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Peter, J.

Publications and source records attributed to Peter, J..

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Pat1 globally activates deadenylation-dependent decapping to clear inefficiently translated oligo(A)-tailed transcripts

In eukaryotes, mRNA turnover occurs mainly through the 5'- 3' mRNA decay pathway and involves deadenylation, decapping, and exonucleolytic mRNA body digestion. While the conserved protein Pat1 has initially been described as an activator of decapping for some deadenylated mRNAs, the role of deadenylation-dependent decapping has recently been questioned. Hence, Pat1 has alternatively been suggested to regulate specific mRNA decay pathways, given its modest impact on overall transcriptome composition. Here, we combine multi-omic and genetic approaches to characterize a PAT1 deletion mutant in Saccharomyces cerevisiae. Although transcriptome and proteome analyses confirm that only a limited subset of genes is affected by Pat1 inactivation, poly(A)-tail sizing demonstrates that Pat1 loss leads to transcriptome-wide accumulation of capped oligo(A)-tailed mRNAs. Together with the observation that oligo(A)-tailed mRNAs are bound by Pat1 in vivo in wild-type cells, this indicates that Pat1 is a general activator of deadenylation-dependent decapping. We further show that oligo-adenylated mRNAs are translated in {Delta}pat1 cells, albeit inefficiently. Altogether, our data indicate that Pat1 mediates the clearance of oligo(A)-tailed mRNAs protecting cells from the ensuing inefficient translation, without inducing major changes in overall transcript distribution.

molecular biology↗

Engineering antigen-driven co-stimulation and T helper cell activity into TCR-T cells with CD8-41BB fusion receptors enhances anti-tumor activity

1Adoptive cell therapy using tumor antigen-targeting T cell receptors (TCRs) offers a compelling approach to treat both hematological cancers and solid tumors due to broad antigen accessibility and the ability to target cancer-specific neoantigens. However, unlike clinically validated second generation CAR-T cells bearing built-in co-stimulatory signaling modules (i.e. 41BB or CD28), TCR-T cells receive little to no co-stimulation within most tumor microenvironments leading to attenuated cellular responses. Additionally, CD4+ TCR-T cells engineered to express HLA-Class I restricted TCRs possess minimal T-helper cell activity and thus do not effectively mobilize CD8+ TCR-T cells or host anti-tumor immune responses. To address these limitations, we used CRISPR-Cas9 to engineer TCR-T cells with targeted integration of chimeric CD8 constructs containing intracellular co-stimulatory domains. We found that expression of wild-type CD8{beta}, but not CD8, could promote CD4+ T cell activities in HLA-Class I restricted TCR-T cells. However, this was insufficient to drive durable anti-tumor responses in challenging tumor mouse models when using a high-affinity WT1-directed TCR. To address this, several CD8 co-stimulatory fusion constructs containing CD28 or 41BB intracellular domains were designed and screened, identifying two CD8-41BB based chimeras that substantially increased TCR-T cell activity relative to wild-type CD8{beta}. WT1-TCR-T cells co-expressing the CD8-41BB fusions demonstrated not only enhanced CD4+ activity including strong and polarized Th1-type cytokine secretion, but also enhanced the proliferation, cytokine release, and cytotoxicity of CD8+ CTLs. Remarkably, when combined with TGFBR2 gene disruption, WT1-TCR-T cells co-expressing CD8-41BB receptors were able to completely regress established cell line-derived ovarian tumors, showed robust in vivo expansion and persistence, and provided long-term protection from tumor rechallenge. Importantly, the specificity profile of the WT1-TCR including its HLA-A*02:01 restriction and WT1 peptide recognition motif was preserved upon expression of CD8-41BB. To simplify cell engineering processes for clinical applications, we configured a homology directed repair (HDR) cassette to allow for efficient CRISPR-Cas9-based insertion of both the TCR and CD8-41BB transgenes in the TRAC locus in a single step with >80% efficiency. Lastly, the enhanced activity conferred by CD8-41BB expression was validated with a second clinically relevant TCR targeting PRAME, suggesting this platform can be a universal approach for enhancing the therapeutic potential of TCR-based cell therapies.

