Abstract Inferring the demographic history of populations provides fundamental insights into species dynamics and is essential for developing a null model to accurately study selective processes. ...However, background selection and selective sweeps can produce genomic signatures at linked sites that mimic or mask signals associated with historical population size change. While the theoretical biases introduced by the linked effects of selection have been well established, it is unclear whether ancestral recombination graph (ARG)-based approaches to demographic inference in typical empirical analyses are susceptible to misinference due to these effects. To address this, we developed highly realistic forward simulations of human and Drosophila melanogaster populations, including empirically estimated variability of gene density, mutation rates, recombination rates, purifying, and positive selection, across different historical demographic scenarios, to broadly assess the impact of selection on demographic inference using a genealogy-based approach. Our results indicate that the linked effects of selection minimally impact demographic inference for human populations, although it could cause misinference in populations with similar genome architecture and population parameters experiencing more frequent recurrent sweeps. We found that accurate demographic inference of D. melanogaster populations by ARG-based methods is compromised by the presence of pervasive background selection alone, leading to spurious inferences of recent population expansion, which may be further worsened by recurrent sweeps, depending on the proportion and strength of beneficial mutations. Caution and additional testing with species-specific simulations are needed when inferring population history with non-human populations using ARG-based approaches to avoid misinference due to the linked effects of selection.
Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem ...cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function, and build-up of tau and P-tau-S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD.
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•Tau and P-tau accumulation and autophagy disruption in tau-V337M organoids•Accelerated synaptic maturation and loss of glutamatergic cortical-layer neurons•Altered ELAVL4 expression, dysregulated splicing, accelerated synaptic maturation•Rescue of susceptibility to glutamatergic toxicity by PIKFYVE inhibitor apilimod
Characterization of iPSC-derived cerebral organoids with the tau-V337M mutation, which causes frontotemporal dementia, reveals changes preceding neuron death as potential targets for therapeutic intervention, as demonstrated by rescue of susceptibility to glutamatergic toxicity by the PIKFYVE inhibitor apilimod.
SUMMARY
Pod dehiscence is a major source of yield loss in legumes, which is exacerbated by aridity. Disruptive mutations in “Pod indehiscent 1” (PDH1), a pod sclerenchyma‐specific lignin biosynthesis ...gene, has been linked to significant reductions in dehiscence in several legume species. We compared syntenic PDH1 regions across 12 legumes and two outgroups to uncover key historical evolutionary trends at this important locus. Our results clarified the extent to which PDH1 orthologs are present in legumes, showing the typical genomic context surrounding PDH1 has only arisen relatively recently in certain phaseoloid species (Vigna, Phaseolus, Glycine). The notable absence of PDH1 in Cajanus cajan may be a major contributor to its indehiscent phenotype compared with other phaseoloids. In addition, we identified a novel PDH1 ortholog in Vigna angularis and detected remarkable increases in PDH1 transcript abundance during Vigna unguiculata pod development. Investigation of the shared genomic context of PDH1 revealed it lies in a hotspot of transcription factors and signaling gene families that respond to abscisic acid and drought stress, which we hypothesize may be an additional factor influencing expression of PDH1 under specific environmental conditions. Our findings provide key insights into the evolutionary history of PDH1 and lay the foundation for optimizing the pod dehiscence role of PDH1 in major and understudied legume species.
Significance Statement
Our findings provide key insights into the evolutionary history of PDH1 and lay the foundation for optimizing the pod dehiscence role of PDH1 in major and understudied legume species.
Neurofibrillary tangles (NFTs) composed of hyperphosphorylated and misfolded tau protein are a pathological hallmark of Alzheimer's disease and other tauopathy conditions. Tau is predominantly an ...intraneuronal protein but is also secreted in physiological and pathological conditions. The extracellular tau has been implicated in the seeding and propagation of tau pathology and is the prime target of the current tau immunotherapy. However, truncated tau species lacking the microtubule-binding repeat (MTBR) domains essential for seeding have been shown to undergo active secretion and the mechanisms and functional consequences of the various extracellular tau are poorly understood. We report here that the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, plays an essential role in the lysosomal exocytosis of selected tau species. TFEB loss of function significantly reduced the levels of interstitial fluid (ISF) tau in PS19 mice expressing P301S mutant tau and in conditioned media of mutant tau expressing primary neurons, while the secretion of endogenous wild-type tau was not affected. Mechanistically we found that TFEB regulates the secretion of truncated mutant tau lacking MTBR and this process is dependent on the lysosomal calcium channel TRPML1. Consistent with the seeding-incompetent nature of the truncated tau and supporting the concept that TFEB-mediated lysosomal exocytosis promotes cellular clearance, we show that reduced ISF tau in the absence of TFEB is associated with enhanced intraneuronal pathology and accelerated spreading. Our results support the idea that TFEB-mediated tau exocytosis serves as a clearance mechanism to reduce intracellular tau under pathological conditions and that effective tau immunotherapy should devoid targeting these extracellular tau species.
Key message
The major soy protein QTL, cqProt-003, was analysed for haplotype diversity and global distribution, and results indicate 304 bp deletion and variable tandem repeats in protein coding ...regions are likely causal candidates.
