Biology subjects

Gabaldon, T.

Publications and source records attributed to Gabaldon, T..

At least 19 recordsLinked to original sources

bioRxiv2026

Ancient whole genomes reveal regional selection during adaptation to Neolithic lifestyle in Western Eurasia

The introduction of agriculture in Western Eurasia during the Mesolithic-Neolithic transition reshaped human lifestyle, demography and pathogen exposure. Yet, the associated selective pressures remain incompletely resolved because previous ancient DNA studies relied on targeted SNP panels and yielded non-overlapping results. Here, using high-coverage whole-genome data from 152 ancient individuals, including 12 newly sequenced genomes from the Iron Gates, we show that adaptation during this transition was geographically structured and involved selection of both Early Farmer and Hunter-Gatherer alleles. By combining scans of population differentiation, extended haplotype homozygosity, and adaptive admixture, we identify candidate loci under selection in ancestral and admixed populations. Extending the analysis beyond SNPs, we also detect differential copy-number variants, ancestry-associated shifts in transposable-element abundance, and an early Neolithic hepatitis B infection. Functional analyses including effects on gene expression suggested selection on immune, metabolic, reproductive, sensory, and behavioural processes. Taken together, our results reveal a broader and more regionally variable adaptive landscape than previously appreciated.

evolutionary biology↗

bioRxiv2026

Reversible haploidisation and convergent genomic routes to antifungal resistance in the Candida parapsilosis species complex

Antifungal resistance is rising among non-albicans Candida, with outbreaks increasingly linked to drug-resistant Candida parapsilosis. Using large-scale experimental evolution under fluconazole and anidulafungin, coupled to phenotyping and genome sequencing, we define resistance strategies across C. parapsilosis, Candida metapsilosis and Candida orthopsilosis. Despite diverse genetic backgrounds, adaptation repeatedly converged on a shared genomic toolkit that combines protein-altering mutations in key regulators and drug targets (including MRR1 and FKS1) with copy-number changes, aneuploidy, as well as loss of heterozygosity driving resistance alleles to homozygosity. Strikingly, drug selection triggered recurrent but reversible haploidisation in C. orthopsilosis, revealing ploidy reduction as a transient, selectable survival strategy. Resistance, particularly after fluconazole selection, imposed fitness costs that promoted compensatory evolution and resistance loss after drug withdrawal. Together, antifungal adaptation in this complex affects convergent targets, while being plastic in its genomic routes, with implications for resistance surveillance and drug cycling therapies.

microbiology↗

bioRxiv2026

Dissection of genotype-phenotype relationships in Candida parapsilosis uncovers drivers of clinically-relevant traits

Hospital outbreaks caused by the fungal pathogen Candida parapsilosis are of growing concern due to their increased drug resistance and high mortality rates. However, the genetic bases of clinically-relevant traits in this species remain poorly explored. Here, we mapped genotype-phenotype relationships across 189 isolates from a multi-hospital Candida parapsilosis outbreak, for which we measured 61 diverse clinical phenotypes and generated complete genome sequences. As variation in previously-known genes explained little of the observed phenotypic diversity, we leveraged convergence genome-wide association studies and interpretable machine-learning models that predict phenotypes from genetic variants. These approaches identified candidate drivers of virulence and antifungal resistance, confirming expected mechanisms while uncovering novel ones. Predictive models were accurate for key traits, including azole resistance and clinical features of infected patients. Our results shed light on the genetic bases of clinically-relevant traits in a major fungal pathogen, and pave the way towards sequence-based diagnostics for improved patient outcomes.

microbiology↗

bioRxiv2026

Host retargeting predominated over gene transfer during early chromatophore integration in Paulinella micropora

