Nonlethal deleterious mutation-induced stress accelerates bacterial aging.

Random mutagenesis, including when it leads to loss of gene function, is a key mechanism enabling microorganisms' long-term adaptation to new environments. However, loss-of-function mutations are often deleterious, triggering, in turn, cellular stress and complex homeostatic stress responses, called "allostasis," to promote cell survival. Here, we characterize the differential impacts of 65 nonlethal, deleterious single-gene deletions on Escherichia coli growth in three different growth environments. Further assessments of select mutants, namely, those bearing single adenosine triphosphate (ATP) synthase subunit deletions, reveal that mutants display reorganized transcriptome profiles that reflect both the environment and the specific gene deletion. We also find that ATP synthase α-subunit deleted (ΔatpA) cells exhibit elevated metabolic rates while having slower growth compared to wild-type (wt) E. coli cells. At the single-cell level, compared to wt cells, individual ΔatpA cells display near normal proliferation profiles but enter a postreplicative state earlier and exhibit a distinct senescence phenotype. These results highlight the complex interplay between genomic diversity, adaptation, and stress response and uncover an "aging cost" to individual bacterial cells for maintaining population-level resilience to environmental and genetic stress; they also suggest potential bacteriostatic antibiotic targets and -as select human genetic diseases display highly similar phenotypes, - a bacterial origin of some human diseases.

SARS-CoV-2 variant of concern fitness and adaptation in primary human airway epithelia.

The severe acute respiratory syndrome coronavirus 2 pandemic is characterized by the emergence of novel variants of concern (VOCs) that replace ancestral strains. Here, we dissect the complex selective pressures by evaluating variant fitness and adaptation in human respiratory tissues. We evaluate viral properties and host responses to reconstruct forces behind D614G through Omicron (BA.1) emergence. We observe differential replication in airway epithelia, differences in cellular tropism, and virus-induced cytotoxicity. D614G accumulates the most mutations after infection, supporting zoonosis and adaptation to the human airway. We perform head-to-head competitions and observe the highest fitness for Gamma and Delta. Under these conditions, RNA recombination favors variants encoding the B.1.617.1 lineage 3' end. Based on viral growth kinetics, Alpha, Gamma, and Delta exhibit increased fitness compared to D614G. In contrast, the global success of Omicron likely derives from increased transmission and antigenic variation. Our data provide molecular evidence to support epidemiological observations of VOC emergence.

Characterization of a novel root-associated diazotrophic rare PGPR taxa, Aquabacter pokkalii sp. nov., isolated from pokkali rice: new insights into the plant-associated lifestyle and brackish adaptation.

Salinity impacts crop growth and productivity and lowers the activities of rhizosphere microbiota. The identification and utilization of habitat-specific salinity-adapted plant growth-promoting rhizobacteria (PGPR) are considered alternative strategies to improve the growth and yields of crops in salinity-affected coastal agricultural fields. In this study, we characterize strain L1I39T, the first Aquabacter species with PGPR traits isolated from a salt-tolerant pokkali rice cultivated in brackish environments. L1I39T is positive for 1-aminocyclopropane-1-carboxylate deaminase activity and nitrogen fixation and can promote pokkali rice growth by supplying fixed nitrogen under a nitrogen-deficient seawater condition. Importantly, enhanced plant growth and efficient root colonization were evident in L1I39T-inoculated plants grown under 20% seawater but not in zero-seawater conditions, identifying brackish conditions as a key local environmental factor critical for L1I39T-pokkali rice symbiosis. Detailed physiological studies revealed that L1I39T is well-adapted to brackish environments. In-depth genome analysis of L1I39T identified multiple gene systems contributing to its plant-associated lifestyle and brackish adaptations. The 16S rRNA-based metagenomic study identified L1I39T as an important rare PGPR taxon. Based on the polyphasic taxonomy analysis, we established strain L1I39T as a novel Aquabacter species and proposed Aquabacter pokkalii sp nov. Overall, this study provides a better understanding of a marine-adapted PGPR strain L1I39T that may perform a substantial role in host growth and health in nitrogen-poor brackish environments.