synthetic biology↗

Coordinate-Based fMRI Meta-Analyses of Episodic Memory Encoding and Retrieval in Depression

BackgroundDepression is a mood disorder frequently associated with episodic memory impairment. However, it remains unclear whether functional brain activity differs between depressed and non-depressed individuals during encoding or retrieval of autobiographical or non-autobiographical memories. Clarifying these differences is important for refining theoretical models of memory impairment in depression and, potentially, for developing targeted interventions. MethodsWe conducted three coordinate-based meta-analyses examining encoding and retrieval of autobiographical and non-autobiographical memory in control participants and individuals with current, remitted, or subthreshold depression, or those at risk for depression. Studies were identified via database searches and analysed using Seed-based d Mapping. ResultsWe included coordinates from 22 fMRI studies. During encoding, depression was associated with reduced activity in the caudate, the salience network, the frontoparietal executive control network, and motor-related areas (11 studies, N = 542). During non-autobiographical retrieval, depression was associated with higher activity in the right inferior frontal gyrus (7 studies, N = 345). During autobiographical retrieval (10 studies, N = 423), depression was associated with reduced activity in the right insula and fusiform gyrus, alongside increased activity in the left anterior cingulate cortex and the left middle frontal gyrus. Between-study heterogeneity was low and no evidence for publication bias was found. DiscussionOur results indicate that depression may be associated with impaired salience integration during encoding and autobiographical retrieval. In contrast, during non-autobiographical retrieval, increased frontal activity suggests a more vigilant or self-monitoring retrieval mode. Functional brain activity changes in depression therefore appear stage- and content-specific.

neuroscience↗

Genetic and adenoviral ablation of the choroid plexus reduces postnatal hippocampal neurogenesis

BackgroundChoroid plexus (ChP) produces cerebrospinal fluid (CSF) and regulates brain development and adult subventricular zone (SVZ) neurogenesis, but its role in postnatal hippocampal subgranular zone (SGZ) neurogenesis is not well understood. Neonatal hydrocephalus, a devastating neurological condition characterized by excessive accumulation of CSF in the brain, is sometimes treated in conjunction with partial ChP cauterization in the lateral ventricles, which results in the resolution of clinical symptoms without large reductions in ventricular volumes. To both understand the roles of the ChP/CSF system in normal CNS function and the impact of ChP ablation or cauterization in hydrocephalus, novel tools for the manipulation of CSF volume and production by ChP are urgently needed. MethodsWe first discovered specific "leaky" expression of diphtheria toxin receptors (DTR) in the ChP of adult ROSA26-iDTR mice, which resulted in a robust and permanent ablation of ChP and reduction of ventricular CSF volume after diphtheria toxin (Dtx) administration. In this study, we first tested the effectiveness of this genetic approach for ChP ablation at neonatal ages. We then generated a novel AAV5-CMV-DTR vector with high ChP tropism to more effectively reduce ventricular volume in these neonatal mice. Genetic (ROSA26-iDTR) and gene therapy (AAV5-DTR) approaches were compared for their extent of ChP ablation, reduction of ventricular CSF volume as assessed by MRI, and impact on postnatal hippocampal neurogenesis at neonatal and young adult ages. Lastly, we tested the therapeutic potential of AAV-mediated ChP ablation using an intracisternal kaolin model of hydrocephalus. ResultsIn our genetic model, ChP ablation and CSF volume reduction was robust at postnatal day (P)10-12, but ineffective at P3-5 with standard Dtx dosing (20 ng/g/day for 3 consecutive days). A higher dose of Dtx (40 ng/g/day) at P3-5 generated a mild reduction of CSF volume but was associated with higher subsequent neonatal mortality. In contrast, AAV5 CMV-DTR virus shows high tropism for ChP epithelial cells and leads to near-complete loss of ventricular CSF in neonates. ChP/CSF loss in neonates or young adult mice leads to a substantial reduction of DCX+ cells within the SVZ, but only a moderate reduction of DCX+ neuroblasts in the SGZ, without altering the number of proliferating or apoptotic cells. In the cisternal kaolin model of hydrocephalus, AAV-mediated ChP ablation within 10 hrs after the onset of hydrocephalus profoundly reduced parenchymal edema and corpus callosum hyperintensity without causing ventricular collapse. ConclusionsThis study reports a novel role of the ChP/CSF in maintaining the neuroblast pool in the neurogenic niches in both early postnatal and adult stages. ROSA26-iDTR-mediated ChP ablation is inefficient before P10, suggesting that this mouse line may be of limited utility in the early postnatal period. In contrast, our novel AAV vector efficiently targets the ChP and CSF production at both neonatal and adult ages, and demonstrates the therapeutic potential of AAV-mediated ChP ablation for the treatment of hydrocephalus. The limited radiographic changes in the kaolin mouse model mirror the clinical findings following choroid plexus cauterization in humans.

