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  • 1. Almeida, Pedro
    et al.
    Proux-Wéra, Estelle
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Churcher, Allison
    Soler, Lucile
    Dainat, Jacques
    Pucholt, Pascal
    Nordlund, Jessica
    Martin, Tom
    Rönnberg-Wästljung, Ann-Christin
    Nystedt, Björn
    Berlin, Sofia
    Mank, Judith E.
    Genome assembly of the basket willow, Salix viminalis, reveals earliest stages of sex chromosome expansion2020In: BMC Biology, E-ISSN 1741-7007, Vol. 18, no 1, article id 78Article in journal (Refereed)
    Abstract [en]

    Background: Sex chromosomes have evolved independently multiple times in eukaryotes and are therefore considered a prime example of convergent genome evolution. Sex chromosomes are known to emerge after recombination is halted between a homologous pair of chromosomes, and this leads to a range of non-adaptive modifications causing gradual degeneration and gene loss on the sex-limited chromosome. However, the proximal causes of recombination suppression and the pace at which degeneration subsequently occurs remain unclear.

    Results: Here, we use long- and short-read single-molecule sequencing approaches to assemble and annotate a draft genome of the basket willow, Salix viminalis, a species with a female heterogametic system at the earliest stages of sex chromosome emergence. Our single-molecule approach allowed us to phase the emerging Z and W haplotypes in a female, and we detected very low levels of Z/W single-nucleotide divergence in the non-recombining region. Linked-read sequencing of the same female and an additional male (ZZ) revealed the presence of two evolutionary strata supported by both divergence between the Z and W haplotypes and by haplotype phylogenetic trees. Gene order is still largely conserved between the Z and W homologs, although the W-linked region contains genes involved in cytokinin signaling regulation that are not syntenic with the Z homolog. Furthermore, we find no support across multiple lines of evidence for inversions, which have long been assumed to halt recombination between the sex chromosomes.

    Conclusions: Our data suggest that selection against recombination is a more gradual process at the earliest stages of sex chromosome formation than would be expected from an inversion and may result instead from the accumulation of transposable elements. Our results present a cohesive understanding of the earliest genomic consequences of recombination suppression as well as valuable insights into the initial stages of sex chromosome formation and regulation of sex differentiation.

  • 2. Almuzzaini, Bader
    et al.
    Sarshad, Aishe A.
    Östlund Farrants, Ann-Kristin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Percipalle, Piergiorgio
    Nuclear myosin 1 contributes to a chromatin landscape compatible with RNA polymerase II transcription activation2015In: BMC Biology, E-ISSN 1741-7007, Vol. 13, article id 35Article in journal (Refereed)
    Abstract [en]

    Background: Nuclear myosin 1c (NM1) is emerging as a regulator of transcription and chromatin organization. Results: Using chromatin immunoprecipitation and deep sequencing (ChIP-Seq) in combination with molecular analyses, we investigated the global association of NM1 with the mammalian genome. Analysis of the ChIP-Seq data demonstrates that NM1 binds across the entire mammalian genome with occupancy peaks correlating with distributions of RNA Polymerase II (Pol II) and active epigenetic marks at class II gene promoters. In mouse embryonic fibroblasts subjected to RNAi mediated NM1 gene silencing, we show that NM1 synergizes with polymerase-associated actin to maintain active Pol II at the promoter. NM1 also co-localizes with the nucleosome remodeler SNF2h at class II promoters where they assemble together with WSTF as part of the B-WICH complex. A high resolution micrococcal nuclease (MNase) assay and quantitative real time PCR shows that this mechanism is required for local chromatin remodeling. Following B-WICH assembly, NM1 mediates physical recruitment of the histone acetyl transferase PCAF and the histone methyl transferase Set1/Ash2 to maintain and preserve H3K9acetylation and H3K4trimethylation for active transcription. Conclusions: We propose a novel genome-wide mechanism where myosin synergizes with Pol II-associated actin to link the polymerase machinery with permissive chromatin for transcription activation.