The genetics of niche-specific behavioral tendencies in an adaptive radiation of cichlid fishes.

Behavior is critical for animal survival and reproduction, and possibly for diversification and evolutionary radiation. However, the genetics behind adaptive variation in behavior are poorly understood. In this work, we examined a fundamental and widespread behavioral trait, exploratory behavior, in one of the largest adaptive radiations on Earth, the cichlid fishes of Lake Tanganyika. By integrating quantitative behavioral data from 57 cichlid species (702 wild-caught individuals) with high-resolution ecomorphological and genomic information, we show that exploratory behavior is linked to macrohabitat niche adaptations in Tanganyikan cichlids. Furthermore, we uncovered a correlation between the genotypes at a single-nucleotide polymorphism upstream of the AMPA glutamate-receptor regulatory gene cacng5b and variation in exploratory tendency. We validated this association using behavioral predictions with a neural network approach and CRISPR-Cas9 genome editing.

Efficient Polyamine-Based Nanodelivery System for Proline: Enhanced Uptake Improves the Drought Tolerance of Tobacco.

Drought stress is one of the most unfavorable factors affecting plant growth and productivity among various environmental stresses. Nanotechnology is expected to enhance the effectiveness of conventional biostimulants. Herein, the current study constructed an efficient proline (Pro) nanodelivery system based on a star polyamine (SPc). The hydroxyl groups of Pro could assemble with carbonyl groups of SPc, and the self-assembly of Pro with SPc formed the nanoscale particles of the Pro/SPc complex. Compared to Pro alone, the contact angle of SPc-loaded Pro decreased, and its retentivity and plant uptake increased. Importantly, the tobacco (Nicotiana benthamiana) seeds and seedlings treated with Pro/SPc complex exhibited stronger drought tolerance. RNA-Seq analysis indicated that the SPc-loaded Pro could further upregulate photosynthesis-related genes and endocytosis-related genes. The current study constructed an efficient nanodelivery system for improving the bioactivity of biostimulants, which has broad application prospects in the agricultural field.

Unraveling the genetic enigma of rice submergence tolerance: Shedding light on the role of ethylene response factor-encoding gene SUB1A-1.

The world's low-lying rice (Oryza sativa) cultivation areas are under threat of submergence or flash flooding due to global warming. Rice plants manifest a variety of physiological and morphological changes to cope with submergence and hypoxia, including lowering carbohydrate consumption, inhibiting shoot elongation, and forming a thicker leaf gas film during submergence. Functional studies have revealed that submergence tolerance in rice is mainly determined by an ethylene response factor (ERF) transcription factor-encoding gene, namely SUBMERGENCE 1A-1 (SUB1A-1) located in the SUB1 quantitative trait locus. The SUB1A-1-dependent submergence tolerance is manifested through hormonal signaling involving ethylene, gibberellic acid, brassinosteroid, auxin and jasmonic acid. Considerable progress has been made toward the introduction of SUB1A-1 into rice varieties through a conventional marker-assisted backcrossing approach. Here, we review the recent advances in the physiological, biochemical and molecular dynamics of rice submergence tolerance mediated by the 'quiescence strategy'. Thus, the present review aims to provide researchers with insights into the genetics of rice submergence tolerance and future perspectives for designing submergence-resilient plants for sustainable agriculture under the uncertainties of climate change.

The NtDEGP5 gene improves drought tolerance in tobacco (Nicotiana tabacum L.) by dampening plastid extracellular Ca2+ and flagellin signaling and thereby reducing ROS production.