neuroscience↗

Automated assessment of tDCS electrode placement accuracy based on structural MRI

Accurate electrode placement is essential for studies using transcranial direct current stimulation (tDCS) since it determines whether - and to what extent - the intended brain region was modulated. Using in-scanner tDCS, placement accuracy can be determined by extracting electrode coordinates from structural MRI and by comparing actual and intended positions. Previous studies extracted coordinates manually, which is time-consuming and prone to error. Here, we present an algorithm to automate this process. The proposed algorithm first segments electrode and electrode-gel blobs visible on MRI. It then separates this segmentation into individual electrode regions and extracts their coordinates as the centroids of these regions. Finally, coordinates are assigned to the intended target positions using linear assignment. We evaluated the algorithm with T1-weighted MRI data from 65 individuals acquired at diferent scanners with diferent magnetic field strengths, image resolutions, and two high-definition montages by comparing the extracted coordinates with manual annotations from two independent readers. The median localization error of the algorithm was 2.4 mm (IQR 1.5 mm). The median variability between human readers was 2.7 mm (IQR 1.7 mm). Distances between algorithm-derived coordinates and the reference were smaller than distances between readers. Our proposed algorithm obviates the need for manual electrode segmentation and allows an objective evaluation of electrode placement accuracy for in-scanner tDCS. It may be used to relate electrode position errors to stimulation efects.

neuroscience↗

Five years of national airborne pollen monitoring in South Africa: Biome-specific calendars to inform allergy diagnosis and prevention

Pollen monitoring is crucial for understanding seasonal patterns, supporting allergy diagnosis and informing early-warning tools to mitigate allergic diseases. The Southern Hemisphere lacks long-term data on pollen seasons, with extremely few from Africa. We present pollen calendars based on five-year data from the South African Pollen Monitoring Network (SAPNET). Airborne pollen from 2019 to 2024 in biomes across South Africa was collected using Hirst-type volumetric spore traps and standard protocols. Daily concentrations were analysed by light microscopy. The five-year mean annual pollen integral (APIn, pollen grains/m3 per year) was calculated for each site. The five-year mean APIn was highest in the Grassland Biome (Bloemfontein, 11654 pg/m3; range 8515 to 14454 pg/m3) and lowest in the Albany Thicket Biome (Gqeberha, 1372; range 853 to 2010 pg/m3). The Grassland Biome (Johannesburg) had the highest averaged tree pollen concentration (7558; range 6575 to 8803 pg/m3). The Savanna Biome (Kimberley) had the highest average grass pollen concentration (3150; 1826 to 3785 pg/m3). The grass family (Poaceae) was the most common pollen type across all biomes. Other common contributing taxa were exotic trees Cupressaceae, Platanus, Morus and Betula. Tree seasons were July to September, whilst grass and weed pollen seasons varied across the different biomes. These five-year pollen calendars provide the first biome-specific national reference for airborne pollen exposure in South Africa. The findings provide baseline data for the clinical management of allergic disease.

