Anneline Pinson, Lei Xing, Takashi Namba, Nereo Kalebic, Jula Peters, Christina Eugster Oegema, Sofia Traikov, Katrin Reppe, Stephan Riesenberg, Tomislav Maricic, Razvan Derihaci, Pauline Wimberger, Svante Pääbo, Wieland Huttner Human TKTL1 implies greater neurogenesis in frontal neocortex of modern humans than Neanderthals. Science, 377(6611) Art. No. eabl6422 (2022) DOI
Neanderthal brains were similar in size to those of modern humans. We sought to investigate potential differences in neurogenesis during neocortex development. Modern human transketolase-like 1 (TKTL1) differs from Neanderthal TKTL1 by a lysine-to-arginine amino acid substitution. Using overexpression in developing mouse and ferret neocortex, knockout in fetal human neocortical tissue, and genome-edited cerebral organoids, we found that the modern human variant, hTKTL1, but not the Neanderthal variant, increases the abundance of basal radial glia (bRG) but not that of intermediate progenitors (bIPs). bRG generate more neocortical neurons than bIPs. The hTKTL1 effect requires the pentose phosphate pathway and fatty acid synthesis. Inhibition of these metabolic pathways reduces bRG abundance in fetal human neocortical tissue. Our data suggest that neocortical neurogenesis in modern humans differs from that in Neanderthals.
Laura Christin Trautenberg, Marko Brankatschk, Andrej Shevchenko, Stuart Wigby, Klaus Reinhardt Ecological lipidology. Elife, 11 Art. No. e79288 (2022)
Open Access DOI
Dietary lipids (DLs), particularly sterols and fatty acids, are precursors for endogenous lipids that, unusually for macronutrients, shape cellular and organismal function long after ingestion. These functions - cell membrane structure, intracellular signalling, and hormonal activity - vary with the identity of DLs, and scale up to influence health, survival, and reproductive fitness, thereby affecting evolutionary change. Our Ecological Lipidology approach integrates biochemical mechanisms and molecular cell biology into evolution and nutritional ecology. It exposes our need to understand environmental impacts on lipidomes, the lipid specificity of cell functions, and predicts the evolution of lipid-based diet choices. Broad interdisciplinary implications of Ecological Lipidology include food web alterations, species responses to environmental change, as well as sex differences and lifestyle impacts on human nutrition, and opportunities for DL-based therapies.
Jamie Woych✳︎, Alonso Ortega Gurrola✳︎, Astrid Deryckere, Eliza C B Jaeger, Elias Gumnit, Gianluca Merello, Jiacheng Gu, Alberto Joven Araus, Nicholas D Leigh, Maximina H Yun, András Simon, Maria Antonietta Tosches Cell-type profiling in salamanders identifies innovations in vertebrate forebrain evolution. Science, 377(6610) Art. No. eabp9186 (2022) DOI
The evolution of advanced cognition in vertebrates is associated with two independent innovations in the forebrain: the six-layered neocortex in mammals and the dorsal ventricular ridge (DVR) in sauropsids (reptiles and birds). How these innovations arose in vertebrate ancestors remains unclear. To reconstruct forebrain evolution in tetrapods, we built a cell-type atlas of the telencephalon of the salamander Pleurodeles waltl. Our molecular, developmental, and connectivity data indicate that parts of the sauropsid DVR trace back to tetrapod ancestors. By contrast, the salamander dorsal pallium is devoid of cellular and molecular characteristics of the mammalian neocortex yet shares similarities with the entorhinal cortex and subiculum. Our findings chart the series of innovations that resulted in the emergence of the mammalian six-layered neocortex and the sauropsid DVR.
Mateusz Susik, Holger Schönborn, Ivo F. Sbalzarini Hamiltonian Monte Carlo with strict convergence criteria reduces run-to-run variability in forensic DNA mixture deconvolution. Forensic Sci Int Genet, 60 Art. No. 102744 (2022)
Analysing mixed DNA profiles is a common task in forensic genetics. Due to the complexity of the data, such analysis is often performed using Markov Chain Monte Carlo (MCMC)-based genotyping algorithms. These trade off precision against execution time. When default settings (including default chain lengths) are used, as large as a 10-fold changes in inferred log-likelihood ratios (LR) are observed when the software is run twice on the same case. So far, this uncertainty has been attributed to the stochasticity of MCMC algorithms. Since LRs translate directly to strength of the evidence in a criminal trial, forensic laboratories desire LR with small run-to-run variability.