Tobacco is an essential cash crop, but drought has become a major factor in the decline of global tobacco production as a result of changes in the global climate. The HtrA protease is an oligomeric serine endopeptidase that responds to stress in plants. DEGP5 is a member of the gene family that encodes HtrA protease, which promotes plant adaptation to adversity. The aim of this study was to investigate the role and mechanism employed by the DEGP5 gene in response to drought stress in tobacco. NtDEGP5-overexpression lines were obtained by genetic transformation and the phenotypes and transcriptomes of NtDEGP5-overexpression lines and wild-type (K326) tobacco seedlings were compared under drought stress. The results demonstrated that plants overexpressing NtDEGP5 exhibited greater drought tolerance. The differentially expressed genes involved in the regulation of drought tolerance by DEGP5 were enriched in metabolic pathways, such as plant-pathogen interaction and glutathione metabolism, with the plant-pathogen interaction pathway having the most differentially expressed genes. An analysis of the plant-pathogen interaction pathway revealed that these genes contributed to the suppression of plastid extracellular Ca2+ signaling and flagellin signaling to inhibit reactive oxygen species production, and that lower levels of reactive oxygen species act as a signal to regulate the activation of the antioxidant system, further balancing the production and removal of reactive oxygen species in tobacco seedlings under drought stress. These findings suggest that the NtDEGP5 gene can enhance the drought tolerance of tobacco by regulating the homeostasis of reactive oxygen species by inhibiting extracellular plastids.

Understanding and leveraging phenotypic plasticity during metastasis formation.

Cancer metastasis is the process of detrimental systemic spread and the primary cause of cancer-related fatalities. Successful metastasis formation requires tumor cells to be proliferative and invasive; however, cells cannot be effective at both tasks simultaneously. Tumor cells compensate for this trade-off by changing their phenotype during metastasis formation through phenotypic plasticity. Given the changing selection pressures and competitive interactions that tumor cells face, it is poorly understood how plasticity shapes the process of metastasis formation. Here, we develop an ecology-inspired mathematical model with phenotypic plasticity and resource competition between phenotypes to address this knowledge gap. We find that phenotypically plastic tumor cell populations attain a stable phenotype equilibrium that maintains tumor cell heterogeneity. Considering treatment types inspired by chemo- and immunotherapy, we highlight that plasticity can protect tumors against interventions. Turning this strength into a weakness, we corroborate current clinical practices to use plasticity as a target for adjuvant therapy. We present a parsimonious view of tumor plasticity-driven metastasis that is quantitative and experimentally testable, and thus potentially improving the mechanistic understanding of metastasis at the cell population level, and its treatment consequences.

Genomic Variation, Population History, and Long-Term Genetic Adaptation to High Altitudes in Tibetan Partridge (Perdix hodgsoniae).

Species residing across elevational gradients display adaptations in response to environmental changes such as oxygen availability, ultraviolet radiation, and temperature. Here, we study genomic variation, gene expression, and long-term adaptation in Tibetan Partridge (Perdix hodgsoniae) populations residing across the elevational gradient of the Tibetan Plateau. We generated a high-quality draft genome and used it to carry out downstream population genomic and transcriptomic analysis. The P. hodgsoniae populations residing across various elevations were genetically distinct, and their phylogenetic clustering was consistent with their geographic distribution. We identified possible evidence of gene flow between populations residing in <3,000 and >4,200 m elevation that is consistent with known habitat expansion of high-altitude populations of P. hodgsoniae to a lower elevation. We identified a 60 kb haplotype encompassing the Estrogen Receptor 1 (ESR1) gene, showing strong genetic divergence between populations of P. hodgsoniae. We identified six single nucleotide polymorphisms within the ESR1 gene fixed for derived alleles in high-altitude populations that are strongly conserved across vertebrates. We also compared blood transcriptome profiles and identified differentially expressed genes (such as GAPDH, LDHA, and ALDOC) that correlated with differences in altitude among populations of P. hodgsoniae. These candidate genes from population genomics and transcriptomics analysis were enriched for neutrophil degranulation and glycolysis pathways, which are known to respond to hypoxia and hence may contribute to long-term adaptation to high altitudes in P. hodgsoniae. Our results highlight Tibetan Partridges as a useful model to study molecular mechanisms underlying long-term adaptation to high altitudes.