The relative contributions of gene acquisition and protein retargeting to early organellogenesis remain debated. We addressed this question for the recently evolved chromatophore of Paulinella micropora, which provides a unique window into the initial stages of primary organelle integration. Using a stringent phylogenomic pipeline, we identified 282 P. micropora gene families whose origin can be attributed to horizontal gene transfer (HGT) with high confidence, including 115 for which we could confidently assess the donor lineages. In addition to the expected cyanobacterial signal from the chromatophore ancestor, we detected recurrent contributions from Gammaproteobacteria, Bacteroidota, Actinobacteriota, and Chlamydiota. Relative stem-length analyses indicate that these donors contributed in temporally structured periods (waves), with several non-cyanobacterial signals older than the median cyanobacterial signal and others clearly more recent. HGT-derived genes are enriched in transport and metabolic functions, which might have been relevant to host-symbiont interaction. However, based on computational predictions, the chromatophore-targeted proteome is dominated by vertically inherited host genes with only 36 of 287 predicted chromatophore-targeted nucleus-encoded proteins being of HGT origin, the majority of which are absent in Paulinella chromatophora, suggesting a recent origin in P. microporalineage. Thus, although repeated horizontal acquisition from multiple bacterial partners shaped the nuclear genome of P. micropora, early chromatophore integration appears to have been dominated by host-derived retargeting, with HGT providing a smaller but detectable complementary contribution. These results support a mixed model of organellogenesis in which targeting and gene transfer act together, but with host retargeting playing the dominant early role.

evolutionary biology↗

bioRxiv2026

PanTEon: a cross-kingdom framework to guide the design of transposable element classifiers

Transposable elements (TEs) are major drivers of genome evolution, yet their annotation and classification remain inconsistent and hard to reproduce across species. Fragmented repeats, lineage-specific innovations, and heterogeneous taxonomies across databases and tools complicate comparisons and slow progress in TE biology. To address this, we developed PanTEon, a cross-kingdom deep learning framework for reproducible TE classification that combines a harmonized database with an open, modular benchmarking platform. The PanTEon Database is an automatically curated, taxonomically broad TE repository spanning animals, plants, and fungi. The PanTEon platform standardizes training, evaluation, and inference across nine Machine Learning methods, while remaining extensible to user-defined architectures. Using this framework, we benchmark state-of-the-art Machine Learning-based TE classifiers across TE superfamilies and major eukaryotic lineages and find that performance varies markedly by kingdom and superfamily. Ensemble approaches and phylum-specific models improve predictive F1 scores, but cross-species generalization remains a major challenge. Together, PanTEon Database and PanTEon platform provide a reproducible, scalable, and extensible foundation for TE classification, enabling standardized evaluation of future AI methods and supporting community-driven annotation efforts.

bioinformatics↗

bioRxiv2026

Evolutionary dynamics of temporal transcription factor series in the insect optic lobe

The nervous system consists of a wide variety of neuronal cell types arranged into complex circuits that support a broad range of behaviors. Patterning of neural stem cells in time through the sequential expression of series of temporal transcription factors is a key contributor to the generation of neuronal diversity. How do temporal series arise and diversify across species to support the evolution of neuronal type? Here, we reconstruct the evolutionary history of the temporal series in the visual brain of insects, spanning 400 million years of evolution; we identify a conserved temporal ground plan, as well as species-specific variations. We find that temporal programs evolve through recurrent modifications of a shared scaffold. Finally, we show that such evolutionary changes in temporal patterning can result in different neuronal type identities. Together, our results reveal both the deep conservation and evolutionary plasticity of temporal patterning programs, and establish temporal transcription factor series as a tractable substrate for the evolution of neuronal diversity.

developmental biology↗

bioRxiv2025

High genomic and phenotypic diversity among Candida dubliniensis isolates from the oral cavity of persons living with HIV