ecology↗

The TUTase URT1 regulates the transcriptome of seeds and their primary dormancy

RNA uridylation is a pervasive mechanism that regulates the degradation of eukaryotic mRNAs. In Arabidopsis, uridylation influences mRNA decay both by favoring 5 to 3 degradation and by preventing excessive deadenylation. Yet, the significance of mRNA uridylation during plant development remains largely unknown. Here, we adapted FLEP-seq2, a method based on nanopore sequencing, to generate a comprehensive inventory of mRNA uridylation events in different Arabidopsis tissues. We also evaluated the respective contribution of the two known Arabidopsis uridylyltransferases, URT1 and HESO1, in mRNA uridylation. Our transcriptome-wide analysis showed that, URT1 is the main enzyme responsible for mRNA uridylation, in all analyzed tissues, while HESO1 can marginally uridylate mRNAs. Importantly, our results revealed the singularity of mRNA uridylation pattern in seeds and the dual function of URT1-dependent uridylation in shaping the transcriptome during seed maturation. We propose that during the late stages of seed maturation, URT1-dependent uridylation facilitates the degradation of unnecessary mRNAs encoding translation-related proteins, while also promoting the accumulation of mRNAs associated with the maturation program, by hindering their deadenylation. In line with its important function in shaping the seed transcriptome, our study also identifies URT1 as a novel regulator of seed dormancy. Overall, our study reveals the biological relevance of mRNA uridylation during the late stages of seed maturation.

plant biology↗

The histone demethylase JMJ27 acts during the UV-induced modulation of H3K9me2 landscape and facilitates photodamage repair

Plants have evolved sophisticated DNA repair mechanisms to cope with the deleterious effects of UV-induced DNA damage. Indeed, DNA repair pathways cooperate with epigenetic-related processes to efficiently maintain genome integrity. However, it remains to be deciphered how photodamages are recognized within different chromatin landscapes, especially in compacted genomic regions such as constitutive heterochromatin. We combined cytogenetics and epigenomics to identify that UV-C irradiation induces modulation of the main epigenetic mark found in constitutive heterochromatin, H3K9me2. We demonstrated that the histone demethylase, Jumonji27 (JMJ27), is responsible for the UV-induced reduction of H3K9me2 content at chromocenters. In addition, we identified that JMJ27 forms a complex with the photodamage recognition factor, DNA Damage Binding protein 2 (DDB2), and that the fine tuning of H3K9me2 contents orchestrates DDB2 dynamics on chromatin in response to UV-C exposure. Hence, this study uncovers the existence of an interplay between photodamage repair and H3K9me2 homeostasis.

plant biology↗

Dog Ecology and Rabies Knowledge, Attitude and Practice (KAP) in the Northern Communal Areas of Namibia

In 2021, a comprehensive dog demographic questionnaire combined with a KAP survey were conducted in the northern communal areas (NCAs) of Namibia with the aim of gaining a better understanding of dog populations, owner behaviour, and knowledge, attitudes and practices (KAP) relating to rabies. The survey of 3,726 households across the eight regions of the NCAs provided insights that will inform interventions on order to improve human rabies prevention and Namibias dog rabies control strategy. The results showed a relatively low average human/dog ratio (HDR) of 5.4:1 indicating a surprisingly high dog population of at least 272,000 dogs in the NCAs, 93% of which appear to be owned but are free-roaming. Data analysis revealed opportunities but also highlighted needs for improvements in rabies surveillance and mass dog vaccinations. Although knowledge, attitude, and practice scores towards epidemiologic and clinical aspects, human rabies prevention, and canine rabies vaccination were deemed to be acceptable, the survey nevertheless revealed deficiencies in some of the population. Interestingly, data seemed to indicate a certain number of unreported human rabies cases. Other findings included the very high number of dogs. However, only 50% of dog-owning households reported having vaccinated their dogs. In order to address these issues, the planning, announcement, and implementation of mass dog vaccination campaigns need to be adapted to achieve adequate vaccination coverage. Another focus needs to be on rabies awareness and education if Namibia is to be significantly contributing to the global goal of "Zero by 30". Author SummaryAs a neglected disease, rabies remains a major One Health problem in Africa and Asia. Here we report the results of an extensive community survey on dog ownership and knowledge, attitudes and practices (KAP) related to rabies control and prevention, covering the Northern Communal Areas of Namibia. Our results showed that the dog population is large with a human/dog ratio (HDR) of 5.4:1, of which the vast majority is free-roaming thus supporting disease transmission but complicating control efforts. The majority of people across this part of Namibia were aware of rabies and had acceptable levels of attitudes and practices. While dog bite incidences per 100,000 people were high, ranging between 262 and 1,369, more than 90% of bite victims reported having visited a hospital after a bite incident. Still, gaps in dog rabies surveillance exist and incomplete or missing post exposure prophylaxes caused human casualties and call for ongoing interventions aimed at increasing knowledge and awareness.