Modelling cell adaptation using internal variables: Accounting for cell plasticity in continuum mathematical biology.

Cellular adaptation is the ability of cells to change in response to different stimuli and environmental conditions. It occurs via phenotypic plasticity, that is, changes in gene expression derived from changes in the physiological environment. This phenomenon is important in many biological processes, in particular in cancer evolution and its treatment. Therefore, it is crucial to understand the mechanisms behind it. Specifically, the emergence of the cancer stem cell phenotype, showing enhanced proliferation and invasion rates, is an essential process in tumour progression. We present a mathematical framework to simulate phenotypic heterogeneity in different cell populations as a result of their interaction with chemical species in their microenvironment, through a continuum model using the well-known concept of internal variables to model cell phenotype. The resulting model, derived from conservation laws, incorporates the relationship between the phenotype and the history of the stimuli to which cells have been subjected, together with the inheritance of that phenotype. To illustrate the model capabilities, it is particularised for glioblastoma adaptation to hypoxia. A parametric analysis is carried out to investigate the impact of each model parameter regulating cellular adaptation, showing that it permits reproducing different trends reported in the scientific literature. The framework can be easily adapted to any particular problem of cell plasticity, with the main limitation of having enough cells to allow working with continuum variables. With appropriate calibration and validation, it could be useful for exploring the underlying processes of cellular adaptation, as well as for proposing favourable/unfavourable conditions or treatments.

The Role of Introgression During the Radiation of Endemic Fishes Adapted to Living at Extreme Altitudes in the Tibetan Plateau.

Recent genomic analyses of evolutionary radiations suggest that ancient introgression may facilitate rapid diversification and adaptive radiation. The loach genus Triplophysa, a genus with most species endemic to Tibetan Plateau, shows ecological diversity and rapid evolution and represents a potential example of adaptive radiation linked to the uplift of the Tibetan Plateau. Here, we interrogate the complex evolutionary history of Triplophysa fishes through the analysis of whole-genome sequences. By reconstructing the phylogeny of Triplophysa, quantifying introgression across this clade, and simulating speciation and migration processes, we confirm that extensive gene flow events occurred across disparate Triplophysa species. Our results suggest that introgression plays a more substantial role than incomplete lineage sorting in underpinning phylogenetic discordance in Triplophysa. The results also indicate that genomic regions affected by ancient gene flow exhibit characteristics of lower recombination rates and nucleotide diversity and may associate with selection. Simulation analysis of Triplophysa tibetana suggests that the species may have been affected by the Gonghe Movement in the third uplift of the Tibetan Plateau, resulting in founder effects and a subsequent reduction in Ne.

Mutation bias and the predictability of evolution.

Predicting evolutionary outcomes is an important research goal in a diversity of contexts. The focus of evolutionary forecasting is usually on adaptive processes, and efforts to improve prediction typically focus on selection. However, adaptive processes often rely on new mutations, which can be strongly influenced by predictable biases in mutation. Here, we provide an overview of existing theory and evidence for such mutation-biased adaptation and consider the implications of these results for the problem of prediction, in regard to topics such as the evolution of infectious diseases, resistance to biochemical agents, as well as cancer and other kinds of somatic evolution. We argue that empirical knowledge of mutational biases is likely to improve in the near future, and that this knowledge is readily applicable to the challenges of short-term prediction. This article is part of the theme issue 'Interdisciplinary approaches to predicting evolutionary biology'.

Molecular Determinants of Mouse Adaptation of Rat Hepacivirus.

