Quantifying the relationship between genetic diversity and population size suggests natural selection cannot explain Lewontin's paradox
Neutral theory predicts that genetic diversity increases with population size, yet observed levels of diversity across metazoans vary only two orders of magnitude while population sizes vary over several. This unexpectedly narrow range of diversity is known as Lewontin ’s Paradox of Variation (1974). While some have suggested selection constrains diversity, tests of this hypothesis seem to fall short. Here, I revisit Lewontin’s Paradox to assess whether current models of linked selection are capable of reducing diversity to this extent. To quantify the discrep ancy between pairwise diversity and census population sizes...
Source: eLife - August 19, 2021 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research
TRPC3 and NALCN channels drive pacemaking in substantia nigra dopaminergic neurons
Midbrain dopamine (DA) neurons are slow pacemakers that maintain extracellular DA levels. During the interspike intervals, subthreshold slow depolarization underlies autonomous pacemaking and determines its rate. However, the ion channels that determine slow depolarization are unknown. Here we show that TRPC3 and NALCN channels together form sustained inward currents responsible for the slow depolarization of nigral DA neurons. Specific TRPC3 channel blockade completely blocked DA neuron pacemaking, but the pacemaking activity in TRPC3 knock-out (KO) mice was perfectly normal, suggesting the presence of compensating ion ch...
Source: eLife - August 19, 2021 Category: Biomedical Science Tags: Cell Biology Neuroscience Source Type: research
The whale shark genome reveals patterns of vertebrate gene family evolution
We report long-read sequencing of the whale shark genome to generate the best gapless chondrichthyan genome assembly yet with higher contig contiguity than all other cartilaginous fish genomes, and studied vertebrate genomic evolution of ancestral gene families, immunity, and gigantism. We found a major increase in gene families at the origin of gnathostomes (jawed vertebrates) independent of their genome duplication. We studied vertebrate pathogen recognition receptors (PRRs), which are key in initiating innate immune defense, and found diverse patterns of gene family evolution, demonstrating that adaptive immunity in gna...
Source: eLife - August 19, 2021 Category: Biomedical Science Tags: Evolutionary Biology Genetics and Genomics Source Type: research
Multi-syndrome, multi-gene risk modeling for individuals with a family history of cancer with the novel R package PanelPRO
We present PanelPRO, a new, open-source R package providing a fast, flexible back-end for multi-gene, multi-cancer risk modeling with pedigree data. It includes a customizable database with default parameter values estimated from published studies and allows users to select any combinations of genes and cancers for their models, including well-established single syndrome BayesMendel models (BRCAPRO and MMRPRO). This leads to more accurate risk predictions and ultimately has a high impact on prevention strategies for cancer and clinical decision making. The package is available for download for research purposes at https://...
Source: eLife - August 18, 2021 Category: Biomedical Science Tags: Cancer Biology Genetics and Genomics Source Type: research
Innate immune activation by checkpoint inhibition in human patient-derived lung cancer tissues
Although Pembrolizumab-based immunotherapy has significantly improved lung cancer patient survival, many patients show variable efficacy and resistance development. A better understanding of the drug's action is needed to improve patient outcomes. Functional heterogeneity of the tumor microenvironment (TME) is crucial to modulating drug resistance; understanding of individual patients' TME that impacts drug response is hampered by lack of appropriate models. Lung organotypic tissue slice cultures (OTC) with patients' native TME procured from primary and brain-metastasized (BM) non-small cell lung cancer (NSCLC) patients we...
Source: eLife - August 18, 2021 Category: Biomedical Science Tags: Cancer Biology Source Type: research
Linker histone H1.8 inhibits chromatin-binding of condensins and DNA topoisomerase II to tune chromosome length and individualization
DNA loop extrusion by condensins and decatenation by DNA topoisomerase II (topo II) are thought to drive mitotic chromosome compaction and individualization. Here, we reveal that the linker histone H1.8 antagonizes condensins and topo II to shape mitotic chromosome organization.In vitro chromatin reconstitution experiments demonstrate that H1.8 inhibits binding of condensins and topo II to nucleosome arrays. Accordingly, H1.8 depletion inXenopus egg extracts increased condensins and topo II levels on mitotic chromatin. Chromosome morphology and Hi-C analyses suggest that H1.8 depletion makes chromosomes thinner and longer ...
Source: eLife - August 18, 2021 Category: Biomedical Science Tags: Chromosomes and Gene Expression Source Type: research
Insulin-producing β-cells regenerate ectopically from a mesodermal origin under the perturbation of hemato-endothelial specification
To investigate the role of the vasculature in pancreatic β-cell regeneration, we crossed a zebrafish β-cell ablation model into the avascularnpas4l mutant (i.e.cloche). Surprisingly, β-cell regeneration increased markedly innpas4l mutants owing to the ectopic differentiation of β-cells in the mesenchyme, a phenotype not previously reported in any models. The ectopic β-cells expressed endocrine markers of pancreatic β-cells, and also responded to glucose with increased calcium influx. Through lineage tracing, we determined that the vast majority of these ectopic β-cells has a mesodermal origin. Notably, ectopic β-ce...
