nils-herrmann/clean_scirepeval huggingface dataset:
Inferring the mammal tree: Species-level sets of phylogenies for questions in ecology, evolution, and conservation
Venue: PLoS biology

Big, time-scaled phylogenies are fundamental to connecting evolutionary processes to modern biodiversity patterns. Yet inferring reliable phylogenetic trees for thousands of species involves numerous trade-offs that have limited their utility to comparative biologists. To establish a robust evolutionary timescale for all approximately 6,000 living species of mammals, we developed credible sets of trees that capture root-to-tip uncertainty in topology and divergence times. Our “backbone-and-patch” approach to tree building applies a newly assembled 31-gene supermatrix to two levels of Bayesian inference: (1) backbone relationships and ages among major lineages, using fossil node or tip dating, and (2) species-level “patch” phylogenies with nonoverlapping in-groups that each correspond to one representative lineage in the backbone. Species unsampled for DNA are either excluded (“DNA-only” trees) or imputed within taxonomic constraints using branch lengths drawn from local birth–death models (“completed” trees). Joining time-scaled patches to backbones results in species-level trees of extant Mammalia with all branches estimated under the same modeling framework, thereby facilitating rate comparisons among lineages as disparate as marsupials and placentals. We compare our phylogenetic trees to previous estimates of mammal-wide phylogeny and divergence times, finding that (1) node ages are broadly concordant among studies, and (2) recent (tip-level) rates of speciation are estimated more accurately in our study than in previous “supertree” approaches, in which unresolved nodes led to branch-length artifacts. Credible sets of mammalian phylogenetic history are now available for download at , enabling investigations of long-standing questions in comparative biology.
Transcription-induced formation of extrachromosomal DNA during yeast ageing
Venue: PLoS biology

Extrachromosomal circular DNA (eccDNA) facilitates adaptive evolution by allowing rapid and extensive gene copy number variation and is implicated in the pathology of cancer and ageing. Here, we demonstrate that yeast aged under environmental copper accumulate high levels of eccDNA containing the copper-resistance gene CUP1. Transcription of the tandemly repeated CUP1 gene causes CUP1 eccDNA accumulation, which occurs in the absence of phenotypic selection. We have developed a sensitive and quantitative eccDNA sequencing pipeline that reveals CUP1 eccDNA accumulation on copper exposure to be exquisitely site specific, with no other detectable changes across the eccDNA complement. eccDNA forms de novo from the CUP1 locus through processing of DNA double-strand breaks (DSBs) by Sae2, Mre11 and Mus81, and genome-wide analyses show that other protein coding eccDNA species in aged yeast share a similar biogenesis pathway. Although abundant, we find that CUP1 eccDNA does not replicate efficiently, and high-copy numbers in aged cells arise through frequent formation events combined with asymmetric DNA segregation. The transcriptional stimulation of CUP1 eccDNA formation shows that age-linked genetic change varies with transcription pattern, resulting in gene copy number profiles tailored by environment.
Coinfections by noninteracting pathogens are not independent and require new tests of interaction
Venue: PLoS biology

If pathogen species, strains, or clones do not interact, intuition suggests the proportion of coinfected hosts should be the product of the individual prevalences. Independence consequently underpins the wide range of methods for detecting pathogen interactions from cross-sectional survey data. However, the very simplest of epidemiological models challenge the underlying assumption of statistical independence. Even if pathogens do not interact, death of coinfected hosts causes net prevalences of individual pathogens to decrease simultaneously. The induced positive correlation between prevalences means the proportion of coinfected hosts is expected to be higher than multiplication would suggest. By modelling the dynamics of multiple noninteracting pathogens causing chronic infections, we develop a pair of novel tests of interaction that properly account for nonindependence between pathogens causing lifelong infection. Our tests allow us to reinterpret data from previous studies including pathogens of humans, plants, and animals. Our work demonstrates how methods to identify interactions between pathogens can be updated using simple epidemic models.
Mechanisms of species diversity in birdsong learning
Venue: PLoS biology