  • 3.
    Dantoft, Widad
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Davis, Monica M.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lindvall, Jessica M.
    Tang, Xiongzhuo
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Uvell, Hanna
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Junell, Anna
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Beskow, Anne
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The Oct1 homolog Nubbin is a repressor of NF-kappa B-dependent immune gene expression that increases the tolerance to gut microbiota2013In: BMC Biology, E-ISSN 1741-7007, Vol. 11, article id 99Article in journal (Refereed)
    Abstract [en]

    Background: Innate immune responses are evolutionarily conserved processes that provide crucial protection against invading organisms. Gene activation by potent NF-kappa B transcription factors is essential both in mammals and Drosophila during infection and stress challenges. If not strictly controlled, this potent defense system can activate autoimmune and inflammatory stress reactions, with deleterious consequences for the organism. Negative regulation to prevent gene activation in healthy organisms, in the presence of the commensal gut flora, is however not well understood. Results: We show that the Drosophila homolog of mammalian Oct1/POU2F1 transcription factor, called Nubbin (Nub), is a repressor of NF-kappa B/Relish-driven antimicrobial peptide gene expression in flies. In nub(1) mutants, which lack Nub-PD protein, excessive expression of antimicrobial peptide genes occurs in the absence of infection, leading to a significant reduction of the numbers of cultivatable gut commensal bacteria. This aberrant immune gene expression was effectively blocked by expression of Nub from a transgene. We have identified an upstream regulatory region, containing a cluster of octamer sites, which is required for repression of antimicrobial peptide gene expression in healthy flies. Chromatin immunoprecipitation experiments demonstrated that Nub binds to octamer-containing promoter fragments of several immune genes. Gene expression profiling revealed that Drosophila Nub negatively regulates many genes that are involved in immune and stress responses, while it is a positive regulator of genes involved in differentiation and metabolism. Conclusions: This study demonstrates that a large number of genes that are activated by NF-kappa B/Relish in response to infection are normally repressed by the evolutionarily conserved Oct/POU transcription factor Nub. This prevents uncontrolled gene activation and supports the existence of a normal gut flora. We suggest that Nub protein plays an ancient role, shared with mammalian Oct/POU transcription factors, to moderate responses to immune challenge, thereby increasing the tolerance to biotic stress.

  • 4.
    Fagundes Macedo, Diego
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Ostrava, Czech Republic.
    Grybchuk, Danyil
    Reznarova, Jana
    Votypka, Jan
    Klocek, Donnamae
    Yurchenko, Tatiana
    Sevcik, Jan
    Magri, Alice
    Dolinska, Michaela Urda
    Zahonova, Kristina
    Lukes, Julius
    Serviene, Elena
    Jaszayova, Alexandra
    Serva, Saulius
    Malysheva, Marina N.
    Frolov, Alexander O.
    Yurchenko, Vyacheslav
    Kostygov, Alexei Yu.
    Diversity of RNA viruses in the cosmopolitan monoxenous trypanosomatid Leptomonas pyrrhocoris2023In: BMC Biology, E-ISSN 1741-7007, Vol. 21, no 1, article id 191Article in journal (Refereed)
    Abstract [en]

    Background Trypanosomatids are parasitic flagellates well known because of some representatives infecting humans, domestic animals, and cultural plants. Many trypanosomatid species bear RNA viruses, which, in the case of human pathogens Leishmania spp., influence the course of the disease. One of the close relatives of leishmaniae, Leptomonas pyrrhocoris, has been previously shown to harbor viruses of the groups not documented in other trypanosomatids. At the same time, this species has a worldwide distribution and high prevalence in the natural populations of its cosmopolitan firebug host. It therefore represents an attractive model to study the diversity of RNA viruses.Results We surveyed 106 axenic cultures of L. pyrrhocoris and found that 64 (60%) of these displayed 2-12 double-stranded RNA fragments. The analysis of next-generation sequencing data revealed four viral groups with seven species, of which up to five were simultaneously detected in a single trypanosomatid isolate. Only two of these species, a tombus-like virus and an Ostravirus, were earlier documented in L. pyrrhocoris. In addition, there were four new species of Leishbuviridae, the family encompassing trypanosomatid-specific viruses, and a new species of Qinviridae, the family previously known only from metatranscriptomes of invertebrates. Currently, this is the only qinvirus with an unambiguously determined host. Our phylogenetic inferences suggest reassortment in the tombus-like virus owing to the interaction of different trypanosomatid strains. Two of the new Leishbuviridae members branch early on the phylogenetic tree of this family and display intermediate stages of genomic segment reduction between insect Phenuiviridae and crown Leishbuviridae.Conclusions The unprecedented wide range of viruses in one protist species and the simultaneous presence of up to five viral species in a single Leptomonas pyrrhocoris isolate indicate the uniqueness of this flagellate. This is likely determined by the peculiarity of its firebug host, a highly abundant cosmopolitan species with several habits ensuring wide distribution and profuseness of L. pyrrhocoris, as well as its exposure to a wider spectrum of viruses compared to other trypanosomatids combined with a limited ability to transmit these viruses to its relatives. Thus, L. pyrrhocoris represents a suitable model to study the adoption of new viruses and their relationships with a protist host.