The opportunistic yeast pathogen Candida dubliniensis is frequently misidentified as its closest relative Candida albicans, due to their high phenotypic similarity. Although Candida dubliniensis is an important cause of fungal infections, especially in the oral cavities of immunocompromised patients, its phenotypic and genomic variability remains poorly understood. We addressed this knowledge gap by performing a comprehensive phenotypic and genomic characterization of 33 C. dubliniensis oral isolates from people living with HIV in Argentina. Our results uncovered significant phenotypic heterogeneity--observed both inter- and intra-patient--impacting clinically relevant traits such as drug susceptibility, stress sensitivity, filamentation, and hypoxic growth. Our isolates expanded the previously known MLST-based genetic diversity of the species. Leveraging whole-genome sequencing, we resolved intricate evolutionary relationships, proposed a more robust MLST scheme for future typing, and identified potential antifungal resistance-causing variants. Collectively, this work represents the most comprehensive population genomics characterization of C. dubliniensis to date, establishing a foundation for improved surveillance and diagnostic strategies to fully define its role in both oral and systemic infections. Author SummaryIn this study we uncover hidden genetic and morphological diversity in Candida dubliniensis, a poorly known opportunistic yeast pathogen related to Candida albicans, by characterising a collection of oral isolates from persons living with HIV in Argentina. Our findings provide the most detailed genetic and phenotypic snapshot of this pathogen to date, providing a much-needed foundation to develop better diagnostic tools and effective surveillance strategies to address infections caused by this overlooked threat.

microbiology↗

bioRxiv2025

Genome-wide Discovery of lncRNAs in Mucorales Reveals Essential Roles in Development and Fungal Biology

Long non-coding RNAs (lncRNAs) emerged as key regulators across eukaryotes, yet their functions in early-diverging fungal (EDF) pathogens remain largely unknown. Here, we provide the first comprehensive identification and characterization of lncRNAs in the EDF order Mucorales, a threatening and WHO high-priority group of opportunistic human pathogens. In this work, we focus on the two major models of this group: Mucor lusitanicus and the clinically relevant pathogen Rhizopus microsporus. We show that EDF lncRNAs exhibit conserved features, dynamic regulation during host interactions, and integration within critical gene regulatory networks. Despite lncRNAs being preferentially encoded in inactive chromatin compartments, we found that their expression is associated with 6mA presence in R. microsporus. Additionally, we also found that lncRNAs can be targeted by both the canonical RNA interference pathway and the non-canonical RNA interference mechanism. Comparative genomics revealed a subset of evolutionarily conserved lncRNAs, including two essential for fungal viability (lncRNA2 and lncRNA4). LncRNA4 disruption, even in heterokaryosis, resulted in severely affected growth and filamentation. These results establish lncRNAs as indispensable regulators of fungal physiology and pathogenicity, highlighting their potential as novel antifungal targets.

genetics↗

bioRxiv2025

Phylogenomics of Asgard archaea reveals a unique blend of prokaryotic-like horizontal transfer and eukaryotic-like gene duplication.

Asgard archaea hold a pivotal position in the tree of life as the closest known relatives to eukaryotes and are therefore crucial for understanding eukaryogenesis. Earlier genomic analyses revealed that Asgard genomes are remarkably larger than those of other archaea and contain a significant number of genes seemingly acquired from bacteria. However, the precise contributions of horizontal gene transfer and gene duplication in shaping Asgard genomes remain largely unknown. Here, we present a comprehensive phylogenomic analysis to dissect the evolutionary dynamics of Asgard genomes, quantifying gene duplication, loss, and both inter- and intra-domain gene transfer events. Our findings reveal that gene transfer is widespread throughout Asgard evolution, predominantly affecting metabolic genes at the periphery of interaction networks. However, our analyses demonstrate that gene duplications, rather than horizontal gene transfers, are the primary drivers behind the increased genome sizes observed in Asgard archaea. This unique evolutionary signature in Asgard archaea--a blend of pervasive prokaryotic-like gene transfer alongside significant eukaryotic-like gene duplication--is consistent with their phylogenetic placement and offers novel insights into the genomic transitions that likely underpinned eukaryogenesis.

evolutionary biology↗

bioRxiv2025

Molecular dynamics reveals a novel Regulatory Ca+2-Binding Site in the Mitochondrial Calcium Uniporter

