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Horizontal gene transfer (HGT) is an important evolutionary force shaping prokaryotic and eukaryotic genomes. HGT-acquired genes have been sporadically reported in insects, a lineage containing >50% of animals. We systematically examined HGT in 218 high-quality genomes of diverse insects and found that they acquired 1,410 genes exhibiting diverse functions, including many not previously reported, via 741 distinct transfers from non-metazoan donors. Lepidopterans had the highest average number of HGT-acquired genes. HGT-acquired genes containing introns exhibited substantially higher expression levels than genes lacking introns, suggesting that intron gains were likely involved in HGT adaptation. Lastly, we used the CRISPR-Cas9 system to edit the prevalent unreported gene LOC105383139, which was transferred into the last common ancestor of moths and butterflies. In diamondback moths, males lacking LOC105383139 courted females significantly less. We conclude that HGT has been a major contributor to insect adaptation.
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Mariposas Diurnas , Transferencia de Gen Horizontal , Animales , Mariposas Diurnas/genética , Cortejo , Evolución Molecular , Masculino , FilogeniaRESUMEN
Operons are a hallmark of bacterial genomes, where they allow concerted expression of functionally related genes as single polycistronic transcripts. They are rare in eukaryotes, where each gene usually drives expression of its own independent messenger RNAs. Here, we report the horizontal operon transfer of a siderophore biosynthesis pathway from relatives of Escherichia coli into a group of budding yeast taxa. We further show that the co-linearly arranged secondary metabolism genes are expressed, exhibit eukaryotic transcriptional features, and enable the sequestration and uptake of iron. After transfer, several genetic changes occurred during subsequent evolution, including the gain of new transcription start sites that were sometimes within protein-coding sequences, acquisition of polyadenylation sites, structural rearrangements, and integration of eukaryotic genes into the cluster. We conclude that the genes were likely acquired as a unit, modified for eukaryotic gene expression, and maintained by selection to adapt to the highly competitive, iron-limited environment.
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Eucariontes/genética , Transferencia de Gen Horizontal/genética , Operón/genética , Bacterias/genética , Escherichia coli/genética , Células Eucariotas , Evolución Molecular , Regulación Bacteriana de la Expresión Génica/genética , Genes Bacterianos/genética , Genoma Bacteriano/genética , Genoma Fúngico/genética , Saccharomycetales/genética , Sideróforos/genéticaRESUMEN
Budding yeasts (subphylum Saccharomycotina) are found in every biome and are as genetically diverse as plants or animals. To understand budding yeast evolution, we analyzed the genomes of 332 yeast species, including 220 newly sequenced ones, which represent nearly one-third of all known budding yeast diversity. Here, we establish a robust genus-level phylogeny comprising 12 major clades, infer the timescale of diversification from the Devonian period to the present, quantify horizontal gene transfer (HGT), and reconstruct the evolution of 45 metabolic traits and the metabolic toolkit of the budding yeast common ancestor (BYCA). We infer that BYCA was metabolically complex and chronicle the tempo and mode of genomic and phenotypic evolution across the subphylum, which is characterized by very low HGT levels and widespread losses of traits and the genes that control them. More generally, our results argue that reductive evolution is a major mode of evolutionary diversification.
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Evolución Molecular , Transferencia de Gen Horizontal , Genoma Fúngico , Filogenia , Saccharomycetales/clasificación , Saccharomycetales/genéticaRESUMEN
Genome-scale data and the development of novel statistical phylogenetic approaches have greatly aided the reconstruction of a broad sketch of the tree of life and resolved many of its branches. However, incongruence - the inference of conflicting evolutionary histories - remains pervasive in phylogenomic data, hampering our ability to reconstruct and interpret the tree of life. Biological factors, such as incomplete lineage sorting, horizontal gene transfer, hybridization, introgression, recombination and convergent molecular evolution, can lead to gene phylogenies that differ from the species tree. In addition, analytical factors, including stochastic, systematic and treatment errors, can drive incongruence. Here, we review these factors, discuss methodological advances to identify and handle incongruence, and highlight avenues for future research.