Maria Luisa Romero Romero, Cedric Landerer, Jonas Poehls, Agnes Toth-Petroczy Phenotypic mutations contribute to protein diversity and shape protein evolution. Protein Sci, 31(9) Art. No. e4397 (2022)
Open Access DOI
Errors in DNA replication generate genetic mutations, while errors in transcription and translation lead to phenotypic mutations. Phenotypic mutations are orders of magnitude more frequent than genetic ones, yet they are less understood. Here, we review the types of phenotypic mutations, their quantifications, and their role in protein evolution and disease. The diversity generated by phenotypic mutation can facilitate adaptive evolution. Indeed, phenotypic mutations, such as ribosomal frameshift and stop codon readthrough, sometimes serve to regulate protein expression and function. Phenotypic mutations have often been linked to fitness decrease and diseases. Thus, understanding the protein heterogeneity and phenotypic diversity caused by phenotypic mutations will advance our understanding of protein evolution and have implications on human health and diseases.
Victoria T Yan✳︎, Arjun Narayanan✳︎#, Tina Wiegand, Frank Jülicher#, Stephan W. Grill# A condensate dynamic instability orchestrates actomyosin cortex activation. Nature, Art. No. doi: 10.1038/s41586-022-05084-3 (2022)
Open Access DOI
A key event at the onset of development is the activation of a contractile actomyosin cortex during the oocyte-to-embryo transition1-3. Here we report on the discovery that, in Caenorhabditis elegans oocytes, actomyosin cortex activation is supported by the emergence of thousands of short-lived protein condensates rich in F-actin, N-WASP and the ARP2/3 complex4-8 that form an active micro-emulsion. A phase portrait analysis of the dynamics of individual cortical condensates reveals that condensates initially grow and then transition to disassembly before dissolving completely. We find that, in contrast to condensate growth through diffusion9, the growth dynamics of cortical condensates are chemically driven. Notably, the associated chemical reactions obey mass action kinetics that govern both composition and size. We suggest that the resultant condensate dynamic instability10 suppresses coarsening of the active micro-emulsion11, ensures reaction kinetics that are independent of condensate size and prevents runaway F-actin nucleation during the formation of the first cortical actin meshwork.
Franziska Hettler, Christina Schreck, Sandra Romero Marquez, Thomas Engleitner, Baiba Vilne, Theresa Landspersky, Heike Weidner, Renate Hausinger, Ritu Mishra, Rupert Oellinger, Martina Rauner, Ronald Naumann, Christian Peschel, Florian Bassermann, Roland Rad, Rouzanna Istvanffy, Robert A J Oostendorp Osteoprogenitor SFRP1 prevents exhaustion of hematopoietic stem cells via PP2A-PR72/130-mediated regulation of p300. Haematologica, Art. No. doi: 10.3324/haematol.2022.280760 (2022)
Open Access DOI
Remodeling of the bone marrow microenvironment in chronic inflammation and in aging reduces hematopoietic stem cell (HSC) function. To assess the mechanisms of HSC functional decline and find strategies to counteract these, we established a model in which Sfrp1 gene was deleted in Osterix+ osteolineage cells (OS1Δ/Δ mice). HSCs from these mice showed severely diminished repopulating activity with associated DNA damage, enriched expression of the `ROS pathway´ and reduced single cell proliferation. Interestingly, not only was the protein level of Catenin beta-1 (beta-catenin) elevated, but so was its association with the phosphorylated coactivator p300 in the nucleus. Since these two proteins play a key role in promotion of differentiation and senescence, we inhibited in vivo phosphorylation of p300 through PP2APR72/130 by IQ-1 administration in OS1Δ/Δ mice. This treatment not only reduced Catenin beta-1/phospho-p300 association, but also decreased nuclear p300. More importantly, in vivo IQ-1 treatment fully restored HSC repopulating activity of the OS1Δ/Δ mice. Our findings show that osteoprogenitor Sfrp1 is essential for maintaining HSC function. Furthermore, pharmacological downregulation of nuclear Catenin beta-1/phospho-p300 association is a new strategy to restore poor HSC function.