microbiology↗

UV-B-induced dynamics of constitutive heterochromatin in Arabidopsis thaliana

Sunlight regulates transcriptional programs and triggers the shaping of the genome throughout plant development. Among the different sunlight wavelengths that reach the surface of the Earth, UV-B (280-315 nm) controls the expression of hundreds of genes for the photomorphogenic responses and also induces the formation of photodamage that interfere with genome integrity and transcriptional programs. The combination of cytogenetics and deep-learning-based analyses allowed determining the location of UV-B-induced photoproducts and quantifying the effects of UV-B irradiation on constitutive heterochromatin content in different Arabidopsis natural variants acclimated to various UV-B regimes. We identified that UV-B-induced photolesions are enriched within chromocenters. Furthermore, we uncovered that UV-B irradiation promotes constitutive heterochromatin dynamics that differs among the Arabidopsis ecotypes having divergent heterochromatin contents. Finally, we identified that the proper restoration of the chromocenter shape, upon DNA repair, relies on the UV-B photoreceptor, UV RESISTANCE LOCUS 8 (UVR8). These findings shed the light on the effect of UV-B exposure and perception in heterochromatin dynamics and structure in Arabidopsis thaliana. Statements and DeclarationsAll authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

plant biology↗

Plastid fatty acid export (FAX) proteins in Arabidopsis thaliana - the role of FAX1 and FAX3 in growth and development

In plant cells, fatty acid (FA) synthesis occurs in the plastid stroma and thus requires subsequent FA export for lipid assembly in the endoplasmic reticulum. In this context, the membrane-intrinsic protein FAX1 has been described to mediate FA-export across the plastid inner envelope (IE). In Arabidopsis, FAX1 function is crucial for pollen cell wall formation, male fertility, cellular lipid homeostasis and plant biomass. Based on conserved structural features and sequence motifs, we here define the plant FAX-protein family localized in plastids. Besides their membrane-intrinsic domain, the plastid-targeted FAX1-FAX3 contain distinct N-terminal stretches. Among them, the apolipoprotein-like -helical bundle of FAX2 is the most prominent. Further, we could unequivocally localize FAX2 and FAX3 proteins together with FAX1 to the IE membrane of chloroplasts and develop a topology model for FAX1, FAX2, and FAX3. In yeast, all plastid FAX proteins - i.e. FAX1, FAX2, FAX3, FAX4 - can complement for FA-transport function. For FAX1 we show a new function in pollen tube growth as well as together with FAX3 in seed/embryo development and in rosette leaf growth. Since in comparison to fax1 single knockout mutants, fax1/fax3 double knockouts are seedling lethal and not able to develop mature rosette leaves, we conclude that FAX1 and FAX3 function together in vegetative leaf growth. HighlightWe define distinct structural features of plant FAX proteins in plastids and demonstrate that FAX1 and FAX3 have complementary functions in vegetative leaf growth.

plant biology↗

Oral rabies vaccination of dogs - experiences from a field trial in Namibia

Dog-mediated rabies is responsible for tens of thousands of human deaths annually, and in resource-constrained settings, vaccinating dogs to control the disease at source remains challenging. Currently, rabies elimination efforts rely on mass dog vaccination by the parenteral route. To increase the herd immunity, free-roaming and stray dogs need to be specifically addressed in the vaccination campaigns, with oral rabies vaccination (ORV) of dogs being a possible solution. Using a third-generation vaccine and a standardized egg-flavoured bait, bait uptake and vaccination was assessed under field conditions in Namibia. During this trial, both veterinary staff as well as dog owners expressed their appreciation to this approach of vaccination. Of 1,115 dogs offered a bait, 90% (n=1,006, 95%CI:91-94) consumed the bait and 72.9% (n=813, 95%CI:70.2-75.4) of dogs were assessed as being vaccinated, while for (11.7%, n=130, 95%CI:9.9-17.7) the status was recorded as "unkown" and 15.4% (n=172, 95%CI: 13.4-17.7) were considered as being not vaccinated. Smaller dogs and dogs offered a bait with multiple other dogs had significantly higher vaccination rates, while other factors, e.g. sex, confinement status and time had no influence. The favorable results of this first large-scale field trial further support the strategic integration of ORV into dog rabies control programmes. Given the acceptance of the egg-flavored bait under various settings worldwide, ORV of dogs could become a game-changer in countries, where control strategies using parenteral vaccination alone failed to reach sufficient vaccination coverage in the dog population.