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Evolución Biológica , Genoma , Filogenia , Evolución Molecular , Hibridación GenéticaRESUMEN
MicroRNAs (miRNAs) are a class of nonprotein-coding short transcripts that provide a layer of post-transcriptional regulation essential to many plant biological processes. MiR858, which targets the transcripts of MYB transcription factors, can affect a range of secondary metabolic processes. Although miR858 and its 187-nt precursor have been well studied in Arabidopsis (Arabidopsis thaliana), a systematic investigation of miR858 precursors and their functions across plant species is lacking due to a problem in identifying the transcripts that generate this subclass. By re-evaluating the transcript of miR858 and relaxing the length cut-off for identifying hairpins, we found in kiwifruit (Actinidia chinensis) that miR858 has long-loop hairpins (1,100 to 2,100 nt), whose intervening sequences between miRNA generating complementary sites were longer than all previously reported miRNA hairpins. Importantly, these precursors of miR858 containing long-loop hairpins (termed MIR858L) are widespread in seed plants including Arabidopsis, varying between 350 and 5,500 nt. Moreover, we showed that MIR858L has a greater impact on proanthocyanidin and flavonol levels in both Arabidopsis and kiwifruit. We suggest that an active MIR858L-MYB regulatory module appeared in the transition of early land plants to large upright flowering plants, making a key contribution to plant secondary metabolism.
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Actinidia , Arabidopsis , Regulación de la Expresión Génica de las Plantas , MicroARNs , ARN de Planta , MicroARNs/genética , MicroARNs/metabolismo , Actinidia/genética , Actinidia/metabolismo , Arabidopsis/genética , ARN de Planta/genética , ARN de Planta/metabolismo , Semillas/genética , Semillas/metabolismo , Secuencia de BasesRESUMEN
How genomic differences contribute to phenotypic differences is a major question in biology. The recently characterized genomes, isolation environments, and qualitative patterns of growth on 122 sources and conditions of 1,154 strains from 1,049 fungal species (nearly all known) in the yeast subphylum Saccharomycotina provide a powerful, yet complex, dataset for addressing this question. We used a random forest algorithm trained on these genomic, metabolic, and environmental data to predict growth on several carbon sources with high accuracy. Known structural genes involved in assimilation of these sources and presence/absence patterns of growth in other sources were important features contributing to prediction accuracy. By further examining growth on galactose, we found that it can be predicted with high accuracy from either genomic (92.2%) or growth data (82.6%) but not from isolation environment data (65.6%). Prediction accuracy was even higher (93.3%) when we combined genomic and growth data. After the GALactose utilization genes, the most important feature for predicting growth on galactose was growth on galactitol, raising the hypothesis that several species in two orders, Serinales and Pichiales (containing the emerging pathogen Candida auris and the genus Ogataea, respectively), have an alternative galactose utilization pathway because they lack the GAL genes. Growth and biochemical assays confirmed that several of these species utilize galactose through an alternative oxidoreductive D-galactose pathway, rather than the canonical GAL pathway. Machine learning approaches are powerful for investigating the evolution of the yeast genotype-phenotype map, and their application will uncover novel biology, even in well-studied traits.
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Galactosa , Aprendizaje Automático , Galactosa/metabolismo , Genoma Fúngico , Redes y Vías Metabólicas/genética , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genéticaRESUMEN
The Saccharomycotina yeasts ("yeasts" hereafter) are a fungal clade of scientific, economic, and medical significance. Yeasts are highly ecologically diverse, found across a broad range of environments in every biome and continent on earth; however, little is known about what rules govern the macroecology of yeast species and their range limits in the wild. Here, we trained machine learning models on 12,816 terrestrial occurrence records and 96 environmental variables to infer global distribution maps at ~1 km2 resolution for 186 yeast species (~15% of described species from 75% of orders) and to test environmental drivers of yeast biogeography and macroecology. We found that predicted yeast diversity hotspots occur in mixed montane forests in temperate climates. Diversity in vegetation type and topography were some of the greatest predictors of yeast species richness, suggesting that microhabitats and environmental clines are key to yeast diversity. We further found that range limits in yeasts are significantly influenced by carbon niche breadth and range overlap with other yeast species, with carbon specialists and species in high-diversity environments exhibiting reduced geographic ranges. Finally, yeasts contravene many long-standing macroecological principles, including the latitudinal diversity gradient, temperature-dependent species richness, and a positive relationship between latitude and range size (Rapoport's rule). These results unveil how the environment governs the global diversity and distribution of species in the yeast subphylum. These high-resolution models of yeast species distributions will facilitate the prediction of economically relevant and emerging pathogenic species under current and future climate scenarios.
