| 1. |
- Botterweg-Paredes, Esther, et al.
(författare)
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Light affects tissue patterning of the hypocotyl in the shade-avoidance response
- 2020
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 16:3
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Tidskriftsartikel (refereegranskat)abstract
- Plants have evolved strategies to avoid shade and optimize the capture of sunlight. While some species are tolerant to shade, plants such as Arabidopsis thaliana are shade-intolerant and induce elongation of their hypocotyl to outcompete neighboring plants. We report the identification of a developmental module acting downstream of shade perception controlling vascular patterning. We show that Arabidopsis plants react to shade by increasing the number and types of water-conducting tracheary elements in the vascular cylinder to maintain vascular density constant. Mutations in genes affecting vascular patterning impair the production of additional xylem and also show defects in the shade-induced hypocotyl elongation response. Comparative analysis of the shade-induced transcriptomes revealed differences between wild type and vascular patterning mutants and it appears that the latter mutants fail to induce sets of genes encoding biosynthetic and cell wall modifying enzymes. Our results thus set the stage for a deeper understanding of how growth and patterning are coordinated in a dynamic environment.
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| 2. |
- Brandis, Gerrit, 1985-, et al.
(författare)
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The SNAP hypothesis : Chromosomal rearrangements could emerge from positive Selection during Niche Adaptation
- 2020
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Ingår i: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 16:3
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Tidskriftsartikel (refereegranskat)abstract
- Author summary All life on earth has evolved from a universal common ancestor with a specific order of genes on the chromosome. This order is not maintained in modern species and the standard hypothesis is that changes reflect a lack of strong selection on gene order. Here, we propose an alternative hypothesis, SNAP. The occupation of a novel environment by bacteria is generally a trade-off situation. For example, while the bacteria may not be adapted to grow well under the new conditions, they may benefit by not having to share available resources with other microorganisms. Bacterial populations frequently acquire duplications of chromosomal segments containing genes that can help them adapt to a new environment. Other genes that are also duplicated are not required in two copies so that over time a superfluous copy can be lost. Eventually, the process of duplication and gene loss can lead to the rearrangement of the gene order in the chromosomal segment. The major benefit of this model over the standard hypothesis is that the process is driven by positive selection and can reach fixation rapidly. The relative linear order of most genes on bacterial chromosomes is not conserved over evolutionary timescales. One explanation is that selection is weak, allowing recombination to randomize gene order by genetic drift. However, most chromosomal rearrangements are deleterious to fitness. In contrast, we propose the hypothesis that rearrangements in gene order are more likely the result of selection during niche adaptation (SNAP). Partial chromosomal duplications occur very frequently by recombination between direct repeat sequences. Duplicated regions may contain tens to hundreds of genes and segregate quickly unless maintained by selection. Bacteria exposed to non-lethal selections (for example, a requirement to grow on a poor nutrient) can adapt by maintaining a duplication that includes a gene that improves relative fitness. Further improvements in fitness result from the loss or inactivation of non-selected genes within each copy of the duplication. When genes that are essential in single copy are lost from different copies of the duplication, segregation is prevented even if the original selection is lifted. Functional gene loss continues until a new genetic equilibrium is reached. The outcome is a rearranged gene order. Mathematical modelling shows that this process of positive selection to adapt to a new niche can rapidly drive rearrangements in gene order to fixation. Signature features (duplication formation and divergence) of the SNAP model were identified in natural isolates from multiple species showing that the initial two steps in the SNAP process can occur with a remarkably high frequency. Further bioinformatic and experimental analyses are required to test if and to which extend the SNAP process acts on bacterial genomes.
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| 3. |
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| 4. |
- Lundtoft, Christian, et al.