The lack of robust immunocompetent animal models for hepatitis C virus (HCV) impedes vaccine development and studies of immune responses. Norway rat hepacivirus (NrHV) infection in rats shares HCV-defining characteristics, including hepatotropism, chronicity, immune responses, and aspects of liver pathology. To exploit genetic variants and research tools, we previously adapted NrHV to prolonged infection in laboratory mice. Through intrahepatic RNA inoculation of molecular clones of the identified variants, we here characterized four mutations in the envelope proteins responsible for mouse adaptation, including one disrupting a glycosylation site. These mutations led to high-titer viremia, similar to that observed in rats. In 4-week-old mice, infection was cleared after around 5 weeks compared to 2 to 3 weeks for nonadapted virus. In contrast, the mutations led to persistent but attenuated infection in rats, and they partially reverted, accompanied by an increase in viremia. Attenuated infection in rat but not mouse hepatoma cells demonstrated that the characterized mutations were indeed mouse adaptive rather than generally adaptive across species and that species determinants and not immune interactions were responsible for attenuation in rats. Unlike persistent NrHV infection in rats, acute resolving infection in mice was not associated with the development of neutralizing antibodies. Finally, infection of scavenger receptor B-I (SR-BI) knockout mice suggested that adaptation to mouse SR-BI was not a primary function of the identified mutations. Rather, the virus may have adapted to lower dependency on SR-BI, thereby potentially surpassing species-specific differences. In conclusion, we identified specific determinants of NrHV mouse adaptation, suggesting species-specific interactions during entry. IMPORTANCE A prophylactic vaccine is required to achieve the World Health Organization's objective for hepatitis C virus elimination as a serious public health threat. However, the lack of robust immunocompetent animal models supporting hepatitis C virus infection impedes vaccine development as well as studies of immune responses and viral evasion. Hepatitis C virus-related hepaciviruses were discovered in a number of animal species and provide useful surrogate infection models. Norway rat hepacivirus is of particular interest, as it enables studies in rats, an immunocompetent and widely used small laboratory animal model. Its adaptation to robust infection also in laboratory mice provides access to a broader set of mouse genetic lines and comprehensive research tools. The presented mouse-adapted infectious clones will be of utility for reverse genetic studies, and the Norway rat hepacivirus mouse model will facilitate studies of hepacivirus infection for in-depth characterization of virus-host interactions, immune responses, and liver pathology.

Promoting extinction or minimizing growth? The impact of treatment on trait trajectories in evolving populations.

When cancers or bacterial infections establish, small populations of cells have to free themselves from homoeostatic regulations that prevent their expansion. Trait evolution allows these populations to evade this regulation, escape stochastic extinction and climb up the fitness landscape. In this study, we analyze this complex process and investigate the fate of a cell population that underlies the basic processes of birth, death, and mutation. We find that the shape of the fitness landscape dictates a circular adaptation trajectory in the trait space spanned by birth and death rates. We show that successful adaptation is less likely for parental populations with higher turnover (higher birth and death rates). Including density- or trait-affecting treatment we find that these treatment types change the adaptation dynamics in agreement with a geometrical analysis of fitness gradients. Treatment strategies that simultaneously target birth and death rates are most effective, but also increase evolvability. By mapping physiological adaptation pathways and molecular drug mechanisms to traits and treatments with clear eco-evolutionary consequences, we can achieve a much better understanding of the adaptation dynamics and the eco-evolutionary mechanisms at play in the dynamics of cancer and bacterial infections.

One genome, multiple phenotypes: decoding the evolution and mechanisms of environmentally induced developmental plasticity in insects.

Plasticity in developmental processes gives rise to remarkable environmentally induced phenotypes. Some of the most striking and well-studied examples of developmental plasticity are seen in insects. For example, beetle horn size responds to nutritional state, butterfly eyespots are enlarged in response to temperature and humidity, and environmental cues also give rise to the queen and worker castes of eusocial insects. These phenotypes arise from essentially identical genomes in response to an environmental cue during development. Developmental plasticity is taxonomically widespread, affects individual fitness, and may act as a rapid-response mechanism allowing individuals to adapt to changing environments. Despite the importance and prevalence of developmental plasticity, there remains scant mechanistic understanding of how it works or evolves. In this review, we use key examples to discuss what is known about developmental plasticity in insects and identify fundamental gaps in the current knowledge. We highlight the importance of working towards a fully integrated understanding of developmental plasticity in a diverse range of species. Furthermore, we advocate for the use of comparative studies in an evo-devo framework to address how developmental plasticity works and how it evolves.