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Biodiversidad , Ecosistema , Clima , Bosques , Carbono , LevadurasRESUMEN
Siderophores are crucial for iron-scavenging in microorganisms. While many yeasts can uptake siderophores produced by other organisms, they are typically unable to synthesize siderophores themselves. In contrast, Wickerhamiella/Starmerella (W/S) clade yeasts gained the capacity to make the siderophore enterobactin following the remarkable horizontal acquisition of a bacterial operon enabling enterobactin synthesis. Yet, how these yeasts absorb the iron bound by enterobactin remains unresolved. Here, we demonstrate that Enb1 is the key enterobactin importer in the W/S-clade species Starmerella bombicola. Through phylogenomic analyses, we show that ENB1 is present in all W/S clade yeast species that retained the enterobactin biosynthetic genes. Conversely, it is absent in species that lost the ent genes, except for Starmerella stellata, making this species the only cheater in the W/S clade that can utilize enterobactin without producing it. Through phylogenetic analyses, we infer that ENB1 is a fungal gene that likely existed in the W/S clade prior to the acquisition of the ent genes and subsequently experienced multiple gene losses and duplications. Through phylogenetic topology tests, we show that ENB1 likely underwent horizontal gene transfer from an ancient W/S clade yeast to the order Saccharomycetales, which includes the model yeast Saccharomyces cerevisiae, followed by extensive secondary losses. Taken together, these results suggest that the fungal ENB1 and bacterial ent genes were cooperatively integrated into a functional unit within the W/S clade that enabled adaptation to iron-limited environments. This integrated fungal-bacterial circuit and its dynamic evolution determine the extant distribution of yeast enterobactin producers and cheaters.
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Enterobactina , Evolución Molecular , Operón , Filogenia , Enterobactina/metabolismo , Enterobactina/genética , Sideróforos/metabolismo , Sideróforos/genética , Genes Fúngicos , Saccharomycetales/genética , Saccharomycetales/metabolismo , Transferencia de Gen HorizontalRESUMEN
Maximum likelihood (ML) phylogenetic inference is widely used in phylogenomics. As heuristic searches most likely find suboptimal trees, it is recommended to conduct multiple (e.g., ten) tree searches in phylogenetic analyses. However, beyond its positive role, how and to what extent multiple tree searches aid ML phylogenetic inference remains poorly explored. Here, we found that a random starting tree was not as effective as the BioNJ and parsimony starting trees in inferring ML gene tree and that RAxML-NG and PhyML were less sensitive to different starting trees than IQ-TREE. We then examined the effect of the number of tree searches on ML tree inference with IQ-TREE and RAxML-NG, by running 100 tree searches on 19,414 gene alignments from 15 animal, plant, and fungal phylogenomic datasets. We found that the number of tree searches substantially impacted the recovery of the best-of-100 ML gene tree topology among 100 searches for a given ML program. In addition, all of the concatenation-based trees were topologically identical if the number of tree searches was ≥ 10. Quartet-based ASTRAL trees inferred from 1 to 80 tree searches differed topologically from those inferred from 100 tree searches for 6 /15 phylogenomic datasets. Lastly, our simulations showed that gene alignments with lower difficulty scores had a higher chance of finding the best-of-100 gene tree topology and were more likely to yield the correct trees.
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Molecular evolution studies, such as phylogenomic studies and genome-wide surveys of selection, often rely on gene families of single-copy orthologs (SC-OGs). Large gene families with multiple homologs in 1 or more species-a phenomenon observed among several important families of genes such as transporters and transcription factors-are often ignored because identifying and retrieving SC-OGs nested within them is challenging. To address this issue and increase the number of markers used in molecular evolution studies, we developed OrthoSNAP, a software that uses a phylogenetic framework to simultaneously split gene families into SC-OGs and prune species-specific inparalogs. We term SC-OGs identified by OrthoSNAP as SNAP-OGs because they are identified using a splitting and pruning procedure analogous to snapping branches on a tree. From 415,129 orthologous groups of genes inferred across 7 eukaryotic phylogenomic datasets, we identified 9,821 SC-OGs; using OrthoSNAP on the remaining 405,308 orthologous groups of genes, we identified an additional 10,704 SNAP-OGs. Comparison of SNAP-OGs and SC-OGs revealed that their phylogenetic information content was similar, even in complex datasets that contain a whole-genome duplication, complex patterns of duplication and loss, transcriptome data where each gene typically has multiple transcripts, and contentious branches in the tree of life. OrthoSNAP is useful for increasing the number of markers used in molecular evolution data matrices, a critical step for robustly inferring and exploring the tree of life.
