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Current rates of habitat degradation and climate change are causing unprecedented declines in global biodiversity. Studies on vertebrates highlight how conservation genomics can be effective in identifying and managing threatened populations, but it is unclear how vertebrate‐derived metrics of genomic erosion translate to invertebrates, with their markedly different population sizes and life histories. The Black‐veined White butterfly (Aporia crataegi) was extirpated from Britain in the 1920s. Here, we sequenced historical DNA from 17 specimens collected between 1854 and 1924 to reconstruct demography and compare levels of genomic erosion between extirpated British and extant European mainland populations. We contrast these results using modern samples of the Common Blue butterfly (Polyommatus icarus); a species with relatively stable demographic trends in Great Britain. We provide evidence for bottlenecks in both these species around the period of post‐glacial colonization of the British Isles. Our results reveal different demographic histories and Ne for both species, consistent with their fates in Britain, likely driven by differences in life history, ecology and genome size. Despite a difference, by an order of magnitude, in historical effective population sizes (Ne), reduction in genome‐wide heterozygosity in A. crataegi was comparable to that in P. icarus. Symptomatic of A. crataegi's disappearance were marked increases in runs‐of‐homozygosity (RoH), potentially indicative of recent inbreeding, and accumulation of putatively mildly and weakly deleterious variants. Our results provide a rare glimpse of genomic erosion in a regionally extinct insect and support the potential use of genomic erosion metrics in identifying invertebrate populations or species in decline. [ABSTRACT FROM AUTHOR]

The last glacial period is known to have greatly influenced the demographic history of temperate forest trees, with important range contractions and post‐glacial expansions that led to the formation of multiple genetic lineages and secondary contact zones in the Northern Hemisphere. These dynamics have been extensively studied for European and North American species but are still poorly understood in other temperate regions of rich biodiversity such as the Caucasus. Our study helps filling that gap by deciphering the genomic landscapes of F. orientalis across the South Caucasus. The use of genome‐wide data confirmed a past demographic history strongly influenced by the Last Glacial Maximum, revealing two disjunct glacial refugia in the Colchis and Hyrcanian regions. The resulting patterns of genetic diversity, load and differentiation are not always concordant across the region, with genetic load pinpointing the location of the glacial refugia more efficiently than genetic diversity alone. The Hyrcanian forests show depleted genetic diversity and substantial isolation, even if long‐distance gene flow is still present with the main centre of diversity in the Greater Caucasus. Finally, we characterize a strong heterogeneity of genetic diversity and differentiation along the species chromosomes, with noticeably a first chromosome showing low diversity and weak differentiation. [ABSTRACT FROM AUTHOR]

The future survival of coral reefs in the Anthropocene depends on the capacity of corals to adapt as oceans warm and extreme weather events become more frequent. Targeted interventions designed to assist evolutionary processes in corals require a comprehensive understanding of the distribution and structure of standing variation, however, efforts to map genomic variation in corals have so far focussed almost exclusively on SNPs, overlooking structural variants that have been shown to drive adaptive processes in other taxa. Here, we show that the reef‐building coral, Acropora kenti, harbours at least five large, highly polymorphic structural variants, all of which exhibit signatures of strongly suppressed recombination in heterokaryotypes, a feature commonly associated with chromosomal inversions. Based on their high minor allele frequency, uniform distribution across habitats and elevated genetic load, we propose that these inversions in A. kenti are likely to be under balancing selection. An excess of SNPs with high impact on protein‐coding genes within these loci elevates their importance both as potential targets for adaptive selection and as contributors to genetic decline if coral populations become fragmented or inbred in future. [ABSTRACT FROM AUTHOR]