Comparative analysis of cold-responsive genes under short-term cold stimulation and cold-adaptive genes under long-term heterogeneous environments reveals a cold adaptation mechanism in weeping forsythia.

Identifying cold-related genes can provide insights into the cold adaptation mechanism of weeping forsythia. In this study, we compared the changes in gene expressions and physiological and biochemical indices under short-term cold stimulation with the changes in gene sequences under a long-term heterogeneous environment to investigate the cold adaptation mechanism in weeping forsythia. The data of adaptive gene sequence changes, e.g., single nucleotide polymorphisms, were obtained from previous landscape genomics studies. The physiological and biochemical indicators and transcriptome results showed that weeping forsythia initiated a series of programs, including increasing cell osmotic pressures, scavenging ROS, activating the defense mechanism that crosses with pathogen infection, and upregulating CBF/DREB1 transcription factor 1, to cope with short-term cold stress. A reanalysis of landscape genomic data suggested that weeping forsythia responded to long-term heterogeneous cold stress by the differentiation of genes related to synthesis of aromatic substances and adenosine triphosphate. Our results supported the hypothesis that the adaptation mechanisms of species to short-term environmental stimulation and long-term stress in heterogeneous environments are different. The differences in cold tolerance among populations are not necessarily obtained by changing cold-responsive gene sequences. This study provides new insights into the cold adaptation mechanisms of plants.

VEGFA rs2010963 GG genotype is associated with superior adaptations to resistance versus endurance training in the same group of healthy, young men.

PURPOSE: We used a within-subject, cross-over study to determine the relationship between the intra-individual adaptations to four weeks' resistance (RT) versus four weeks' endurance (END) training, and we investigated whether three single nucleotide polymorphisms (SNPs) were associated with these adaptations. METHODS: Thirty untrained, healthy, young men completed a cycling test to exhaustion to determine peak oxygen uptake (V̇O2peak), and a knee extension (KE) maximum voluntary isometric contraction (MVIC) of the right leg before and after four weeks' supervised RT (four sets of 10 repetitions at 80% single repetition maximum unilateral KE exercise, three times weekly) and four weeks' supervised END (30 min combined continuous/interval cycling, three times weekly), separated by a three-week washout phase. Participants were genotyped for the ACTN3 rs1815739, NOS3 rs2070744 and VEGFA rs2010963 SNPs. RESULTS: The intra-individual adaptations regarding percentage changes in MVIC force and V̇O2peak following RT and END, respectively, were unrelated (r2 = 0.003; P = 0.79). However, a VEGFA genotype × training modality interaction (P = 0.007) demonstrated that VEGFA GG homozygotes increased their MVIC force after RT (+ 20.9 ± 13.2%) more than they increased their V̇O2peak after END (+ 8.4 ± 9.1%, P = 0.005), and more than VEGFA C-allele carriers increased their MVIC force after RT (+ 12.2 ± 8.1%, P = 0.04). There were no genotype × training modality interactions for the ACTN3 or NOS3 SNPs. CONCLUSION: High/low responders to RT were not consequently high/low responders to END or vice versa. However, preferential adaptation of VEGFA rs2010963 GG homozygotes to RT over END, and their greater adaptation to RT compared to VEGFA C-allele carriers, indicate a novel genetic predisposition for superior RT adaptation.

Phenotypic plasticity and genetic control in colorectal cancer evolution.