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Algoritmos , Evolución Molecular , Filogenia , Linaje , Factores de TranscripciónRESUMEN
Tethered nonplanar aromatics (TNAs) make up an important class of nonplanar aromatic compounds showing unique features. However, the knowledge on the synthesis, structures, and properties of TNAs remains insufficient. In this work, a new type of TNAs, the tethered aromatic lactams, is synthesized via Pd-catalyzed consecutive intramolecular direct arylations. These molecules possess a helical ladder-type conjugated system of up to 13 fused rings. The overall yields ranged from 3.4 to 4.3%. The largest of the tethered aromatic lactams, 6L-Bu-C14, demonstrates a guest-adaptive hosting capability of TNAs for the first time. When binding fullerene guests, the cavity of 6L-Bu-C14 became more circular to better accommodate spherical fullerene molecules. The host-guest interaction is thoroughly studied by X-ray crystallography, theoretical calculations, fluorescence titration, and nuclear magnetic resonance (NMR) titration experiments. 6L-Bu-C14 shows stronger binding with C70 than with C60 due to the better convex-concave π-π interaction. P and M enantiomers of all tethered aromatic lactams show distinct and persistent chiroptical properties and demonstrate the potential of chiral TNAs as circularly polarized luminescence (CPL) emitters.
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Eukaryotes have evolved sophisticated post-translational modifications to regulate protein function and numerous biological processes, including ubiquitination controlled by the coordinated action of ubiquitin-conjugating enzymes and deubiquitinating enzymes (Dubs). However, the function of deubiquitination in pathogenic fungi is largely unknown. Here, the distribution of Dubs in the fungal kingdom was surveyed and their functions were systematically characterized using the phytopathogen Fusarium graminearum as the model species, which causes devastating diseases of all cereal species world-wide. Our findings demonstrate that Dubs are critical for fungal development and virulence, especially the ubiquitin-specific protease 15 (Ubp15). Global ubiquitome analysis and subsequent experiments identified three important substrates of Ubp15, including the autophagy-related protein Atg8, the mitogen-activated protein kinase Gpmk1, and the mycotoxin deoxynivalenol (DON) biosynthetic protein Tri4. Ubp15 regulates the deubiquitination of the Atg8, thereby impacting its subcellular localization and the autophagy process. Moreover, Ubp15 also modulates the deubiquitination of Gpmk1 and Tri4. This modulation subsequently influences their protein stabilities and further affects the formation of penetration structures and the biosynthetic process of DON, respectively. Collectively, our findings reveal a previously unknown regulatory pathway of a deubiquitinating enzyme for fungal virulence and highlight the potential of Ubp15 as a target for combating fungal diseases.
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Fusarium , Micotoxinas , Virulencia , Proteínas Fúngicas/metabolismo , Micotoxinas/metabolismo , Enzimas Desubicuitinizantes/metabolismo , Enfermedades de las Plantas/microbiologíaRESUMEN
Phylogenomic analyses of hundreds of protein-coding genes aimed at resolving phylogenetic relationships is now a common practice. However, no software currently exists that includes tools for dataset construction and subsequent analysis with diverse validation strategies to assess robustness. Furthermore, there are no publicly available high-quality curated databases designed to assess deep (>100 million years) relationships in the tree of eukaryotes. To address these issues, we developed an easy-to-use software package, PhyloFisher (https://github.com/TheBrownLab/PhyloFisher), written in Python 3. PhyloFisher includes a manually curated database of 240 protein-coding genes from 304 eukaryotic taxa covering known eukaryotic diversity, a novel tool for ortholog selection, and utilities that will perform diverse analyses required by state-of-the-art phylogenomic investigations. Through phylogenetic reconstructions of the tree of eukaryotes and of the Saccharomycetaceae clade of budding yeasts, we demonstrate the utility of the PhyloFisher workflow and the provided starting database to address phylogenetic questions across a large range of evolutionary time points for diverse groups of organisms. We also demonstrate that undetected paralogy can remain in phylogenomic "single-copy orthogroup" datasets constructed using widely accepted methods such as all vs. all BLAST searches followed by Markov Cluster Algorithm (MCL) clustering and application of automated tree pruning algorithms. Finally, we show how the PhyloFisher workflow helps detect inadvertent paralog inclusions, allowing the user to make more informed decisions regarding orthology assignments, leading to a more accurate final dataset.