microbiology↗

Human 5p-tailed Mirtrons are Processed by RNaseP

Approximately a thousand microRNAs (miRNAs) are documented from human cells. A third appear to transit non-canonical pathways that typically bypass processing by Drosha, the dedicated nuclear miRNA producing enzyme. The largest class of non-canonical miRNAs are mirtrons which eschew Drosha to mature through spliceosome activity. While mirtrons are found in several configurations, the vast majority of human mirtron species are 5-tailed. For these mirtrons, a 3 splice site defines the 3 end of their hairpin precursor while a "tail" of variable length separates the 5 base of the hairpin from the nearest splice site. How this tail is removed is not understood. Here we examine sequence motifs in 5-tailed mirtrons and interactions with RNA turnover processes to characterize biogenesis processes. Through studying the high confidence 5-tailed mirtron, hsa-miR-5010, we identify RNaseP as necessary and sufficient for "severing" the 5 tail of this mirtron. Further, depletion of RNaseP activity globally decreased 5-tailed mirtron expression implicating this endoribonuclease in biogenesis of the entire class. Moreover, as 5-tailed mirtron biogenesis appears to be connected to tRNA processing we found a strong correlation between accumulation of tRNA fragments (tRFs) and 5-tailed mirtron abundance. This suggests that dysregulation of tRNA processing seen in cancers may also impact expression of the [~]400 5-tailed mirtrons encoded in the human genome. SUMMARYAbundant non-canonical human miRNAs referred to as tailed mirtrons are processed by RNaseP, which "severs" tail nucleotides to yield a precursor hairpin suitable for Dicer processing. Biogenesis of these miRNAs is correlated with tRFs, which are also products of RNaseP processing.

molecular biology↗

Assessing Environmental RNAi in a Non-Model Organism

RNA interference (RNAi) regulates gene expression in most multicellular organisms through binding of small RNA effectors to target transcripts. Exploiting this process is a popular strategy for genetic manipulation in invertebrates and has applications that includes control of pests. Successful RNAi technologies are dependent on delivery method. The most convenient method is likely feeding which is effective in some animals while others are insensitive. Thus, there is a need to develop RNAi technology on a per-species basis, which will require a comprehensive approach for assessing small RNA production from synthetic nucleic acids. Using a biochemical and sequencing approaches we investigated the metabolism of ingested RNAs using the two-spotted spider mite, Tetranychus urticae, as a model for RNAi insensitivity. This chelicerae arthropod shows only modest response to oral RNAi and has biogenesis pathways distinct from model organisms. To identify RNAi substrates in T. urticae we characterized processing of synthetic RNAs and those derived from plant transcripts ingested during feeding. Through characterization of read size length and overlaps of small RNA reads, visualization methods were developed that facilitate distinguish trans-acting small RNAs from degradation fragments. Using a strategy that delineates small RNA classes, we found a variety of RNA species are gated into spider mite RNAi pathways, however, potential mature trans-acting RNAs appear very unstable and rare. This suggests spider mite RNAi pathway products that originate as ingested materials may be preferentially metabolized instead of converted into regulators of gene expression. Spider mites infest a variety of plants, and it would be maladaptive to generate diverse gene regulators from dietary RNAs. This study provides a framework for assessing RNAi technology in organisms where genetic and biochemical tools are absent and benefit rationale design of RNAi triggers.

bioinformatics↗

UFMylation of MRE11 is essential for telomere length and hematopoietic stem cell survival