Genetic and epigenetic variation, together with transcriptional plasticity, contribute to intratumour heterogeneity1. The interplay of these biological processes and their respective contributions to tumour evolution remain unknown. Here we show that intratumour genetic ancestry only infrequently affects gene expression traits and subclonal evolution in colorectal cancer (CRC). Using spatially resolved paired whole-genome and transcriptome sequencing, we find that the majority of intratumour variation in gene expression is not strongly heritable but rather 'plastic'. Somatic expression quantitative trait loci analysis identified a number of putative genetic controls of expression by cis-acting coding and non-coding mutations, the majority of which were clonal within a tumour, alongside frequent structural alterations. Consistently, computational inference on the spatial patterning of tumour phylogenies finds that a considerable proportion of CRCs did not show evidence of subclonal selection, with only a subset of putative genetic drivers associated with subclone expansions. Spatial intermixing of clones is common, with some tumours growing exponentially and others only at the periphery. Together, our data suggest that most genetic intratumour variation in CRC has no major phenotypic consequence and that transcriptional plasticity is, instead, widespread within a tumour.

Adaptation of the yeast gene knockout collection is near-perfectly predicted by fitness and diminishing return epistasis.

Adaptive evolution of clonally dividing cells and microbes is the ultimate cause of cancer and infectious diseases. The possibility of constraining the adaptation of cell populations, by inhibiting proteins enhancing the evolvability, has therefore attracted interest. However, our current understanding of how genes influence adaptation kinetics is limited, partly because accurately measuring adaptation for many cell populations is challenging. We used a high-throughput adaptive laboratory evolution platform to track the adaptation of >18,000 cell populations corresponding to single-gene deletion strains in the haploid yeast deletion collection. We report that the preadaptation fitness of gene knockouts near-perfectly (R2= 0.91) predicts their adaptation to arsenic, leaving at the most a marginal role for dedicated evolvability gene functions. We tracked the adaptation of another >23,000 gene knockout populations to a diverse range of selection pressures and generalized the almost perfect (R2=0.72-0.98) capacity of preadaptation fitness to predict adaptation. We also reconstructed mutations in FPS1, ASK10, and ARR3, which together account for almost all arsenic adaptation in wild-type cells, in gene deletions covering a broad fitness range and show that the predictability of arsenic adaptation can be understood as a by global epistasis, where excluding arsenic is more beneficial to arsenic unfit cells. The paucity of genes with a meaningful evolvability effect on adaptation diminishes the prospects of developing adjuvant drugs aiming to slow antimicrobial and chemotherapy resistance.

Genome of Laudakia sacra Provides New Insights into High-Altitude Adaptation of Ectotherms.

Anan's rock agama (Laudakia sacra) is a lizard species endemic to the harsh high-altitude environment of the Qinghai-Tibet Plateau, a region characterized by low oxygen tension and high ultraviolet (UV) radiation. To better understand the genetic mechanisms underlying highland adaptation of ectotherms, we assembled a 1.80-Gb L. sacra genome, which contained 284 contigs with an N50 of 20.19 Mb and a BUSCO score of 93.54%. Comparative genomic analysis indicated that mutations in certain genes, including HIF1A, TIE2, and NFAT family members and genes in the respiratory chain, may be common adaptations to hypoxia among high-altitude animals. Compared with lowland reptiles, MLIP showed a convergent mutation in L. sacra and the Tibetan hot-spring snake (Thermophis baileyi), which may affect their hypoxia adaptation. In L. sacra, several genes related to cardiovascular remodeling, erythropoiesis, oxidative phosphorylation, and DNA repair may also be tailored for adaptation to UV radiation and hypoxia. Of note, ERCC6 and MSH2, two genes associated with adaptation to UV radiation in T. baileyi, exhibited L. sacra-specific mutations that may affect peptide function. Thus, this study provides new insights into the potential mechanisms underpinning high-altitude adaptation in ectotherms and reveals certain genetic generalities for animals' survival on the plateau.