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Eucariontes/genética , Filogenia , Programas InformáticosRESUMEN
The limited exciton lifetime (τ, generally <1â ns) leads to short exciton diffusion length (LD ) of organic semiconductors, which is the bottleneck issue impeding the further improvement of power conversion efficiencies (PCEs) for organic solar cells (OSCs). However, efficient strategies to prolong intrinsic τ are rare and vague. Herein, we propose a facile method to efficiently reduce vibrational frequency of molecular skeleton and suppress exciton-vibration coupling to decrease non-radiative decay rate and thus prolong τ via deuterating nonfullerene acceptors. The τ remarkably increases from 0.90â ns (non-deuterated L8-BO) to 1.35â ns (deuterated L8-BO-D), which is the record for organic photovoltaic materials. Besides, the inhibited molecular vibration improves molecular planarity of L8-BO-D for enhanced exciton diffusion coefficient. Consequently, the LD increases from 7.9â nm (L8-BO) to 10.7â nm (L8-BO-D). The prolonged LD of L8-BO-D enables PM6 : L8-BO-D-based bulk heterojunction OSCs to acquire higher PCEs of 18.5 % with more efficient exciton dissociation and weaker charge carrier recombination than PM6 : L8-BO-based counterparts. Moreover, benefiting from the prolonged LD , D18/L8-BO-D-based pseudo-planar heterojunction OSCs achieve an impressive PCE of 19.3 %, which is among the highest values. This work provides an efficient strategy to increase the τ and thus LD of organic semiconductors, boosting PCEs of OSCs.
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Peroxisomes are universal eukaryotic organelles essential to plants and animals. Most peroxisomal matrix proteins carry peroxisome targeting signal type 1 (PTS1), a C-terminal tripeptide. Studies from various kingdoms have revealed influences from sequence upstream of the tripeptide on peroxisome targeting, supporting the view that positive charges in the upstream region are the major enhancing elements. However, a systematic approach to better define the upstream elements influencing PTS1 targeting capability is needed. Here, we used protein sequences from 177 plant genomes to perform large-scale and in-depth analysis of the PTS1 domain, which includes the PTS1 tripeptide and upstream sequence elements. We identified and verified 12 low-frequency PTS1 tripeptides and revealed upstream enhancing and inhibiting sequence patterns for peroxisome targeting, which were subsequently validated in vivo. Follow-up analysis revealed that nonpolar and acidic residues have relatively strong enhancing and inhibiting effects, respectively, on peroxisome targeting. However, in contrast to the previous understanding, positive charges alone do not show the anticipated enhancing effect and that both the position and property of the residues within these patterns are important for peroxisome targeting. We further demonstrated that the three residues immediately upstream of the tripeptide are the core influencers, with a 'basic-nonpolar-basic' pattern serving as a strong and universal enhancing pattern for peroxisome targeting. These findings have significantly advanced our knowledge of the PTS1 domain in plants and likely other eukaryotic species as well. The principles and strategies employed in the present study may also be applied to deciphering auxiliary targeting signals for other organelles.
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Señales de Direccionamiento al Peroxisoma , Señales de Clasificación de Proteína , Secuencia de Aminoácidos , Animales , Peroxisomas/metabolismo , PlantasRESUMEN
As the most diverse group of animals on Earth, insects are key organisms in ecosystems. Horizontal gene transfer (HGT) refers to the transfer of genetic material between species by non-reproductive means. HGT is a major evolutionary force in prokaryotic genome evolution, but its importance in different eukaryotic groups, such as insects, has only recently begun to be understood. Genomic data from hundreds of insect species have enabled the detection of large numbers of HGT events and the elucidation of the functions of some of these foreign genes. Although quantification of the extent of HGT in insects broadens our understanding of its role in insect evolution, the scope of its influence and underlying mechanism(s) of its occurrence remain open questions for the field.
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Evolución Molecular , Transferencia de Gen Horizontal , Animales , Ecosistema , Células Procariotas , Insectos , Genoma de los Insectos , FilogeniaRESUMEN
Highly divergent sites in multiple sequence alignments (MSAs), which can stem from erroneous inference of homology and saturation of substitutions, are thought to negatively impact phylogenetic inference. Thus, several different trimming strategies have been developed for identifying and removing these sites prior to phylogenetic inference. However, a recent study reported that doing so can worsen inference, underscoring the need for alternative alignment trimming strategies. Here, we introduce ClipKIT, an alignment trimming software that, rather than identifying and removing putatively phylogenetically uninformative sites, instead aims to identify and retain parsimony-informative sites, which are known to be phylogenetically informative. To test the efficacy of ClipKIT, we examined the accuracy and support of phylogenies inferred from 14 different alignment trimming strategies, including those implemented in ClipKIT, across nearly 140,000 alignments from a broad sampling of evolutionary histories. Phylogenies inferred from ClipKIT-trimmed alignments are accurate, robust, and time saving. Furthermore, ClipKIT consistently outperformed other trimming methods across diverse datasets, suggesting that strategies based on identifying and retaining parsimony-informative sites provide a robust framework for alignment trimming.
