciences}, keywords = {History and Philosophy of Science, General Biochemistry, Genetics and Molecular Biology, General Neuroscience}, number = {1}, pages = {191--201}, publisher = {Wiley}, title = {{Morphology control in crystalline nanoparticle–polymer aggregates}}, doi = {10.1111/nyas.14674}, volume = {1505}, year = {2021}, } @article{9252, abstract = {This paper analyses the conditions for local adaptation in a metapopulation with infinitely many islands under a model of hard selection, where population size depends on local fitness. Each island belongs to one of two distinct ecological niches or habitats. Fitness is influenced by an additive trait which is under habitat‐dependent directional selection. Our analysis is based on the diffusion approximation and accounts for both genetic drift and demographic stochasticity. By neglecting linkage disequilibria, it yields the joint distribution of allele frequencies and population size on each island. We find that under hard selection, the conditions for local adaptation in a rare habitat are more restrictive for more polygenic traits: even moderate migration load per locus at very many loci is sufficient for population sizes to decline. This further reduces the efficacy of selection at individual loci due to increased drift and because smaller populations are more prone to swamping due to migration, causing a positive feedback between increasing maladaptation and declining population sizes. Our analysis also highlights the importance of demographic stochasticity, which exacerbates the decline in numbers of maladapted populations, leading to population collapse in the rare habitat at significantly lower migration than predicted by deterministic arguments.}, author = {Szep, Eniko and Sachdeva, Himani and Barton, Nicholas H}, issn = {1558-5646}, journal = {Evolution}, keywords = {Genetics, Ecology, Evolution, Behavior and Systematics, General Agricultural and Biological Sciences}, number = {5}, pages = {1030--1045}, publisher = {Wiley}, title = {{Polygenic local adaptation in metapopulations: A stochastic eco‐evolutionary model}}, doi = {10.1111/evo.14210}, volume = {75}, year = {2021}, } @article{9283, abstract = {Gene expression levels are influenced by multiple coexisting molecular mechanisms. Some of these interactions such as those of transcription factors and promoters have been studied extensively. However, predicting phenotypes of gene regulatory networks (GRNs) remains a major challenge. Here, we use a well-defined synthetic GRN to study in Escherichia coli how network phenotypes depend on local genetic context, i.e. the genetic neighborhood of a transcription factor and its relative position. We show that one GRN with fixed topology can display not only quantitatively but also qualitatively different phenotypes, depending solely on the local genetic context of its components. Transcriptional read-through is the main molecular mechanism that places one transcriptional unit (TU) within two separate regulons without the need for complex regulatory sequences. We propose that relative order of individual TUs, with its potential for combinatorial complexity, plays an important role in shaping phenotypes of GRNs.}, author = {Nagy-Staron, Anna A and Tomasek, Kathrin and Caruso Carter, Caroline and Sonnleitner, Elisabeth and Kavcic, Bor and Paixão, Tiago and Guet, Calin C}, issn = {2050-084X}, journal = {eLife}, keywords = {Genetics and Molecular Biology}, publisher = {eLife Sciences Publications}, title = {{Local genetic context shapes the function of a gene regulatory network}}, doi = {10.7554/elife.65993}, volume = {10}, year = {2021}, } @article{9374, abstract = {If there are no constraints on the process of speciation, then the number of species might be expected to match the number of available niches and this number might be indefinitely large. One possible constraint is the opportunity for allopatric divergence. In 1981, Felsenstein used a simple and elegant model to ask if there might also be genetic constraints. He showed that progress towards speciation could be described by the build‐up of linkage disequilibrium among divergently selected loci and between these loci and those contributing to other forms of reproductive isolation. Therefore, speciation is opposed by recombination, because it tends to break down linkage disequilibria. Felsenstein then introduced a crucial distinction between “two‐allele” models, which are subject to this effect, and “one‐allele” models, which are free from the recombination constraint. These fundamentally important insights have been the foundation for both empirical and theoretical studies of speciation ever since.}, author = {Butlin, Roger K. and Servedio, Maria R. and Smadja, Carole M. and Bank, Claudia and Barton, Nicholas H and Flaxman, Samuel M. and Giraud, Tatiana and Hopkins, Robin and Larson, Erica L. and Maan, Martine E. and Meier, Joana and Merrill, Richard and Noor, Mohamed A. F. and Ortiz‐Barrientos, Daniel and Qvarnström, Anna}, issn = {1558-5646}, journal = {Evolution}, keywords = {Genetics, Ecology, Evolution, Behavior and Systematics, General Agricultural and Biological Sciences}, number = {5}, pages = {978--988}, publisher = {Wiley}, title = {{Homage to Felsenstein 1981, or why are there so few/many species?