Hollis A Dahn✳︎, Jacquelyn Mountcastle✳︎, Jennifer Balacco, Sylke Winkler, Iliana Bista, Anthony D Schmitt, Olga Vinnere Pettersson, Giulio Formenti, Karen Oliver, Michelle Smith, Wenhua Tan, Anne Kraus, Stephen Mac, Lisa M Komoroske, Tanya M Lama, Andrew J Crawford, Robert F Murphy, Samara Brown, Alan F Scott, Phillip A Morin, Erich D Jarvis, Olivier Fedrigo Benchmarking ultra-high molecular weight DNA preservation methods for long-read and long-range sequencing. GigaScience, 11 Art. No. giac068 (2022)
Open Access DOI
Studies in vertebrate genomics require sampling from a broad range of tissue types, taxa, and localities. Recent advancements in long-read and long-range genome sequencing have made it possible to produce high-quality chromosome-level genome assemblies for almost any organism. However, adequate tissue preservation for the requisite ultra-high molecular weight DNA (uHMW DNA) remains a major challenge. Here we present a comparative study of preservation methods for field and laboratory tissue sampling, across vertebrate classes and different tissue types.
Jeffrey G McDonald✳︎, Christer S. Ejsing✳︎, Dominik Kopczynski✳︎, Michal Holčapek✳︎, Junken Aoki, Makoto Arita, Masanori Arita, Erin S Baker, Justine Bertrand-Michel, John A Bowden, Britta Brügger, Shane R Ellis, Maria Fedorova, William J Griffiths, Xianlin Han, Jürgen Hartler, Nils Hoffmann, Jeremy P Koelmel, Harald C Köfeler, Todd W Mitchell, Valerie B O'Donnell, Daisuke Saigusa, Dominik Schwudke, Andrej Shevchenko, Candice Z Ulmer, Markus R Wenk, Michael Witting, Denise Wolrab, Yu Xia, R Ahrends#, Gerhard Liebisch#, Kim Ekroos# Introducing the Lipidomics Minimal Reporting Checklist. Nat Metab, Art. No. doi: 10.1038/s42255-022-00628-3 (2022) DOI
Mukesh Kumar, Canan Has, Khanh Lam-Kamath, Sophie Ayciriex, Deepshe Dewett, Mina Bashir, Clara Poupault, Kai Schuhmann, Oskar Knittelfelder, Bharath Kumar Raghuraman, R Ahrends, Jens Rister#, Andrej Shevchenko# Vitamin A Deficiency Alters the Phototransduction Machinery and Distinct Non-Vision-Specific Pathways in the Drosophila Eye Proteome. Biomolecules, 12(8) Art. No. 1083 (2022)
Open Access DOI
The requirement of vitamin A for the synthesis of the visual chromophore and the light-sensing pigments has been studied in vertebrate and invertebrate model organisms. To identify the molecular mechanisms that orchestrate the ocular response to vitamin A deprivation, we took advantage of the fact that Drosophila melanogaster predominantly requires vitamin A for vision, but not for development or survival. We analyzed the impacts of vitamin A deficiency on the morphology, the lipidome, and the proteome of the Drosophila eye. We found that chronic vitamin A deprivation damaged the light-sensing compartments and caused a dramatic loss of visual pigments, but also decreased the molar abundance of most phototransduction proteins that amplify and transduce the visual signal. Unexpectedly, vitamin A deficiency also decreased the abundances of specific subunits of mitochondrial TCA cycle and respiratory chain components but increased the levels of cuticle- and lens-related proteins. In contrast, we found no apparent effects of vitamin A deficiency on the ocular lipidome. In summary, chronic vitamin A deficiency decreases the levels of most components of the visual signaling pathway, but also affects molecular pathways that are not vision-specific and whose mechanistic connection to vitamin A remains to be elucidated.