Vocal communication is critical for social interactions across a diversity of animals. A subset of those animals, including humans and songbirds, must learn how to produce their vocal communication signals. In this issue of PLOS Biology, Wang and colleagues use genome-wide investigations of gene expression in species hybrids to uncover transcriptional networks that could influence species differences in song learning and production. We provide an overview of birdsong learning and discuss how the study by Wang and colleagues advances our understanding of mechanisms of song learning and evolution.
Dynamic trafficking and turnover of JAM-C is essential for endothelial cell migration
Venue: PLoS biology

Junctional complexes between endothelial cells form a dynamic barrier that hinders passive diffusion of blood constituents into interstitial tissues. Remodelling of junctions is an essential process during leukocyte trafficking, vascular permeability, and angiogenesis. However, for many junctional proteins, the mechanisms of junctional remodelling have yet to be determined. Here, we used receptor mutagenesis, horseradish peroxidase (HRP), and ascorbate peroxidase 2 (APEX-2) proximity labelling, alongside light and electron microscopy (EM), to map the intracellular trafficking routes of junctional adhesion molecule-C (JAM-C). We found that JAM-C cotraffics with receptors associated with changes in permeability such as vascular endothelial cadherin (VE-Cadherin) and neuropilin (NRP)-1 and 2, but not with junctional proteins associated with the transmigration of leukocytes. Dynamic JAM-C trafficking and degradation are necessary for junctional remodelling during cell migration and angiogenesis. By identifying new potential trafficking machinery, we show that a key point of regulation is the ubiquitylation of JAM-C by the E3 ligase Casitas B-lineage lymphoma (CBL), which controls the rate of trafficking versus lysosomal degradation.
Language evolution and complexity considerations: The no half-Merge fallacy
Venue: PLoS biology

Recently, prominent theoretical linguists have argued for an explicit scenario for the evolution of the human language capacity on the basis of its computational properties. Concretely, the simplicity of a minimalist formulation of the operation Merge, which allows humans to recursively compute hierarchical relations in language, has been used to promote a sudden-emergence, single-mutation scenario. In support of this view, Merge is said to be either fully present or fully absent: one cannot have half-Merge. On this basis, it is inferred that the emergence of our fully fledged language capacity had to be sudden. Thus, proponents of this view draw a parallelism between the formal complexity of the operation at the computational level and the number of evolutionary steps it must imply. Here, we examine this argument in detail and show that the jump from the atomicity of Merge to a single-mutation scenario is not valid and therefore cannot be used as justification for a theory of language evolution along those lines.
All or nothing: No half-Merge and the evolution of syntax
Venue: PLoS biology

In their Essay on the evolution of human language, Martins and Boeckx seek to refute what they call the “half-Merge fallacy”—the conclusion that the most elementary computational operation for human language syntax, binary set formation, or “Merge,” evolved in a single step. We show that their argument collapses. It is based on a serious misunderstanding of binary set formation as well as formal language theory. Furthermore, their specific evolutionary scenario counterproposal for a “two-step” evolution of Merge does not work. Although we agree with their Essay on several points, including that there must have been many steps in the evolution of human language and the importance of understanding how language and language syntax are implemented in the brain, we disagree that there is any justification, empirical or conceptual, for the decomposition of binary set formation into separate steps.
A specific type of insulin-like peptide regulates the conditional growth of a beetle weapon
Venue: PLoS biology