  • 5. Fernandez-Acosta, Magdalena
    et al.
    Romero, Juan
    Bernabó, Guillermo
    Velázquez-Campos, Giovanna M.
    Gonzalez, Nerina
    Mares, M. Lucía
    Werbajh, Santiago
    Avendaño-Vázquez, L. Amaranta
    Rechberger, Gerald N.
    Kühnlein, Ronald P.
    Marino-Buslje, Cristina
    Cantera, Rafael
    Stockholm University, Faculty of Science, Department of Zoology. Instituto de Investigaciones Biológicas Clemente Estable, Uruguay.
    Rezaval, Carolina
    Ceriani, M. Fernanda
    orsai, the Drosophila homolog of human ETFRF1, links lipid catabolism to growth control2022In: BMC Biology, E-ISSN 1741-7007, Vol. 20, no 1, article id 233Article in journal (Refereed)
    Abstract [en]

    Background: Lipid homeostasis is an evolutionarily conserved process that is crucial for energy production, storage and consumption. Drosophila larvae feed continuously to achieve the roughly 200-fold increase in size and accumulate sufficient reserves to provide all energy and nutrients necessary for the development of the adult fly. The mechanisms controlling this metabolic program are poorly understood.

    Results: Herein we identified a highly conserved gene, orsai (osi), as a key player in lipid metabolism in Drosophila. Lack of osi function in the larval fat body, the regulatory hub of lipid homeostasis, reduces lipid reserves and energy output, evidenced by decreased ATP production and increased ROS levels. Metabolic defects due to reduced Orsai (Osi) in time trigger defective food-seeking behavior and lethality. Further, we demonstrate that downregulation of Lipase 3, a fat body-specific lipase involved in lipid catabolism in response to starvation, rescues the reduced lipid droplet size associated with defective orsai. Finally, we show that osi-related phenotypes are rescued through the expression of its human ortholog ETFRF1/LYRm5, known to modulate the entry of β-oxidation products into the electron transport chain; moreover, knocking down electron transport flavoproteins EtfQ0 and walrus/ETFA rescues osi-related phenotypes, further supporting this mode of action.

    Conclusions: These findings suggest that Osi may act in concert with the ETF complex to coordinate lipid homeostasis in the fat body in response to stage-specific demands, supporting cellular functions that in turn result in an adaptive behavioral response.

  • 6.
    Hilscher, Markus M.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Mattsson Langseth, Christoffer
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Kukanja, Petra
    Yokota, Chika
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Castelo‑Branco, Gonçalo
    Spatial and temporal heterogeneity in the lineage progression of fine oligodendrocyte subtypes2022In: BMC Biology, E-ISSN 1741-7007, Vol. 20, no 1, article id 122Article in journal (Refereed)
    Abstract [en]

    Background: Oligodendrocytes are glial cells that support and insulate axons in the central nervous system through the production of myelin. Oligodendrocytes arise throughout embryonic and early postnatal development from oligodendrocyte precursor cells (OPCs), and recent work demonstrated that they are a transcriptional heterogeneous cell population, but the regional and functional implications of this heterogeneity are less clear. Here, we apply in situ sequencing (ISS) to simultaneously probe the expression of 124 marker genes of distinct oligodendrocyte populations, providing comprehensive maps of the corpus callosum, cingulate, motor, and somatosensory cortex in the brain, as well as gray matter (GM) and white matter (WM) regions in the spinal cord, at postnatal (P10), juvenile (P20), and young adult (P60) stages. We systematically compare the abundances of these populations and investigate the neighboring preference of distinct oligodendrocyte populations.