The mitochondrial Ca{superscript 2} uniporter (MCU) channel is essential for energy production, cytosolic Ca{superscript 2} signalling, and regulation of cell death. Its activity is regulated by the core proteins MICU1 and MICU2, which respond to intracellular Ca{superscript 2} levels. In cardiomyocytes, MICU1 inhibits mtMCU activity at basal Ca{superscript 2}, with Ca{superscript 2}-binding relieving this inhibition via a conformational change. However, the precise molecular basis for this dual regulation is unclear. While twelve MICU1 structures exist, each is approximately 30% of their structure missing, omitting key flexible regions and limits the understanding of the Ca{superscript 2}-sensing mechanism. Here, we provide structural and computational evidence to address this gap. Using structural modelling, molecular dynamics simulations, and large-scale sequence analysis, we investigate MICU1s Ca{superscript 2} binding sites from both conformational and evolutionary perspectives. Simulations based on human MICU1 models revealed a previously uncharacterized pseudo-EF-hand (pEF-h) motif. Our findings indicate that this motif functions as an early Ca{superscript 2} sensor, triggering conformational transitions, including shifts in surface charge distribution and isoelectric point, that prime the canonical EF-hand sites for subsequent binding. This hierarchical activation mechanism refines MICU1s on-off regulation of the MCU. To link this mechanism to experimental observations, we simulated a series of point and double mutants targeting the pEF-h, EF-h1, and EF-h2 sites. Our simulations demonstrate that double mutants disrupt Ca{superscript 2} binding not only within the mutated site but also reduce the occupation of the other sites, reaffirming the cooperative nature of Ca{superscript 2} sensing in MICU1. The biological relevance of the EF-hand motifs would be supported by its evolutionary conservation. Therefore, we analysed the evolutionary shaping of MICU1 EF-hand motifs across major eukaryotic lineages using clustering analysis and found strong lineage-specific segregation: canonical DXN/DXD-type motifs predominated in EF-h1 and EF-h2 in plants and protists, while non-canonical EXE(X)DEG(X)E motifs were exclusive to Opisthokonts, coinciding with the emergence of the auxiliary subunit EMRE. This pattern suggests that high-affinity Ca{superscript 2} binding evolved in parallel with increasing regulatory complexity in metazoans. Together, these findings support previous research linking EF-hand function as sensors to specialised Ca{superscript 2} gatekeepers in multicellular lineages. By integrating structural and evolutionary perspectives, our study provides mechanistic insight into how MICU1 can act as a Ca{superscript 2}-dependent molecular switch, clarifying the cooperative and threshold-setting behaviour underlying its regulatory role in mitochondrial Ca{superscript 2} uptake. HighlightsO_LIThe hierarchical activation mechanism refines MICU1s on-off regulation of the MCU. C_LIO_LIA novel Ca{superscript 2}-binding site in human MICU1, featuring a unique helix-loop-{beta}-sheet structure, was identified and functionally characterized. C_LIO_LIThis new Ca{superscript 2}-binding site in MICU1 acts as an early sensor, triggering structural changes key to its regulatory function. C_LIO_LICa{superscript 2}-binding motif distributions and phylogenetic constraints indicate possible functional divergence. C_LI

bioinformatics↗

bioRxiv2025

Epistasis at the cell surface: what is the role of Erg3 loss-of-function in acquired echinocandin resistance?

Echinocandins, which target the fungal {beta}-1,3-glucan synthase (Fks), are essential for treating invasive fungal infections, yet resistance is increasingly reported. While resistance typically arises through mutations in Fks hotspots, emerging evidence suggests a contributing role of changes in membrane sterol composition due to ERG3 mutations. Here, we present a clinical case of Nakaseomyces glabratus (Candida glabrata) in which combined mutations in ERG3 and FKS2, but not FKS2 alone, appear to confer echinocandin resistance. Integrated analyses reveal a recurrent association between Erg3 loss-of-function and echinocandin resistance mediated by Fks variation across Candida species, but exclude ERG3 loss-of-function as an independent resistance mechanism. Advances in Fks structural biology and insights into echinocandin-Fks interactions support a model of epistatic crosstalk between membrane sterols and Fks function. Understanding this interaction is crucial, as it may underlie not only acquired echinocandin resistance but also the broader development of multidrug resistance across major antifungal drug classes.