Source: eLife - August 17, 2021 Category: Biomedical Science Tags: Developmental Biology Stem Cells and Regenerative Medicine Source Type: research
An in vitro stem cell model of human epiblast and yolk sac interaction
Human embryogenesis entails complex signalling interactions between embryonic and extra-embryonic cells. However, how extra-embryonic cells direct morphogenesis within the human embryo remains largely unknown due to a lack of relevant stem cell models. Here, we have established conditions to differentiate human pluripotent stem cells (hPSCs) into yolk sac-like cells (YSLCs) that resemble the post-implantation human hypoblast molecularly and functionally. YSLCs induce the expression of pluripotency and anterior ectoderm markers in human embryonic stem cells (hESCs) at the expense of mesoderm and endoderm markers. This activ...
Source: eLife - August 17, 2021 Category: Biomedical Science Tags: Cell Biology Developmental Biology Source Type: research
Receptor repertoires of murine follicular T helper cells reveal a high clonal overlap in separate lymph nodes in autoimmunity
Follicular T helper cells (Tfh) are a specialized subset of CD4 effector T cells that are crucial for germinal center (GC) reactions and for selecting B cells to undergo affinity maturation. Despite this central role for humoral immunity, only few data exist about their clonal distribution when multiple lymphoid organs are exposed to the same antigen (Ag) as it is the case in autoimmunity. Here, we used an autoantibody-mediated disease model of the skin and injected one auto-Ag into the two footpads of the same mouse and analyzed the T cell receptor (TCR) β sequences of Tfh located in GCs of both contralateral draining ly...
Source: eLife - August 17, 2021 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research
NF1 regulates mesenchymal glioblastoma plasticity and aggressiveness through the AP-1 transcription factor FOSL1
The molecular basis underlying glioblastoma (GBM) heterogeneity and plasticity is not fully understood. Using transcriptomic data of human patient-derived brain tumor stem cell lines (BTSCs), classified based on GBM-intrinsic signatures, we identify the AP-1 transcription factorFOSL1 as a key regulator of the mesenchymal (MES) subtype. We provide a mechanistic basis to the role of the neurofibromatosis type 1 gene (NF1), a negative regulator of the RAS/MAPK pathway, in GBM mesenchymal transformation through the modulation ofFOSL1 expression. Depletion ofFOSL1 inNF1-mutant human BTSCs andKras-mutant mouse neural stem cells ...
Source: eLife - August 17, 2021 Category: Biomedical Science Tags: Cancer Biology Source Type: research
Cost-precision trade-off relation determines the optimal morphogen gradient for accurate biological pattern formation
Spatial boundaries formed during animal development originate from the pre-patterning of tissues by signaling molecules, called morphogens. The accuracy of boundary location is limited by the fluctuations of morphogen concentration that thresholds the expression level of target gene. Producing more morphogen molecules, which gives rise to smaller relative fluctuations, would better serve to shape more precise target boundaries; however, it incurs more thermodynamic cost. In the classical diffusion-depletion model of morphogen profile formation, the morphogen molecules synthesized from a local source display an exponentiall...
Source: eLife - August 17, 2021 Category: Biomedical Science Tags: Developmental Biology Physics of Living Systems Source Type: research
How will mosquitoes adapt to climate warming?
We describe how common garden and selection experiments can be used to fill these data gaps. Lastly, we investigate the consequences of mosquito climate adaptation on disease transmission usingAedes aegypti-transmitted dengue virus in Northern Brazil as a case study. The approach outlined here can be applied to any disease vector or pest species and type of environmental change. (Source: eLife)
Source: eLife - August 17, 2021 Category: Biomedical Science Tags: Ecology Source Type: research
KLF10 integrates circadian timing and sugar signaling to coordinate hepatic metabolism
The mammalian circadian timing system and metabolism are highly interconnected, and disruption of this coupling is associated with negative health outcomes. Kr üppel-like factors (KLFs) are transcription factors that govern metabolic homeostasis in various organs. Many KLFs show a circadian expression in the liver. Here, we show that the loss of the clock-controlled KLF10 in hepatocytes results in extensive reprogramming of the mouse liver circadian trans criptome, which in turn, alters the temporal coordination of pathways associated with energy metabolism. We also show that glucose and fructose induceKlf10,which helps m...
Source: eLife - August 17, 2021 Category: Biomedical Science Tags: Cell Biology Source Type: research
Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network
The analgesic utility of opioid-based drugs is limited by the life-threatening risk of respiratory depression. Opioid-induced respiratory depression (OIRD), mediated by the μ-opioid receptor (MOR), is characterized by a pronounced decrease in the frequency and regularity of the inspiratory rhythm, which originates from the medullary preBӧtzinger Complex (preBӧtC). To unravel the cellular- and network-level consequences of MOR activation in the preBӧtC, MOR- express ing neurons were optogenetically identified and manipulated in transgenic micein vitro andin vivo. Based on these results, a model of OIRD was developedin s...
Source: eLife - August 17, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research
Cardiac pathologies in mouse loss of imprinting models are due to misexpression of H19 long noncoding RNA
Maternal loss of imprinting (LOI) at theH19/IGF2 locus results in biallelicIGF2 and reducedH19 expression and is associated with Beckwith-Wiedemann syndrome (BWS). We use mouse models for LOI to understand the relative importance ofIgf2 andH19 mis-expression in BWS phenotypes. Here we focus on cardiovascular phenotypes and show that neonatal cardiomegaly is exclusively dependent on increasedIgf2. Circulating IGF2 binds cardiomyocyte receptors to hyperactivate mTOR signaling, resulting in cellular hyperplasia and hypertrophy. TheseIgf2-dependent phenotypes are transient: cardiac size returns to normal onceIgf2 expression is...
Source: eLife - August 17, 2021 Category: Biomedical Science Tags: Developmental Biology Genetics and Genomics Source Type: research