    Results: We observed that oligodendrocyte lineage progression is more advanced in the juvenile spinal cord compared to the brain, corroborating with previous studies. We found myelination still ongoing in the adult corpus callosum while it was more advanced in the cortex. Interestingly, we also observed a lateral-to-medial gradient of oligodendrocyte lineage progression in the juvenile cortex, which could be linked to arealization, as well as a deep-to-superficial gradient with mature oligodendrocytes preferentially accumulating in the deeper layers of the cortex. The ISS experiments also exposed differences in abundances and population dynamics over time between GM and WM regions in the brain and spinal cord, indicating regional differences within GM and WM, and we found that neighboring preferences of some oligodendroglia populations are altered from the juvenile to the adult CNS.

    Conclusions: Overall, our ISS experiments reveal spatial heterogeneity of oligodendrocyte lineage progression in the brain and spinal cord and uncover differences in the timing of oligodendrocyte differentiation and myelination, which could be relevant to further investigate functional heterogeneity of oligodendroglia, especially in the context of injury or disease.

  • 7.
    Kahle, Maximilian
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Appelgren, Sofia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Carroni, Marta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Ädelroth, Pia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Insights into the structure-function relationship of the NorQ/NorD chaperones from Paracoccus denitrificans reveal shared principles of interacting MoxR AAA+/VWA domain proteins2023In: BMC Biology, E-ISSN 1741-7007, Vol. 21, article id 47Article in journal (Refereed)
    Abstract [en]

    Background NorQ, a member of the MoxR-class of AAA+ ATPases, and NorD, a protein containing a Von Willebrand Factor Type A (VWA) domain, are essential for non-heme iron (FeB) cofactor insertion into cytochrome c-dependent nitric oxide reductase (cNOR). cNOR catalyzes NO reduction, a key step of bacterial denitrification. This work aimed at elucidating the specific mechanism of NorQD-catalyzed FeB insertion, and the general mechanism of the MoxR/VWA interacting protein families.

    Results We show that NorQ-catalyzed ATP hydrolysis, an intact VWA domain in NorD, and specific surface carboxylates on cNOR are all features required for cNOR activation. Supported by BN-PAGE, low-resolution cryo-EM structures of NorQ and the NorQD complex show that NorQ forms a circular hexamer with a monomer of NorD binding both to the side and to the central pore of the NorQ ring. Guided by AlphaFold predictions, we assign the density that “plugs” the NorQ ring pore to the VWA domain of NorD with a protruding “finger” inserting through the pore and suggest this binding mode to be general for MoxR/VWA couples.

    Conclusions Based on our results, we present a tentative model for the mechanism of NorQD-catalyzed cNOR remodeling and suggest many of its features to be applicable to the whole MoxR/VWA family.

  • 8.
    Lindenfors, Patrik
    et al.
    Stockholm University, Faculty of Science, Department of Zoology. Stockholm University, Faculty of Humanities, Centre for the Study of Cultural Evolution.
    Nunn, Charles L
    University of California, Berkeley.
    Barton, Robert A
    Durham University, Durham.
    Primate brain architecture and selection in relation to sex2007In: BMC Biology, E-ISSN 1741-7007, Vol. 5, no 20Article in journal (Refereed)
    Abstract [en]

    Background: Social and competitive demands often differ between the sexes in mammals. These differing demands should be expected to produce variation in the relative sizes of various brain structures. Sexual selection on males can be predicted to influence brain components handling sensory-motor skills that are important for physical competition or neural pathways involving aggression. Conversely, because female fitness is more closely linked to ecological factors and social interactions that enable better acquisition of resources, social selection on females should select for brain components important for navigating social networks. Sexual and social selection acting on one sex could produce sexual dimorphism in brain structures, which would result in larger species averages for those same brain structures. Alternatively, sex-specific selection pressures could produce correlated effects in the other sex, resulting in larger brain structures for both males and females of a species. Data are presently unavailable for the sex-specific sizes of brain structures for anthropoid primates, but under either scenario, the effects of sexual and social selection should leave a detectable signal in average sizes of brain structures for different species.