molecular biology↗

bioRxiv2025

The Multiomics Blueprint of Extreme Human Lifespan

The indexed individual, from now on termed M116, was the worlds oldest verified living person from January 17th 2023 until her passing on August 19th 2024, reaching the age of 117 years and 168 days (https://www.supercentenarian.com/records.html). She was a Caucasian woman born on March 4th 1907 in San Francisco, USA, from Spanish parents and settled in Spain since she was 8. A timeline of her life events and her genealogical tree are shown in Supplementary Fig. 1a-b. Although centenarians are becoming more common in the demographics of human populations, the so-called supercentenarians (over 110 years old) are still a rarity. In Catalonia, the historic nation where M116 lived, the life-expectancy for women is 86 years, so she exceeded the average by more than 30 years (https://www.idescat.cat). In a similar manner to premature aging syndromes, such as Hutchinson-Gilford Progeria and Werner syndrome, which can provide relevant clues about the mechanisms of aging, the study of supercentenarians might also shed light on the pathways involved in lifespan. To unfold the biological properties exhibited by such a remarkable human being, we developed a comprehensive multiomics analysis of her genomic, transcriptomic, metabolomic, proteomic, microbiomic and epigenomic landscapes in different tissues, as depicted in Fig. 1a, comparing the results with those observed in non-supercentenarian populations. The picture that emerges from our study shows that extremely advanced age and poor health are not intrinsically linked and that both processes can be distinguished and dissected at the molecular level. O_FIG O_LINKSMALLFIG WIDTH=156 HEIGHT=200 SRC="FIGDIR/small/639740v1_fig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@1705be6org.highwire.dtl.DTLVardef@1a16e4borg.highwire.dtl.DTLVardef@15005f1org.highwire.dtl.DTLVardef@b6297b_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFig. 1C_FLOATNO Chromosomes and genes.a, Schematic representation of all -omics studied in the supercentenarian. b, Telomeres marked with Cy3 (yellow) in nuclei stained with DAPI (blue) observed in HT-qFISH from M116 and younger womens PBMCs. Scale bars: 20 {micro}m. c, Telomere length (Kb) calculation (left) and percentage of extremely short telomeres (below the 20th percentile) (right) in M116 (orange) using standard curve from samples previously analyzed (black) and control women (blue) (Online Methods). d, Circos plot with chromosomal alterations detected through optical genome mapping in supercentenarian. e, Variants of interest (VOI)-harboring genes found in supercentenarians genomic DNA contributing to immune function, cardiovascular health, neuroprotection, metabolism, and DNA dynamics. f, Significantly enriched functions of VOI-harboring genes in the supercentenarian. g, VOI-harbouring genes significantly contributing to enriched functions. h, VOI-harboring genes found in supercentenarians genomic and mitochondrial DNA contributing to mitochondrial function. i, Mean fluorescence intensity of TMRE (a marker of mitochondrial membrane potential) and SOX (a marker of mitochondrial superoxide ion) in PBMCs from the supercentenarian (orange) and healthy controls across various ages (gray). Unpaired t-test was used to statistically compare M116 to the mean of all control women. *p < 0.05. C_FIG

genomics↗

bioRxiv2025

Survival of the unfittest: clinical emergence of hyper-multidrug-resistant Nakaseomyces glabratus with rare nonfunctional Erg3 and Erg11 and severely impaired fitness.