Evolutionarily conserved insulin/insulin-like growth factor (IGF) signaling (IIS) has been identified as a major physiological mechanism underlying the nutrient-dependent regulation of sexually selected weapon growth in animals. However, the molecular mechanisms that couple nutritional state with weapon growth remain largely unknown. Here, we show that one specific subtype of insulin-like peptide (ILP) responds to nutrient status and thereby regulates weapon size in the broad-horned flour beetle Gnatocerus cornutus. By using transcriptome information, we identified five G. cornutus ILP (GcorILP1–5) and two G. cornutus insulin-like receptor (GcorInR1, -2) genes in the G. cornutus genome. RNA interference (RNAi)-mediated gene silencing revealed that a certain subtype of ILP, GcorILP2, specifically regulated weapon size. Importantly, GcorILP2 was highly and specifically expressed in the fat body in a condition-dependent manner. We further found that GcorInR1 and GcorInR2 are functionally redundant but that the latter is partially specialized for regulating weapon growth. These results strongly suggest that GcorILP2 is an important component of the developmental mechanism that couples nutritional state to weapon growth in G. cornutus. We propose that the duplication and subsequent diversification of IIS genes played a pivotal role in the evolution of the complex growth regulation of secondary sexual traits.
Framing the discussion of microorganisms as a facet of social equity in human health
Venue: PLoS biology

What do “microbes” have to do with social equity? These microorganisms are integral to our health, that of our natural environment, and even the “health” of the environments we build. The loss, gain, and retention of microorganisms—their flow between humans and the environment—can greatly impact our health. It is well-known that inequalities in access to perinatal care, healthy foods, quality housing, and the natural environment can create and arise from social inequality. Here, we focus on the argument that access to beneficial microorganisms is a facet of public health, and health inequality may be compounded by inequitable microbial exposure.
Tissue tropism and transmission ecology predict virulence of human RNA viruses
Venue: PLoS biology

Novel infectious diseases continue to emerge within human populations. Predictive studies have begun to identify pathogen traits associated with emergence. However, emerging pathogens vary widely in virulence, a key determinant of their ultimate risk to public health. Here, we use structured literature searches to review the virulence of each of the 214 known human-infective RNA virus species. We then use a machine learning framework to determine whether viral virulence can be predicted by ecological traits, including human-to-human transmissibility, transmission routes, tissue tropisms, and host range. Using severity of clinical disease as a measurement of virulence, we identified potential risk factors using predictive classification tree and random forest ensemble models. The random forest approach predicted literature-assigned disease severity of test data with mean accuracy of 89.4% compared to a null accuracy of 74.2%. In addition to viral taxonomy, the ability to cause systemic infection was the strongest predictor of severe disease. Further notable predictors of severe disease included having neural and/or renal tropism, direct contact or respiratory transmission, and limited (0 < R0 ≤ 1) human-to-human transmissibility. We present a novel, to our knowledge, comparative perspective on the virulence of all currently known human RNA virus species. The risk factors identified may provide novel perspectives in understanding the evolution of virulence and elucidating molecular virulence mechanisms. These risk factors could also improve planning and preparedness in public health strategies as part of a predictive framework for novel human infections.
Loss of adenomatous polyposis coli function renders intestinal epithelial cells resistant to the cytokine IL-22
Venue: PLoS biology

Interleukin-22 (IL-22) is a critical immune defence cytokine that maintains intestinal homeostasis and promotes wound healing and tissue regeneration, which can support the growth of colorectal tumours. Mutations in the adenomatous polyposis coli gene (Apc) are a major driver of familial colorectal cancers (CRCs). How IL-22 contributes to APC-mediated tumorigenesis is poorly understood. To investigate IL-22 signalling in wild-type (WT) and APC-mutant cells, we performed RNA sequencing (RNAseq) of IL-22–treated murine small intestinal epithelial organoids. In WT epithelia, antimicrobial defence and cellular stress response pathways were most strongly induced by IL-22. Surprisingly, although IL-22 activates signal transducer and activator of transcription 3 (STAT3) in APC-mutant cells, STAT3 target genes were not induced. Our analyses revealed that ApcMin/Min cells are resistant to IL-22 due to reduced expression of the IL-22 receptor, and increased expression of inhibitors of STAT3, particularly histone deacetylases (HDACs). We further show that IL-22 increases DNA damage and genomic instability, which can accelerate cellular transition from heterozygosity (ApcMin/+) to homozygosity (ApcMin/Min) to drive tumour formation. Our data reveal an unexpected role for IL-22 in promoting early tumorigenesis while excluding a function for IL-22 in transformed epithelial cells.
Parental breeding age effects on descendants’ longevity interact over 2 generations in matrilines and patrilines
Venue: PLoS biology