    Results: The degree of male intra-sexual selection was positively correlated with several structures involved in autonomic functions and sensory-motor skills, and in pathways relating to aggression and aggression control. The degree of male intra-sexual selection was not correlated with relative neocortex size, which instead was significantly positively correlated with female social group size, but negatively correlated with male group size.

    Conclusion: Sexual selection on males and social selection on females have exerted different effects on primate brain architecture. Species with a higher degree of male intra-sexual selection carry a neural signature of an evolutionary history centered on physical conflicts, but no traces of increased demands on sociocognitive tasks. Conversely, female sociality is indicated to have driven the evolution of socio-cognitive skills. Primate brain architecture is therefore likely to be a product of ecological and species-specific social factors as well as different sex-specific selection pressures. Our results also highlight the need for acquisition and analysis of sex-specific brain components in mammals.

  • 9.
    Lundin, Elin
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Wu, Chenglin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Widmark, Albin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Behm, Mikaela
    Hjerling-Leffler, Jens
    Daniel, Chammiran
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Spatiotemporal mapping of RNA editing in the developing mouse brain using in situ sequencing reveals regional and cell-type-specific regulation2020In: BMC Biology, E-ISSN 1741-7007, Vol. 18, no 1, article id 6Article in journal (Refereed)
    Abstract [en]

    Background Adenosine-to-inosine (A-to-I) RNA editing is a process that contributes to the diversification of proteins that has been shown to be essential for neurotransmission and other neuronal functions. However, the spatiotemporal and diversification properties of RNA editing in the brain are largely unknown. Here, we applied in situ sequencing to distinguish between edited and unedited transcripts in distinct regions of the mouse brain at four developmental stages, and investigate the diversity of the RNA landscape. Results We analyzed RNA editing at codon-altering sites using in situ sequencing at single-cell resolution, in combination with the detection of individual ADAR enzymes and specific cell type marker transcripts. This approach revealed cell-type-specific regulation of RNA editing of a set of transcripts, and developmental and regional variation in editing levels for many of the targeted sites. We found increasing editing diversity throughout development, which arises through regional- and cell type-specific regulation of ADAR enzymes and target transcripts. Conclusions Our single-cell in situ sequencing method has proved useful to study the complex landscape of RNA editing and our results indicate that this complexity arises due to distinct mechanisms of regulating individual RNA editing sites, acting both regionally and in specific cell types.

  • 10. Partel, Gabriele
    et al.
    Hilscher, Markus M.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Milli, Giorgia
    Solorzano, Leslie
    Klemm, Anna H.
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Wählby, Carolina
    Automated identification of the mouse brain's spatial compartments from in situ sequencing data2020In: BMC Biology, E-ISSN 1741-7007, Vol. 18, no 1, article id 144Article in journal (Refereed)
    Abstract [en]

    Background: Neuroanatomical compartments of the mouse brain are identified and outlined mainly based on manual annotations of samples using features related to tissue and cellular morphology, taking advantage of publicly available reference atlases. However, this task is challenging since sliced tissue sections are rarely perfectly parallel or angled with respect to sections in the reference atlas and organs from different individuals may vary in size and shape and requires manual annotation. With the advent of in situ sequencing technologies and automated approaches, it is now possible to profile the gene expression of targeted genes inside preserved tissue samples and thus spatially map biological processes across anatomical compartments.

    Results: Here, we show how in situ sequencing data combined with dimensionality reduction and clustering can be used to identify spatial compartments that correspond to known anatomical compartments of the brain. We also visualize gradients in gene expression and sharp as well as smooth transitions between different compartments. We apply our method on mouse brain sections and show that a fully unsupervised approach can computationally define anatomical compartments, which are highly reproducible across individuals, using as few as 18 gene markers. We also show that morphological variation does not always follow gene expression, and different spatial compartments can be defined by various cell types with common morphological features but distinct gene expression profiles.