BackgroundNakaseomyces glabratus (Candida gabrata) poses a significant clinical challenge due to common drug resistance. We report a case of a complicated urinary tract infection (UTI) progressing to prostatitis and urosepsis, with the emergence of a hyper-multidrug-resistant isolate with low stress tolerance, slow growth and a short life span. This study elucidates the genetic mechanisms and phenotypic characteristics underlying antifungal hyper-resistance with strong fitness trade-offs, and explores potential alternative therapies for resistant UTIs. MethodsWhole-genome sequencing was performed to identify resistance-associated mutations and gene knock-out strains were generated to assess the relative impact of putative loss-of-function (LoF) mutations on antifungal resistance, fitness and membrane sterol composition. Drug susceptibility testing of the antibiotic nitroxoline and related compounds was conducted to evaluate it as a therapeutic alternative and study the mechanism of action. FindingsLoss-of-function mutations in ERG3 and ERG11 were identified and linked to the accumulation of 4,14-dimethylzymosterol and lanosterol instead of ergosterol. Engineered ERG3{Delta}+ERG11{Delta} strains recapitulated the clinical isolates hyper-multidrug resistance and associated fitness deficits. While ERG3{Delta} strains showed no resistance but enhanced thermotolerance, ERG11{Delta} and ERG3{Delta}+ERG11{Delta} strains exhibited multidrug resistance with severe fitness trade-offs. Interestingly, ERG3{Delta}+ERG11{Delta} strains showed mild resistance to flucytosine, but an additional FUR1 mutation in the clinical isolate most probably underlies hyper-resistance to flucytosine. The UTI antibiotic nitroxoline demonstrated high antifungal activity against all strains, and the LoF of ERG3 and/or ERG11 induced collateral sensitivity to this drug. Testing of related compounds suggest a mode of action beyond iron chelation. InterpretationThis case demonstrates that hyper-resistant strains of N. glabratus can emerge despite significant fitness costs and persist under prolonged antifungal therapy in specific clinical settings. These findings underscore the importance of vigilant antifungal resistance monitoring and highlight nitroxoline as a promising alternative treatment for complicated fungal UTIs. These results challenge the notion that strains with fitness deficits are clinically irrelevant and emphasize the need for novel therapeutic strategies including repurposed agents.

microbiology↗

bioRxiv2024

Diverse ancestries reveal complex symbiotic interactions during eukaryogenesis

Summary paragraphThe origin of eukaryotes remains a central enigma in biology1. Ongoing debates agree on the pivotal role of a symbiosis between an alphaproteobacterium and an Asgard archaeon2,3. However, the nature, timing and contributions of other potential bacterial partners4-6 or the role of interactions with viruses7-9 remain contentious. To address these questions, we employed advanced phylogenomic approaches and comprehensive datasets spanning the known diversity of cellular life and viruses. Our analysis provided an updated reconstruction of the last eukaryotic common ancestor (LECA) proteome, in which we traced the phylogenetic origin of each protein family. We found compelling evidence for multiple waves of horizontal gene transfer from diverse bacterial donors, with some likely preceding the mitochondrial endosymbiosis. We inferred plausible traits of the major donors and their functional contributions to LECA. Our findings underscore the contribution of horizontal gene transfers in shaping the proteomes of pre-LECA ancestors and hint to a facilitating role of Nucleocytoviricota viruses. Altogether, our results suggest that ancient eukaryotes originated within complex microbial ecosystems through a succession of diverse associations that left a footprint of horizontally transferred genes.

evolutionary biology↗

bioRxiv2024

Phylogeny-aware simulations suggest a low impact of unsampled lineages in the inference of gene flow during eukaryogenesis

Gene phylogenies are broadly used to analyse events of horizontal gene transfer, namely, their presence, the potential donor and acceptor lineages, and their relative timing. Recent phylogenomics analyses have reconstructed a relative chronology of gene acquisitions in the lineage leading to the eukaryotes, revealing waves of acquisition from different donors before and after the mitochondrial endosymbiosis. However, a recognised caveat is the potential biases introduced by the presence of incomplete taxon sampling resulting in so-called "ghost" lineages. Here, we assessed the robustness of the gene phylogeny-based branch length ratio method in the inference of the relative ordering of gene acquisition events during eukaryogenesis. We introduce a novel simulation framework that populates a known dated Tree of Life with plausible "ghost" lineages and simulates their gene transfers to the lineage leading to the last eukaryotic common ancestor. Our simulations suggest a generally low probability of misinterpreting the relative order of gene acquisitions from distinct ghost donors. However, we identify specific problematic phylogenetic placements where unsampled lineages are more likely to produce misleading results. Overall, our approach offers valuable guidance for the interpretation of future work on eukaryogenesis, and can be readily adapted to other evolutionary scenarios.