Humans have impacted most of the planet, and the ensuing fragmentation results in small, isolated habitat patches posing a risk of genetic diversity loss, inbreeding, and genetic load. Understanding how natural and anthropogenic landscape features affect gene flow among habitat patches is critical for maintaining connectivity. Genome‐wide data are required to comprehend the impacts of recent fragmentation, which can be challenging when only non‐invasive samples are available. Here, we build upon advancements in conservation genomics to address connectivity of two large herbivores, gaur (Bos gaurus) and sambar (Rusa unicolor) in central India. Given their habitat associations, we expected these species to respond similarly to habitat fragmentation. We used faecal‐DNA and methylation‐based host‐DNA enrichment with modified ddRAD protocol to generate genome‐wide single‐nucleotide polymorphism (SNP) data for 124 gaur and 99 sambar individuals. Our findings reveal that gaur populations in central India are fragmented, displaying high genetic differentiation, with drift significantly affecting small populations like Umred Karhandla Wildlife Sanctuary. Although sambar shows low genetic structure, another small population, Bor Tiger Reserve is genetically differentiated. Our results suggest that although land cover change and roads restrict animal movement, the extent of this impact varies across the two species. We show that different species respond differently to landscape features, even with similar habitat associations. We highlight small and isolated populations requiring urgent conservation intervention. Such multi‐species approaches enhance our understanding of cross‐species connectivity patterns. We suggest shifting from single‐species to multi‐species holistic conservation approach in rapidly developing landscapes to better manage co‐occurring endangered species. [ABSTRACT FROM AUTHOR]

Summary Understanding how life history shapes genetic diversity is a fundamental issue in evolutionary biology, with important consequences for conservation. However, we still have an incomplete picture of the impact of life history on genome‐wide patterns of diversity, especially in long‐lived semelparous plants. Puya raimondii is a high‐altitude semelparous species from the Andes that flowers at 40–100 years of age. We sequenced the whole genome and estimated the nucleotide diversity of 200 individuals sampled from nine populations. Coalescent‐based approaches were then used to infer past population dynamics. Finally, these results were compared with results obtained for the iteroparous species, Puya macrura. The nine populations of P. raimondii were highly divergent, highly inbred, and carried an exceptionally high genetic load. They are genetically depauperate, although, locally in the genome, balancing selection contributed to the maintenance of genetic polymorphism. While both P. raimondii and P. macrura went through a severe bottleneck during the Pleistocene, P. raimondii did not recover from it and continuously declined, while P. macrura managed to bounce back. Our results demonstrate the importance of life history, in particular generation time and reproductive strategy, in affecting population dynamics and genomic variation, and illustrate the genetic fragility of long‐lived semelparous plants. [ABSTRACT FROM AUTHOR]

Previous research on autism spectrum disorders (ASD) have showed important volumetric alterations in the cerebellum and brainstem. Most of these studies are however limited to case-control studies with small clinical samples and including mainly children or adolescents. Herein, we aimed to explore the association between the cumulative genetic load (polygenic risk score, PRS) for ASD and volumetric alterations in the cerebellum and brainstem, as well as global brain tissue volumes of the brain among adults at the population level. We utilized the latest genome-wide association study of ASD by the Psychiatric Genetics Consortium (18,381 cases, 27,969 controls) and constructed the ASD PRS in an independent cohort, the UK Biobank. Regression analyses controlled for multiple comparisons with the false-discovery rate (FDR) at 5% were performed to investigate the association between ASD PRS and forty-four brain magnetic resonance imaging (MRI) phenotypes among ~ 31,000 participants. Primary analyses included sixteen MRI phenotypes: total volumes of the brain, cerebrospinal fluid (CSF), grey matter (GM), white matter (WM), GM of whole cerebellum, brainstem, and ten regions of the cerebellum (I_IV, V, VI, VIIb, VIIIa, VIIIb, IX, X, CrusI and CrusII). Secondary analyses included twenty-eight MRI phenotypes: the sub-regional volumes of cerebellum including the GM of the vermis and both left and right lobules of each cerebellar region. ASD PRS were significantly associated with the volumes of seven brain areas, whereby higher PRS were associated to reduced volumes of the whole brain, WM, brainstem, and cerebellar regions I-IV, IX, and X, and an increased volume of the CSF. Three sub-regional volumes including the left cerebellar lobule I-IV, cerebellar vermes VIIIb, and X were significantly and negatively associated with ASD PRS. The study highlights a substantial connection between susceptibility to ASD, its underlying genetic etiology, and neuroanatomical alterations of the adult brain. [ABSTRACT FROM AUTHOR]