    Conclusion: We show that spatial gene expression data can be used for unsupervised and unbiased annotations of mouse brain spatial compartments based only on molecular markers, without the need of subjective manual annotations based on tissue and cell morphology or matching reference atlases.

  • 11. Srivathsan, Amrita
    et al.
    Hartop, Emily
    Stockholm University, Faculty of Science, Department of Zoology. Station Linné, Sweden.
    Puniamoorthy, Jayanthi
    Lee, Wan Ting
    Narayanan Kutty, Sujatha
    Kurina, Olavi
    Meier, Rudolf
    Rapid, large-scale species discovery in hyperdiverse taxa using 1D MinION sequencing2019In: BMC Biology, E-ISSN 1741-7007, Vol. 17, article id 96Article in journal (Refereed)
    Abstract [en]

    Background: More than 80% of all animal species remain unknown to science. Most of these species live in the tropics and belong to animal taxa that combine small body size with high specimen abundance and large species richness. For such clades, using morphology for species discovery is slow because large numbers of specimens must be sorted based on detailed microscopic investigations. Fortunately, species discovery could be greatly accelerated if DNA sequences could be used for sorting specimens to species. Morphological verification of such “molecular operational taxonomic units” (mOTUs) could then be based on dissection of a small subset of specimens. However, this approach requires cost-effective and low-tech DNA barcoding techniques because well-equipped, well-funded molecular laboratories are not readily available in many biodiverse countries.

    Results: We here document how MinION sequencing can be used for large-scale species discovery in a specimen- and species-rich taxon like the hyperdiverse fly family Phoridae (Diptera). We sequenced 7059 specimens collected in a single Malaise trap in Kibale National Park, Uganda, over the short period of 8 weeks. We discovered > 650 species which exceeds the number of phorid species currently described for the entire Afrotropical region. The barcodes were obtained using an improved low-cost MinION pipeline that increased the barcoding capacity sevenfold from 500 to 3500 barcodes per flowcell. This was achieved by adopting 1D sequencing, resequencing weak amplicons on a used flowcell, and improving demultiplexing. Comparison with Illumina data revealed that the MinION barcodes were very accurate (99.99% accuracy, 0.46% Ns) and thus yielded very similar species units (match ratio 0.991). Morphological examination of 100 mOTUs also confirmed good congruence with morphology (93% of mOTUs; > 99% of specimens) and revealed that 90% of the putative species belong to the neglected, megadiverse genus Megaselia. We demonstrate for one Megaselia species how the molecular data can guide the description of a new species (Megaselia sepsioides sp. nov.).

    Conclusions: We document that one field site in Africa can be home to an estimated 1000 species of phorids and speculate that the Afrotropical diversity could exceed 200,000 species. We furthermore conclude that low-cost MinION sequencers are very suitable for reliable, rapid, and large-scale species discovery in hyperdiverse taxa. MinION sequencing could quickly reveal the extent of the unknown diversity and is especially suitable for biodiverse countries with limited access to capital-intensive sequencing facilities.

  • 12.
    Vicente, Mário
    et al.
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies. Uppsala University, Sweden; Centre for Palaeogenetics, Sweden.
    Lankheet, Imke
    Russell, Thembi
    Hollfelder, Nina
    Coetzee, Vinet
    Soodyall, Himla
    De Jongh, Michael
    Schlebusch, Carina M.
    Male-biased migration from East Africa introduced pastoralism into southern Africa2021In: BMC Biology, E-ISSN 1741-7007, Vol. 19, no 1, article id 259Article in journal (Refereed)
    Abstract [en]

    Background: Hunter-gatherer lifestyles dominated the southern African landscape up to ~ 2000 years ago, when herding and farming groups started to arrive in the area. First, herding and livestock, likely of East African origin, appeared in southern Africa, preceding the arrival of the large-scale Bantu-speaking agro-pastoralist expansion that introduced West African-related genetic ancestry into the area. Present-day Khoekhoe-speaking Namaqua (or Nama in short) pastoralists show high proportions of East African admixture, linking the East African ancestry with Khoekhoe herders. Most other historical Khoekhoe populations have, however, disappeared over the last few centuries and their contribution to the genetic structure of present-day populations is not well understood. In our study, we analyzed genome-wide autosomal and full mitochondrial data from a population who trace their ancestry to the Khoekhoe-speaking Hessequa herders from the southern Cape region of what is now South Africa.