Individuals within populations vary enormously in mortality risk and longevity, but the causes of this variation remain poorly understood. A potentially important and phylogenetically widespread source of such variation is maternal age at breeding, which typically has negative effects on offspring longevity. Here, we show that paternal age can affect offspring longevity as strongly as maternal age does and that breeding age effects can interact over 2 generations in both matrilines and patrilines. We manipulated maternal and paternal ages at breeding over 2 generations in the neriid fly Telostylinus angusticollis. To determine whether breeding age effects can be modulated by the environment, we also manipulated larval diet and male competitive environment in the first generation. We found separate and interactive effects of parental and grand-parental ages at breeding on descendants’ mortality rate and life span in both matrilines and patrilines. These breeding age effects were not modulated by grand-parental larval diet quality or competitive environment. Our findings suggest that variation in maternal and paternal ages at breeding could contribute substantially to intrapopulation variation in mortality and longevity.
GPCRs show widespread differential mRNA expression and frequent mutation and copy number variation in solid tumors
Venue: PLoS biology

G protein-coupled receptors (GPCRs) are the most widely targeted gene family for Food and Drug Administration (FDA)-approved drugs. To assess possible roles for GPCRs in cancer, we analyzed The Cancer Genome Atlas (TCGA) data for mRNA expression, mutations, and copy number variation (CNV) in 20 categories and 45 subtypes of solid tumors and quantified differential expression (DE) of GPCRs by comparing tumors against normal tissue from the Gene Tissue Expression Project (GTEx) database. GPCRs are overrepresented among coding genes with elevated expression in solid tumors. This analysis reveals that most tumor types differentially express >50 GPCRs, including many targets for approved drugs, hitherto largely unrecognized as targets of interest in cancer. GPCR mRNA signatures characterize specific tumor types and correlate with expression of cancer-related pathways. Tumor GPCR mRNA signatures have prognostic relevance for survival and correlate with expression of numerous cancer-related genes and pathways. GPCR expression in tumors is largely independent of staging, grading, metastasis, and/or driver mutations. GPCRs expressed in cancer cell lines largely parallel GPCR expression in tumors. Certain GPCRs are frequently mutated and appear to be hotspots, serving as bellwethers of accumulated genomic damage. CNV of GPCRs is common but does not generally correlate with mRNA expression. Our results suggest a previously underappreciated role for GPCRs in cancer, perhaps as functional oncogenes, biomarkers, surface antigens, and pharmacological targets.
Regulation plays a multifaceted role in the retention of gene duplicates
Venue: PLoS biology

A gene duplication can lead to all sorts of problems in a cell. However, it can also lead to all sorts of benefits. Beneficial or not, the gene duplicates might be kept in the genome because of several different reasons. For instance, if natural selection works towards optimizing one function of a gene at the expense of another, then gene duplication could resolve this conflict by separating the functions in two genes. Here, we outline evolutionary incentives to keep a duplicated gene in the genome, focusing on divergence in expression and trade-off resolution as featured in a new and exciting paper published in this edition of PLOS Biology.
Resolving noise–control conflict by gene duplication
Venue: PLoS biology

Gene duplication promotes adaptive evolution in two main ways: allowing one duplicate to evolve a new function and splitting ancestral functions between the duplicates. The second scenario may resolve adaptive conflicts that can rise when one gene performs different functions. In an apparent departure from both scenarios, low-expressing transcription factor (TF) duplicates commonly bind to the same DNA motifs and act in overlapping conditions. To examine for possible benefits of this apparent redundancy, we examined the Msn2 and Msn4 duplicates in budding yeast. We show that Msn2,4 function as one unit by inducing the same set of target genes in overlapping conditions. Yet, the two-factor composition allows this unit’s expression to be both environmentally responsive and with low noise, resolving an adaptive conflict that limits expression of single genes. We propose that duplication can provide adaptive benefit through cooperation rather than functional divergence, allowing two-factor dynamics with beneficial properties that cannot be achieved by a single gene.
Single-cell transcriptomics of the naked mole-rat reveals unexpected features of mammalian immunity
Venue: PLoS biology