Aim Location Methods Results Main Conclusions Marginal tree populations, either those located at the edges of the species' range or in suboptimal environments, are often a valuable genetic resource for biological conservation. However, there is a lack of knowledge about the genetic consequences of population marginality, estimated across entire species' ranges. Our study addresses this gap by providing information about several genetic indicators and their variability in marginal and core populations identified using quantitative marginality indices.Southwestern Europe and North Africa.Using 10,185 SNPs across 82 populations of maritime pine (Pinus pinaster Ait.), a widespread conifer characterised by a fragmented range, we modelled the relationship of seven genetic indicators potentially related to population evolutionary resilience, namely genetic diversity (based on both all SNPs and outlier SNPs), inbreeding, genetic differentiation, recessive genetic load and genomic offset, with population geographical, demo‐historical and ecological marginality (as estimated by nine quantitative indices). Models were constructed for both regional (introducing gene pool as a random factor) and range‐wide spatial scales.We showed a trend towards decreasing overall genetic diversity and increasing differentiation with geographic marginality, supporting the centre‐periphery hypothesis (CPH). However, we found no correlation between population inbreeding and marginality, while geographically marginal populations had a lower recessive genetic load (only models without the gene pool effect). Ecologically marginal populations had a higher genomic offset, suggesting higher maladaptation to future climate, albeit some of these populations also had high genetic diversity for climate outliers.Overall genetic diversity (but not outlier‐based estimates) and differentiation patterns support the CPH. Ecologically marginal populations and those at the southern edge could be more vulnerable to climate change due to higher climate maladaptation, as predicted by genomic offsets, and/or lower potentially adaptive genetic diversity. This risk is exacerbated by typically small effective population sizes and increasing human impact in marginal populations. [ABSTRACT FROM AUTHOR]

Indicator models of sexual selection posit that females choose males on the basis of traits that reveal male genetic quality and thereby enjoy increased offspring production. Here, we report that females of the butterfly Eurema hecabe receive indirect benefits from choosing males based on their ultraviolet (UV) wing coloration, a heritable and condition-dependent trait in this species. We first used a large laboratory-bred pedigree to demonstrate a per-family association between inbreeding and male UV trait value. Females exerted choice for UV-bright males within this protocol, and the average male UV trait value increased over six consecutive generations, presumably due to such selection and despite an increasing rate of pedigree-wide inbreeding. We then experimentally imposed a standard strength of inbreeding upon lines of divergent male UV trait values. Inbreeding depressed the siring performance of low UV treatment males more severely and resulted in a marginal reduction of their UV brightness, which rebounded sharply following subsequent outcrossing. These findings are consistent with the ornament-based signaling of genetic quality as a function of underlying individual-level mutational load. [ABSTRACT FROM AUTHOR]

Plasticity is found in all domains of life and is particularly relevant when populations experience variable environmental conditions. Traditionally, evolutionary models of plasticity are non-mechanistic: they typically view reactions norms as the target of selection, without considering the underlying genetics explicitly. Consequently, there have been difficulties in understanding the emergence of plasticity, and in explaining its limits and costs. In this paper, we offer a novel mechanistic approximation for the emergence and evolution of plasticity. We simulate random "epigenetic mutations" in the genotype–phenotype mapping, of the kind enabled by DNA-methylations/demethylations. The frequency of epigenetic mutations at loci affecting the phenotype is sensitive to organism stress (trait–environment mismatch), but is also genetically determined and evolvable. Thus, the "random motion" of epigenetic markers enables developmental learning-like behaviors that can improve adaptation within the limits imposed by the genotypes. However, with random motion being "goal-less," this mechanism is also vulnerable to developmental noise leading to maladaptation. Our individual-based simulations show that epigenetic mutations can hide alleles that are temporarily unfavorable, thus enabling cryptic genetic variation. These alleles can be advantageous at later times, under regimes of environmental change, in spite of the accumulation of genetic loads. Simulations also demonstrate that plasticity is favored by natural selection in constant environments, but more under periodic environmental change. Plasticity also evolves under directional environmental change as long as the pace of change is not too fast and costs are low. [ABSTRACT FROM AUTHOR]