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Alineación de Secuencia/métodos , Análisis de Secuencia de ADN/métodos , Algoritmos , Simulación por Computador , Evolución Molecular , Modelos Genéticos , Filogenia , Programas InformáticosRESUMEN
Neoneuromus ignobilis is an archaic holometabolous aquatic predatory insect. However, a lack of genomic resources hinders the use of whole genome sequencing to explore their genetic basis and molecular mechanisms for adaptive evolution. Here, we provided a high-contiguity, chromosome-level genome assembly of N. ignobilis using high coverage Nanopore and PacBio reads with the Hi-C technique. The final assembly is 480.67 MB in size, containing 12 telomere-ended pseudochromosomes with only 17 gaps. We compared 42 hexapod species genomes including six independent lineages comprising 11 aquatic insects, and found convergent expansions of long wavelength-sensitive and blue-sensitive opsins, thermal stress response TRP channels, and sulfotransferases in aquatic insects, which may be related to their aquatic adaptation. We also detected strong nonrandom signals of convergent amino acid substitutions in aquatic insects. Collectively, our comparative genomic analysis revealed the evidence of molecular convergences in aquatic insects during both gene family evolution and convergent amino acid substitutions.
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Genoma , Insectos , Animales , Insectos/genética , Opsinas/genética , Filogenia , Sulfotransferasas/genéticaRESUMEN
Identifying our most distant animal relatives has emerged as one of the most challenging problems in phylogenetics. This debate has major implications for our understanding of the origin of multicellular animals and of the earliest events in animal evolution, including the origin of the nervous system. Some analyses identify sponges as our most distant animal relatives (Porifera-sister hypothesis), and others identify comb jellies (Ctenophora-sister hypothesis). These analyses vary in many respects, making it difficult to interpret previous tests of these hypotheses. To gain insight into why different studies yield different results, an important next step in the ongoing debate, we systematically test these hypotheses by synthesizing 15 previous phylogenomic studies and performing new standardized analyses under consistent conditions with additional models. We find that Ctenophora-sister is recovered across the full range of examined conditions, and Porifera-sister is recovered in some analyses under narrow conditions when most outgroups are excluded and site-heterogeneous CAT models are used. We additionally find that the number of categories in site-heterogeneous models is sufficient to explain the Porifera-sister results. Furthermore, our cross-validation analyses show CAT models that recover Porifera-sister have hundreds of additional categories and fail to fit significantly better than site-heterogenuous models with far fewer categories. Systematic and standardized testing of diverse phylogenetic models suggests that we should be skeptical of Porifera-sister results both because they are recovered under such narrow conditions and because the models in these conditions fit the data no better than other models that recover Ctenophora-sister.
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Ctenóforos , Animales , FilogeniaRESUMEN
DNA glycosylases preserve genome integrity and define the specificity of the base excision repair pathway for discreet, detrimental modifications, and thus, the mechanisms by which glycosylases locate DNA damage are of particular interest. Bacterial AlkC and AlkD are specific for cationic alkylated nucleobases and have a distinctive HEAT-like repeat (HLR) fold. AlkD uses a unique non-base-flipping mechanism that enables excision of bulky lesions more commonly associated with nucleotide excision repair. In contrast, AlkC has a much narrower specificity for small lesions, principally N3-methyladenine (3mA). Here, we describe how AlkC selects for and excises 3mA using a non-base-flipping strategy distinct from that of AlkD. A crystal structure resembling a catalytic intermediate complex shows how AlkC uses unique HLR and immunoglobulin-like domains to induce a sharp kink in the DNA, exposing the damaged nucleobase to active site residues that project into the DNA This active site can accommodate and excise N3-methylcytosine (3mC) and N1-methyladenine (1mA), which are also repaired by AlkB-catalyzed oxidative demethylation, providing a potential alternative mechanism for repair of these lesions in bacteria.