Here, we present association and linkage analysis of 985 wild, landrace and cultivar soybean accessions in a pan genomic dataset to characterize the major high-protein/low-oil associated locus cqProt-003 located on chromosome 20. A significant trait-associated region within a 173 kb linkage block was identified, and variants in the region were characterized, identifying 34 high confidence SNPs, 4 insertions, 1 deletion and a larger 304 bp structural variant in the high-protein haplotype. Trinucleotide tandem repeats of variable length present in the second exon of gene
Glyma.20G085100
are strongly correlated with the high-protein phenotype and likely represent causal variation. Structural variation has previously been found in the same gene, for which we report the global distribution of the 304 bp deletion and have identified additional nested variation present in high-protein individuals. Mapping variation at the cqProt-003 locus across demographic groups suggests that the high-protein haplotype is common in wild accessions (94.7%), rare in landraces (10.6%) and near absent in cultivated breeding pools (4.1%), suggesting its decrease in frequency primarily correlates with domestication and continued during subsequent improvement. However, the variation that has persisted in under-utilized wild and landrace populations holds high breeding potential for breeders willing to forego seed oil to maximize protein content. The results of this study include the identification of distinct haplotype structures within the high-protein population, and a broad characterization of the genomic context and linkage patterns of cqProt-003 across global populations, supporting future functional characterization and modification.
Pangenomes aim to represent the complete repertoire of the genome diversity present within a species or cohort of species, capturing the genomic structural variance between individuals. This genomic ...information coupled with phenotypic data can be applied to identify genes and alleles involved with abiotic stress tolerance, disease resistance, and other desirable traits. The characterisation of novel structural variants from pangenomes can support genome editing approaches such as Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR associated protein Cas (CRISPR-Cas), providing functional information on gene sequences and new target sites in variant-specific genes with increased efficiency. This review discusses the application of pangenomes in genome editing and crop improvement, focusing on the potential of pangenomes to accurately identify target genes for CRISPR-Cas editing of plant genomes while avoiding adverse off-target effects. We consider the limitations of applying CRISPR-Cas editing with pangenome references and potential solutions to overcome these limitations.
We revisit the analysis of transverse single-spin asymmetries AN in lepton-nucleon scattering where only a single pion is detected in the final state, ℓN↑→hX. This observable is the Electron-Ion ...Collider (EIC) analogue to AN in proton-proton collisions, p↑p→hX, that has been studied intensely for decades, especially at the Relativistic Heavy Ion Collider (RHIC). We incorporate new theoretical developments in the collinear twist-3 framework and utilize recent extractions of (Sivers-like and Collins-like) quark-gluon-quark correlators in the numerical computations. We compare our calculations to HERMES measurements as well as make predictions for Jefferson Lab, COMPASS, and EIC kinematics. We further explore the role of next-to-leading order (NLO) corrections to the (twist-2) unpolarized cross section (denominator of AN) and consider what can be deduced empirically about the potential numerical significance of the full NLO calculation of AN in this process. We consider sources of theoretical uncertainty in our predictions, which present potential opportunities then for future measurements to improve our understanding of AN and multi-parton correlations in hadrons.
Rye (Secale cereale) is a climate-resilient cereal grown extensively as grain or forage crop in Northern and Eastern Europe. In addition to being an important crop, it has been used to improve wheat ...through introgression of genomic regions for improved yield and disease resistance. Understanding the genomic diversity of rye will assist both the improvement of this crop and facilitate the introgression of more valuable traits into wheat. Here, we isolated and sequenced the short arm of rye chromosome 7 (7RS) from Triticale 380SD using flow cytometry and compared it to the public Lo7 rye whole genome reference assembly. We identify 2747 Lo7 genes present on the isolated chromosome arm and two clusters containing seven and sixty-five genes that are present on Triticale 380SD 7RS, but absent from Lo7 7RS. We identified 29 genes that are not assigned to chromosomal locations in the Lo7 assembly but are present on Triticale 380SD 7RS, suggesting a chromosome arm location for these genes. Our study supports the Lo7 reference assembly and provides a repertoire of genes on Triticale 7RS.
The gene content of plants varies between individuals of the same species due to gene presence/absence variation, and selection can alter the frequency of specific genes in a population. Selection ...during domestication and breeding will modify the genomic landscape, though the nature of these modifications is only understood for specific genes or on a more general level (e.g., by a loss of genetic diversity). Here we have assembled and analyzed a soybean (Glycine spp.) pangenome representing more than 1,000 soybean accessions derived from the USDA Soybean Germplasm Collection, including both wild and cultivated lineages, to assess genomewide changes in gene and allele frequency during domestication and breeding. We identified 3,765 genes that are absent from the Lee reference genome assembly and assessed the presence/absence of all genes across this population. In addition to a loss of genetic diversity, we found a significant reduction in the average number of protein‐coding genes per individual during domestication and subsequent breeding, though with some genes and allelic variants increasing in frequency associated with selection for agronomic traits. This analysis provides a genomic perspective of domestication and breeding in this important oilseed crop.
Core Ideas
We assembled a soybean pangenome based on more than 1,000 lines from the USDA Soybean Germplasm Collection.
We found 3,765 genes absent from the reference assembly.
We found a reduction in the number of genes per individual during domestication and breeding.
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