}}, doi = {10.1111/evo.14235}, volume = {75}, year = {2021}, } @article{9387, abstract = {We report the complete analysis of a deterministic model of deleterious mutations and negative selection against them at two haploid loci without recombination. As long as mutation is a weaker force than selection, mutant alleles remain rare at the only stable equilibrium, and otherwise, a variety of dynamics are possible. If the mutation-free genotype is absent, generally the only stable equilibrium is the one that corresponds to fixation of the mutant allele at the locus where it is less deleterious. This result suggests that fixation of a deleterious allele that follows a click of the Muller’s ratchet is governed by natural selection, instead of random drift.}, author = {Khudiakova, Kseniia and Neretina, Tatiana Yu. and Kondrashov, Alexey S.}, issn = {0022-5193}, journal = {Journal of Theoretical Biology}, keywords = {General Biochemistry, Genetics and Molecular Biology, Modelling and Simulation, Statistics and Probability, General Immunology and Microbiology, Applied Mathematics, General Agricultural and Biological Sciences, General Medicine}, publisher = {Elsevier }, title = {{Two linked loci under mutation-selection balance and Muller’s ratchet}}, doi = {10.1016/j.jtbi.2021.110729}, volume = {524}, year = {2021}, } @article{9429, abstract = {De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 lead to autism spectrum disorder (ASD). In mouse, constitutive haploinsufficiency leads to motor coordination deficits as well as ASD-relevant social and cognitive impairments. However, induction of Cul3 haploinsufficiency later in life does not lead to ASD-relevant behaviors, pointing to an important role of Cul3 during a critical developmental window. Here we show that Cul3 is essential to regulate neuronal migration and, therefore, constitutive Cul3 heterozygous mutant mice display cortical lamination abnormalities. At the molecular level, we found that Cul3 controls neuronal migration by tightly regulating the amount of Plastin3 (Pls3), a previously unrecognized player of neural migration. Furthermore, we found that Pls3 cell-autonomously regulates cell migration by regulating actin cytoskeleton organization, and its levels are inversely proportional to neural migration speed. Finally, we provide evidence that cellular phenotypes associated with autism-linked gene haploinsufficiency can be rescued by transcriptional activation of the intact allele in vitro, offering a proof of concept for a potential therapeutic approach for ASDs.}, author = {Morandell, Jasmin and Schwarz, Lena A and Basilico, Bernadette and Tasciyan, Saren and Dimchev, Georgi A and Nicolas, Armel and Sommer, Christoph M and Kreuzinger, Caroline and Dotter, Christoph and Knaus, Lisa and Dobler, Zoe and Cacci, Emanuele and Schur, Florian KM and Danzl, Johann G and Novarino, Gaia}, issn = {2041-1723}, journal = {Nature Communications}, keywords = {General Biochemistry, Genetics and Molecular Biology}, number = {1}, publisher = {Springer Nature}, title = {{Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development}}, doi = {10.1038/s41467-021-23123-x}, volume = {12}, year = {2021}, } @article{9431, abstract = {Inositol hexakisphosphate (IP6) is an assembly cofactor for HIV-1. We report here that IP6 is also used for assembly of Rous sarcoma virus (RSV), a retrovirus from a different genus. IP6 is ~100-fold more potent at promoting RSV mature capsid protein (CA) assembly than observed for HIV-1 and removal of IP6 in cells reduces infectivity by 100-fold. Here, visualized by cryo-electron tomography and subtomogram averaging, mature capsid-like particles show an IP6-like density in the CA hexamer, coordinated by rings of six lysines and six arginines. Phosphate and IP6 have opposing effects on CA in vitro assembly, inducing formation of T = 1 icosahedrons and tubes, respectively, implying that phosphate promotes pentamer and IP6 hexamer formation. Subtomogram averaging and classification optimized for analysis of pleomorphic retrovirus particles reveal that the heterogeneity of mature RSV CA polyhedrons results from an unexpected, intrinsic CA hexamer flexibility. In contrast, the CA pentamer forms rigid units organizing the local architecture. These different features of hexamers and pentamers determine the structural mechanism to form CA polyhedrons of variable shape in mature RSV particles.}, author = {Obr, Martin and Ricana, Clifton L. and Nikulin, Nadia and Feathers, Jon-Philip R. and Klanschnig, Marco and Thader, Andreas and Johnson, Marc C. and Vogt, Volker M. and Schur, Florian KM and Dick, Robert A.}, issn = {2041-1723}, journal = {Nature Communications}, keywords = {General Biochemistry, Genetics and Molecular Biology, General Physics and Astronomy, General Chemistry}, number = {1}, publisher = {Nature Research}, title = {{Structure of the mature Rous sarcoma virus lattice reveals a role for IP6 in the formation of the capsid hexamer}}, doi = {10.1038/s41467-021-23506-0}, volume = {12}, year = {2021}, }