    Results: We generated genome-wide data from 162 individuals and mitochondrial DNA data of a subset of 87 individuals, sampled in the Western Cape Province, South Africa, where the Hessequa population once lived. Using available comparative data from Khoe-speaking and related groups, we aligned genetic date estimates and admixture proportions to the archaeological proposed dates and routes for the arrival of the East African pastoralists in southern Africa. We identified several Afro-Asiatic-speaking pastoralist groups from Ethiopia and Tanzania who share high affinities with the East African ancestry present in southern Africa. We also found that the East African pastoralist expansion was heavily male-biased, akin to a pastoralist migration previously observed on the genetic level in ancient Europe, by which Pontic-Caspian Steppe pastoralist groups represented by the Yamnaya culture spread across the Eurasian continent during the late Neolithic/Bronze Age.

    Conclusion: We propose that pastoralism in southern Africa arrived through male-biased migration of an East African Afro-Asiatic-related group(s) who introduced new subsistence and livestock practices to local southern African hunter-gatherers. Our results add to the understanding of historical human migration and mobility in Africa, connected to the spread of food-producing and livestock practices.

  • 13. Zarsky, Vojtech
    et al.
    Karnkowska, Anna
    Boscaro, Vittorio
    Trznadel, Morelia
    Whelan, Thomas A.
    Hiltunen-Thoren, Markus
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Uppsala University, Uppsala, Sweden.
    Onut-Brannstrom, Ioana
    Abbott, Cathryn L.
    Fast, Naomi M.
    Burki, Fabien
    Keeling, Patrick J.
    Contrasting outcomes of genome reduction in mikrocytids and microsporidians2023In: BMC Biology, E-ISSN 1741-7007, Vol. 21, no 1, article id 137Article in journal (Refereed)
    Abstract [en]

    BackgroundIntracellular symbionts often undergo genome reduction, losing both coding and non-coding DNA in a process that ultimately produces small, gene-dense genomes with few genes. Among eukaryotes, an extreme example is found in microsporidians, which are anaerobic, obligate intracellular parasites related to fungi that have the smallest nuclear genomes known (except for the relic nucleomorphs of some secondary plastids). Mikrocytids are superficially similar to microsporidians: they are also small, reduced, obligate parasites; however, as they belong to a very different branch of the tree of eukaryotes, the rhizarians, such similarities must have evolved in parallel. Since little genomic data are available from mikrocytids, we assembled a draft genome of the type species, Mikrocytos mackini, and compared the genomic architecture and content of microsporidians and mikrocytids to identify common characteristics of reduction and possible convergent evolution.ResultsAt the coarsest level, the genome of M. mackini does not exhibit signs of extreme genome reduction; at 49.7 Mbp with 14,372 genes, the assembly is much larger and gene-rich than those of microsporidians. However, much of the genomic sequence and most (8075) of the protein-coding genes code for transposons, and may not contribute much of functional relevance to the parasite. Indeed, the energy and carbon metabolism of M. mackini share several similarities with those of microsporidians. Overall, the predicted proteome involved in cellular functions is quite reduced and gene sequences are extremely divergent. Microsporidians and mikrocytids also share highly reduced spliceosomes that have retained a strikingly similar subset of proteins despite having reduced independently. In contrast, the spliceosomal introns in mikrocytids are very different from those of microsporidians in that they are numerous, conserved in sequence, and constrained to an exceptionally narrow size range (all 16 or 17 nucleotides long) at the shortest extreme of known intron lengths.ConclusionsNuclear genome reduction has taken place many times and has proceeded along different routes in different lineages. Mikrocytids show a mix of similarities and differences with other extreme cases, including uncoupling the actual size of a genome with its functional reduction.