Genetic studies using knockout mouse models provide strong evidence for the essential role of the ubiquitin-like protein UFM1 for hematopoiesis, especially erythroid development, yet its biological roles in this process are largely unknown. Here we have identified a UFL1-dependent UFMylation of the MRE11 nuclease on the K281 and K282 residues. We show that Hela cells lacking the specific UFM1 E3 ligase display severe telomere shortening. We further demonstrate either by deleting UFM1 or by mutating MRE11 UFMylation sites that preventing MRE11 UFMylation impacts its interaction with the telomere protein TRF2. However, the MRE11 function in double-strand-break repair remains intact. We validate these results in vivo by showing that Zebrafish knockouts for the genes ufl1 and ufm1 have shorter telomeres in hematopoietic cells. Here we present UFMylation has a new mechanisms of regulation for telomere length maintenance with a role in hematopoiesis. Key pointsModification of MRE11 by UFM1 regulates telomere maintenance and cell death in HSCs Scientific categoryUFMylation, telomere maintenance, hematopoietic stem cell survival.

molecular biology↗

Extensive impact of low-frequency variants on the phenotypic landscape at population-scale

Genome-wide association studies (GWAS) allows to dissect the genetic basis of complex traits at the population level1. However, despite the extensive number of trait-associated loci found, they often fail to explain a large part of the observed phenotypic variance2-4. One potential source of this discrepancy could be the preponderance of undetected low-frequency genetic variants in natural populations5,6. To increase the allele frequency of those variants and assess their phenotypic effects at the population level, we generated a diallel panel consisting of 3,025 hybrids, derived from pairwise crosses between a subset of natural isolates from a completely sequenced 1,011 Saccharomyces cerevisiae population. We examined each hybrid across a large number of growth traits, resulting in a total of 148,225 cross/trait combinations. Parental versus hybrid regression analysis showed that while most phenotypic variance is explained by additivity, a significant proportion (29%) is governed by non-additive effects. This is confirmed by the fact that a majority of complete dominance is observed in 25% of the traits. By performing GWAS on the diallel panel, we detected 1,723 significantly associated genetic variants, with 16.3% of them being low-frequency variants in the initial population. These variants, which would not be detected using classical GWAS, explain 21% of the phenotypic variance on average. Altogether, our results demonstrate that low-frequency variants should be accounted for as they contribute to a large part of the phenotypic variation observed in a population.

genomics↗

Variation Of The Meiotic Recombination Landscape And Properties Over A Broad Evolutionary Distance In Yeasts

Meiotic recombination is a major factor of genome evolution, deeply characterized in only a few model species, notably the yeast Saccharomyces cerevisiae. Consequently, little is known about variations of its properties across species. In this respect, we explored the recombination landscape of Lachancea kluyveri, a protoploid yeast species that diverged from the Saccharomyces genus more than 100 million years ago and we found striking differences with S. cerevisiae. These variations include a lower recombination rate, a higher frequency of chromosomes segregating without any crossover and the absence of recombination on the chromosome arm containing the sex locus. In addition, although well conserved within the Saccharomyces clade, the S. cerevisiae recombination hotspots are not conserved over a broader evolutionary distance. Finally and strikingly, we found evidence of frequent reversion of meiotic commitment to mitotic growth allowing allele shuffling without meiosis completion. Identification of this major but underestimated evolutionary phenomenon illustrates the relevance of exploring non-model species.\n\nAuthor summaryMeiotic recombination promotes accurate chromosome segregation and genetic diversity. To date, the mechanisms and rules lying behind recombination were dissected using model organisms such as the budding yeast Saccharomyces cerevisiae. To assess the conservation and variation of this process over a broad evolutionary distance, we explored the meiotic recombination landscape in Lachancea kluyveri, a budding yeast species that diverged from S. cerevisiae more than 100 million years ago. The meiotic recombination map we generated revealed that the meiotic recombination landscape and properties significantly vary across distantly related yeast species, supporting that recombination hotspots conservation across yeast species is likely associated to the conservation of synteny. Finally, the frequent meiotic reversions we observed led us to re-evaluate their evolutionary importance.

genomics↗