(författare)
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Function of multiple sclerosis-protective HLA class I alleles revealed by genome-wide protein-quantitative trait loci mapping of interferon signalling
- 2020
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 16:10
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Tidskriftsartikel (refereegranskat)abstract
- Interferons (IFNs) are cytokines that are central to the host defence against viruses and other microorganisms. If not properly regulated, IFNs may contribute to the pathogenesis of inflammatory autoimmune, or infectious diseases. To identify genetic polymorphisms regulating the IFN system we performed an unbiased genome-wide protein-quantitative trait loci (pQTL) mapping of cell-type specific type I and type II IFN receptor levels and their responses in immune cells from 303 healthy individuals. Seven genome-wide significant (p < 5.0E-8) pQTLs were identified. Two independent SNPs that tagged the multiple sclerosis (MS)-protective HLA class I alleles A*02/A*68 and B*44, respectively, were associated with increased levels of IFNAR2 in B and T cells, with the most prominent effect in IgD–CD27+ memory B cells. The increased IFNAR2 levels in B cells were replicated in cells from an independent set of healthy individuals and in MS patients. Despite increased IFNAR2 levels, B and T cells carrying the MS-protective alleles displayed a reduced response to type I IFN stimulation. Expression and methylation-QTL analysis demonstrated increased mRNA expression of the pseudogene HLA-J in B cells carrying the MS-protective class I alleles, possibly driven via methylation-dependent transcriptional regulation. Together these data suggest that the MS-protective effects of HLA class I alleles are unrelated to their antigen-presenting function, and propose a previously unappreciated function of type I IFN signalling in B and T cells in MS immune-pathogenesis.Author summaryGenetic association studies have been very successful in identifying disease-associated single nucleotide polymorphisms (SNPs), but it has been challenging to define the molecular mechanisms underlying these associations. As interferons (IFNs) have a central role in the immune system, we hypothesized that some of the SNPs associated to immune-mediated diseases would affect the IFN system. By combining genetic data with characterization of interferon receptor levels and their responses on the protein level in immune cells from 303 genotyped healthy individuals, we show that two SNPs tagging the HLA class I alleles A*02/A*68 and B*44 are associated with a decreased response to type I IFN stimulation in B cells and T cells. Notably, both HLA-A*02 and HLA-B*44 confer protection from developing multiple sclerosis (MS), which is a chronic inflammatory neurologic disease. In addition to suggesting a pathogenic role of enhanced type I interferon signalling in B cells and T cells in MS, our data emphasize the fact that genetic associations in the HLA locus can affect functions not directly associated to antigen presentation, which conceptually may be important for other diseases genetically associated to the HLA locus.
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| 5. |
- Natri, H. M., et al.
(författare)
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Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago
- 2020
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 16:5
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Tidskriftsartikel (refereegranskat)abstract
- Indonesia is the world’s fourth most populous country, host to striking levels of human diversity, regional patterns of admixture, and varying degrees of introgression from both Neanderthals and Denisovans. However, it has been largely excluded from the human genomics sequencing boom of the last decade. To serve as a benchmark dataset of molecular phenotypes across the region, we generated genome-wide CpG methylation and gene expression measurements in over 100 individuals from three locations that capture the major genomic and geographical axes of diversity across the Indonesian archipelago. Investigating between- and within-island differences, we find up to 10.55% of tested genes are differentially expressed between the islands of Sumba and New Guinea. Variation in gene expression is closely associated with DNA methylation, with expression levels of 9.80% of genes correlating with nearby promoter CpG methylation, and many of these genes being differentially expressed between islands. Genes identified in our differential expression and methylation analyses are enriched in pathways involved in immunity, highlighting Indonesia's tropical role as a source of infectious disease diversity and the strong selective pressures these diseases have exerted on humans. Finally, we identify robust within-island variation in DNA methylation and gene expression, likely driven by fine-scale environmental differences across sampling sites. Together, these results strongly suggest complex relationships between DNA methylation, transcription, archaic hominin introgression and immunity, all jointly shaped by the environment. This has implications for the application of genomic medicine, both in critically understudied Indonesia and globally, and will allow a better understanding of the interacting roles of genomic and environmental factors shaping molecular and complex phenotypes.
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| 6. |
- Ramachandran, Sohini, et al.
(författare)
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Estimation of non-null SNP effect size distributions enables the detection of enriched genes underlying complex traits
- 2020
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 16:6
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Tidskriftsartikel (refereegranskat)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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| 7. |
- Stårsta, Magnus, et al.
(författare)
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RHS-elements function as type II toxin-antitoxin modules that regulate intra-macrophage replication of Salmonella Typhimurium
- 2020
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Ingår i: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 16:2
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Tidskriftsartikel (refereegranskat)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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| 8. |
- Tomic, Tajana Tesan, et al.
(författare)
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MYO5B mutations in pheochromocytoma/paraganglioma promote cancer progression
- 2020
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Ingår i: PLOS Genetics. - : Public Library of Science. - 1553-7390 .- 1553-7404. ; 16:6
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Tidskriftsartikel (refereegranskat)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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| 9. |
- Woldemeskel, Selamawit Abi, et al.