The immune system comprises a complex network of specialized cells that protects against infection, eliminates cancerous cells, and regulates tissue repair, thus serving a critical role in homeostasis, health span, and life span. The subterranean-dwelling naked mole-rat (NM-R; Heterocephalus glaber) exhibits prolonged life span relative to its body size, is unusually cancer resistant, and manifests few physiological or molecular changes with advancing age. We therefore hypothesized that the immune system of NM-Rs evolved unique features that confer enhanced cancer immunosurveillance and prevent the age-associated decline in homeostasis. Using single-cell RNA-sequencing (scRNA-seq) we mapped the immune system of the NM-R and compared it to that of the short-lived, cancer-prone mouse. In contrast to the mouse, we find that the NM-R immune system is characterized by a high myeloid-to-lymphoid cell ratio that includes a novel, lipopolysaccharide (LPS)-responsive, granulocyte cell subset. Surprisingly, we also find that NM-Rs lack canonical natural killer (NK) cells. Our comparative genomics analyses support this finding, showing that the NM-R genome lacks an expanded gene family that controls NK cell function in several other species. Furthermore, we reconstructed the evolutionary history that likely led to this genomic state. The NM-R thus challenges our current understanding of mammalian immunity, favoring an atypical, myeloid-biased mode of innate immunosurveillance, which may contribute to its remarkable health span.
Local vulnerability and global connectivity jointly shape neurodegenerative disease propagation
Venue: PLoS biology

It is becoming increasingly clear that brain network organization shapes the course and expression of neurodegenerative diseases. Parkinson disease (PD) is marked by progressive spread of atrophy from the midbrain to subcortical structures and, eventually, to the cerebral cortex. Recent discoveries suggest that the neurodegenerative process involves the misfolding and prion-like propagation of endogenous α-synuclein via axonal projections. However, the mechanisms that translate local "synucleinopathy" to large-scale network dysfunction and atrophy remain unknown. Here, we use an agent-based epidemic spreading model to integrate structural connectivity, functional connectivity, and gene expression and to predict sequential volume loss due to neurodegeneration. The dynamic model replicates the spatial and temporal patterning of empirical atrophy in PD and implicates the substantia nigra as the disease epicenter. We reveal a significant role for both connectome topology and geometry in shaping the distribution of atrophy. The model also demonstrates that SNCA and GBA transcription influence α-synuclein concentration and local regional vulnerability. Functional coactivation further amplifies the course set by connectome architecture and gene expression. Altogether, these results support the theory that the progression of PD is a multifactorial process that depends on both cell-to-cell spreading of misfolded proteins and regional vulnerability.
Data-driven analyses of motor impairments in animal models of neurological disorders
Venue: PLoS biology

Behavior provides important insights into neuronal processes. For example, analysis of reaching movements can give a reliable indication of the degree of impairment in neurological disorders such as stroke, Parkinson disease, or Huntington disease. The analysis of such movement abnormalities is notoriously difficult and requires a trained evaluator. Here, we show that a deep neural network is able to score behavioral impairments with expert accuracy in rodent models of stroke. The same network was also trained to successfully score movements in a variety of other behavioral tasks. The neural network also uncovered novel movement alterations related to stroke, which had higher predictive power of stroke volume than the movement components defined by human experts. Moreover, when the regression network was trained only on categorical information (control = 0; stroke = 1), it generated predictions with intermediate values between 0 and 1 that matched the human expert scores of stroke severity. The network thus offers a new data-driven approach to automatically derive ratings of motor impairments. Altogether, this network can provide a reliable neurological assessment and can assist the design of behavioral indices to diagnose and monitor neurological disorders.