evolutionary biology↗

bioRxiv2024

Probabilistic modelling improves relative dating from gene phylogenies

O_LIEstablishing the timing of past evolutionary events is a fundamental task in the reconstruction of the history of life. State-of-the-art molecular dating methods generally involve the reconstruction of a species tree from conserved, vertically evolving genes, and the assumption of a molecular clock calibrated with the fossil record. Although this approach is extremely useful, its use is limited to speciation events and does not account for genes following different evolutionary paths. Recently, an alternative methodology for the relative dating of evolutionary events has been proposed that considers the distribution of branch lengths across sets of gene trees. C_LIO_LIHere, we validate this methodology by comparing the relative age estimates with a fossil-calibrated phylogeny and propose a model-based formalisation using a Bayesian framework. C_LIO_LIOur analyses revealed that the normalisation of the distances of interest with the branch lengths of a reference clade present across the set of gene trees results in narrower distributions, allowing the correct inference of the relative ordering of evolutionary events. C_LIO_LIWe show that distributions of normalised lengths can be modelled using gamma or lognormal distributions and demonstrate that inference of the posterior distribution of the mode allows accurate relative age estimation, as assessed by a strong correlation with the molecular clock-dated tree. C_LI

evolutionary biology↗

bioRxiv2024

Newly developed structure-based methods do not outperform standard sequence-based methods for large-scale phylogenomics

Recent developments in protein structure prediction have allowed the use of this previously limited source of information at genome-wide scales. It has been proposed that the use of structural information may offer advantages over sequences in phylogenetic reconstruction, due to their slower rate of evolution and direct correlation to function. Here, we examined how recently developed methods for structure-based homology search and tree reconstruction compare to current state-of-the-art sequence-based methods in reconstructing genome-wide collections of gene phylogenies (i.e. phylomes). While structure-based methods can be useful in specific scenarios, we found that their current performance does not justify using the newly developed structured-based methods as a default choice in large-scale phylogenetic studies. On the one hand, the best performing sequence-based tree reconstruction methods still outperform structure-based methods for this task. On the other hand, structure-based homology detection methods provide larger lists of candidate homologs, as previously reported. However, this comes at the expense of missing hits identified by sequence-based methods, as well as providing homolog candidate sets with higher fractions of false positives. These insights help guide the use of structural data in comparative genomics and highlight the need to continue improving structure-based approaches. Our pipeline is fully reproducible and has been implemented in a snakemake workflow. This will facilitate a continuous assessment of future improvements of structure-based tools in the Alphafold era.

bioinformatics↗

bioRxiv2024

A chromosome-level genome assembly of the Hispid cotton rat (Sigmodon hispidus), a model for human pathogenic virus infections

BackgroundThe cotton rat (Sigmodon hispidus), a rodent species native to the Americas, has emerged as a valuable laboratory model of infections by numerous human pathogens including poliovirus and respiratory syncytial virus (RSV). ResultsHere we report the first reference assembly of the cotton rat genome organized at a chromosomal level, providing annotation of 24,878 protein-coding genes. Data from PCR-free whole genome sequencing, linked-read sequencing and RNA sequencing from pooled cotton rat tissues were analyzed to assemble and annotate this novel genome sequence. Spectral karyotyping data using fluorescent probes derived from mouse chromosomes facilitated the assignment of cotton rat orthologs to syntenic chromosomes, comprising 25 autosomes and a sex chromosome in the haploid genome. Comparative phylome analysis revealed both gains and losses of numerous genes including immune defense genes against pathogens. We identified thousands of recently retrotransposed L1 and SINE B2 elements, revealing widespread genetic innovations unique to this species. ConclusionsWe anticipate that annotation and characterization of the first chromosome-level cotton rat genome assembly as described here will enable and accelerate ongoing investigations into its host defenses against viral and other pathogens, genome biology and mammalian evolution.

genomics↗