  • 14.
    Zhao, Yunpo
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lindberg, Bo Gustav
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Seyedoleslami Esfahani, Shiva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Tang, Xiongzhuo
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Piazza, Stefano
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Stop codon readthrough alters the activity of a POU/Oct transcription factor during Drosophila development2021In: BMC Biology, E-ISSN 1741-7007, Vol. 19, no 1, article id 185Article in journal (Refereed)
    Abstract [en]

    Background: A number of cellular processes have evolved in metazoans that increase the proteome repertoire in relation to the genome, such as alternative splicing and translation recoding. Another such process, translational stop codon readthrough (SCR), generates C-terminally extended protein isoforms in many eukaryotes, including yeast, plants, insects, and humans. While comparative genome analyses have predicted the existence of programmed SCR in many species including humans, experimental proof of its functional consequences are scarce.

    Results: We show that SCR of the Drosophila POU/Oct transcription factor Ventral veins lacking/Drifter (Vvl/Dfr) mRNA is prevalent in certain tissues in vivo, reaching a rate of 50% in the larval prothoracic gland. Phylogenetically, the C-terminal extension is conserved and harbors intrinsically disordered regions and amino acid stretches implied in transcriptional activation. Elimination of Vvl/Dfr translational readthrough by CRISPR/Cas9 mutagenesis changed the expression of a large number of downstream genes involved in processes such as chromatin regulation, neurogenesis, development, and immune response. As a proof-of-principle, we demonstrate that the C-terminal extension of Vvl/Dfr is necessary for correct timing of pupariation, by increasing the capacity to regulate its target genes. The extended Vvl/Dfr isoform acts in synergy with the transcription factor Molting defective (Mld) to increase the expression and biosynthesis of the steroid hormone ecdysone, thereby advancing pupariation. Consequently, late-stage larval development was prolonged and metamorphosis delayed in vvl/dfr readthrough mutants.

    Conclusions: We demonstrate that translational recoding of a POU/Oct transcription factor takes place in a highly tissue-specific and temporally controlled manner. This dynamic and regulated recoding is necessary for normal expression of a large number of genes involved in many cellular and developmental processes. Loss of Vvl/Dfr translational readthrough negatively affects steroid hormone biosynthesis and delays larval development and progression into metamorphosis. Thus, this study demonstrates how SCR of a transcription factor can act as a developmental switch in a spatiotemporal manner, feeding into the timing of developmental transitions between different life-cycle stages.

  • 15.
    Zhou, Shu
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Pettersson, Pontus
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Björck, Markus L.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Dawitz, Hannah
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Brzezinski, Peter
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mäler, Lena
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ädelroth, Pia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    NMR structural analysis of the yeast cytochrome c oxidase subunit Cox13 and its interaction with ATP2021In: BMC Biology, E-ISSN 1741-7007, Vol. 19, no 1, article id 98Article in journal (Refereed)
    Abstract [en]

    Background: Mitochondrial respiration is organized in a series of enzyme complexes in turn forming dynamic supercomplexes. In Saccharomyces cerevisiae (baker's yeast), Cox13 (CoxVIa in mammals) is a conserved peripheral subunit of Complex IV (cytochrome c oxidase, CytcO), localized at the interface of dimeric bovine CytcO, which has been implicated in the regulation of the complex.

    Results: Here, we report the solution NMR structure of Cox13, which forms a dimer in detergent micelles. Each Cox13 monomer has three short helices (SH), corresponding to disordered regions in X-ray or cryo-EM structures of homologous proteins. Dimer formation is mainly induced by hydrophobic interactions between the transmembrane (TM) helix of each monomer. Furthermore, an analysis of chemical shift changes upon addition of ATP revealed that ATP binds at a conserved region of the C terminus with considerable conformational flexibility.

    Conclusions: Together with functional analysis of purified CytcO, we suggest that this ATP interaction is inhibitory of catalytic activity. Our results shed light on the structural flexibility of an important subunit of yeast CytcO and provide structure-based insight into how ATP could regulate mitochondrial respiration.

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