(författare)
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The conserved transcriptional regulator CdnL is required for metabolic homeostasis and morphogenesis in Caulobacter
- 2020
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Ingår i: PLOS Genetics. - : Public Library of Science (PLOS). - 1553-7390 .- 1553-7404. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Bacterial growth and division require regulated synthesis of the macromolecules used to expand and replicate components of the cell. Transcription of housekeeping genes required for metabolic homeostasis and cell proliferation is guided by the sigma factor sigma(70). The conserved CarD-like transcriptional regulator, CdnL, associates with promoter regions where sigma(70) localizes and stabilizes the open promoter complex. However, the contributions of CdnL to metabolic homeostasis and bacterial physiology are not well understood. Here, we show that Caulobacter crescentus cells lacking CdnL have severe morphological and growth defects. Specifically, Delta cdnL cells grow slowly in both rich and defined media, and are wider, more curved, and have shorter stalks than WT cells. These defects arise from transcriptional downregulation of most major classes of biosynthetic genes, leading to significant decreases in the levels of critical metabolites, including pyruvate, alpha-ketoglutarate, ATP, NAD(+), UDP-N-acetyl-glucosamine, lipid II, and purine and pyrimidine precursors. Notably, we find that Delta cdnL cells are glutamate auxotrophs, and Delta cdnL is synthetic lethal with other genetic perturbations that limit glutamate synthesis and lipid II production. Our findings implicate CdnL as a direct and indirect regulator of genes required for metabolic homeostasis that impacts morphogenesis through availability of lipid II and other metabolites. Author summary To grow and divide, bacteria must accumulate precursor molecules to support duplication and expansion of cellular materials. One mechanism by which bacteria do this is by regulating the expression of genes whose products are important for production of these molecules. How gene expression is maintained or altered to support synthesis of appropriate molecules to balance growth with nutrient availability is not fully understood. In this paper, we describe the role of a regulator of gene expression called CdnL in maintaining levels of molecules required for bacterial growth and reproduction. CdnL broadly impacts the levels of genes required for most biosynthetic processes. CdnL's broad impact on transcription has downstream consequences on growth rate, cell shape, and nutrient requirements for growth. We report that CdnL is particularly important for maintaining levels of the amino acid glutamate and the cell wall precursor lipid II, each of which is critical for supporting proper growth and cell morphology. Our results implicate CdnL as a broadly conserved regulator of metabolic homeostasis, growth, and cell shape in bacteria.
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| 10. |
- Zan, Yanjun, et al.
(författare)
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Dynamic genetic architecture of yeast response to environmental perturbation shed light on origin of cryptic genetic variation
- 2020
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Ingår i: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 16:5
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Tidskriftsartikel (refereegranskat)abstract
- Cryptic genetic variation could arise from, for example, Gene-by-Gene (G-by-G) or Gene-by-Environment (G-by-E) interactions. The underlying molecular mechanisms and how they influence allelic effects and the genetic variance of complex traits is largely unclear. Here, we empirically explored the role of environmentally influenced epistasis on the suppression and release of cryptic variation by reanalysing a dataset of 4,390 haploid yeast segregants phenotyped on 20 different media. The focus was on 130 epistatic loci, each contributing to segregant growth in at least one environment and that together explained most (69-100%) of the narrow sense heritability of growth in the individual environments. We revealed that the epistatic growth network reorganised upon environmental changes to alter the estimated marginal (additive) effects of the individual loci, how multi-locus interactions contributed to individual segregant growth and the level of expressed genetic variance in growth. The estimated additive effects varied most across environments for loci that were highly interactive network hubs in some environments but had few or no interactors in other environments, resulting in changes in total genetic variance across environments. This environmentally dependent epistasis was thus an important mechanism for the suppression and release of cryptic variation in this population. Our findings increase the understanding of the complex genetic mechanisms leading to cryptic variation in populations, providing a basis for future studies on the genetic maintenance of trait robustness and development of genetic models for studying and predicting selection responses for quantitative traits in breeding and evolution. Author summary Many biological traits are polygenic, with complex interplay between underlying genes and the surrounding environment. As a result, individuals with the same allele might have distinctive phenotypes due to differences in the polygenic background and/or the environment. Such differences often create additional genetic variation that is highly relevant to quantitative and evolutionary genetics by limiting our ability to accurately predict the phenotypes in medical or agricultural applications and providing opportunities for long term evolution. Previously, yeast growth regulating genes were found to be organised in large interacting networks. Here, we found that these networks were reorganised upon environmental changes, and that this resulted in altered effect sizes of individual genes, and how the whole network contributed to growth and the level of total genetic variance, providing a basis for future studies on the genetic maintenance of trait robustness and development of genetic models for studying and predicting selection responses for quantitative traits.
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