Summary: Scots pine is the foundation species of diverse forested ecosystems across Eurasia and displays remarkable ecological breadth, occurring in environments ranging from temperate rainforests to arid tundra margins. Such expansive distributions can be favored by various demographic and adaptive processes and the interactions between them.To understand the impact of neutral and selective forces on genetic structure in Scots pine, we conducted range‐wide population genetic analyses on 2321 trees from 202 populations using genotyping‐by‐sequencing, reconstructed the recent demography of the species and examined signals of genetic adaptation.We found a high and uniform genetic diversity across the entire range (global FST 0.048), no increased genetic load in expanding populations and minor impact of the last glacial maximum on historical population sizes. Genetic‐environmental associations identified only a handful of single‐nucleotide polymorphisms significantly linked to environmental gradients.The results suggest that extensive gene flow is predominantly responsible for the observed genetic patterns in Scots pine. The apparent missing signal of genetic adaptation is likely attributed to the intricate genetic architecture controlling adaptation to multi‐dimensional environments. The panmixia metapopulation of Scots pine offers a good study system for further exploration into how genetic adaptation and plasticity evolve under gene flow and changing environment. See also the Commentary on this article by Duffy, 243: 830–832. [ABSTRACT FROM AUTHOR]

This cohort replication study investigates the ability of multitrait polygenic risk scores to strengthen genetic prediction of longitudinal depression across adolescence. Key Points: Question: Could multitrait polygenic risk scores be used to strengthen genetic prediction of longitudinal depression across adolescence? Findings: In this longitudinal cohort replication study of 14 112 adolescents, stronger effect sizes of multitrait polygenic risk association with adverse depression trajectories were found compared with unitrait genetic risk. Meaning: Longitudinal depression has a robust genetic underpinning, and leveraging shared genetic information across multiple psychiatric traits may strengthen prediction models of depression in adolescence. Importance: Adolescent depression is characterized by diverse symptom trajectories over time and has a strong genetic influence. Research has determined genetic overlap between depression and other psychiatric conditions; investigating the shared genetic architecture of heterogeneous depression trajectories is crucial for understanding disease etiology, prediction, and early intervention. Objective: To investigate univariate and multivariate genetic risk for adolescent depression trajectories and assess generalizability across ancestries. Design, Setting, and Participants: This cohort study entailed longitudinal growth modeling followed by polygenic risk score (PRS) association testing for individual and multitrait genetic models. Two longitudinal cohorts from the US and UK were used: the Adolescent Brain and Cognitive Development (ABCD; N = 11 876) study and the Avon Longitudinal Study of Parents and Children (ALSPAC; N = 8787) study. Included were adolescents with genetic information and depression measures at up to 8 and 4 occasions, respectively. Study data were analyzed January to July 2023. Main Outcomes and Measures: Trajectories were derived from growth mixture modeling of longitudinal depression symptoms. PRSs were computed for depression, anxiety, neuroticism, bipolar disorder, schizophrenia, attention-deficit/hyperactivity disorder, and autism in European ancestry. Genomic structural equation modeling was used to build multitrait genetic models of psychopathology followed by multitrait PRS. Depression PRSs were computed in African, East Asian, and Hispanic ancestries in the ABCD cohort only. Association testing was performed between all PRSs and trajectories for both cohorts. Results: A total sample size of 14 112 adolescents (at baseline: mean [SD] age, 10.5 [0.5] years; 7269 male sex [52%]) from both cohorts were included in this analysis. Distinct depression trajectories (stable low, adolescent persistent, increasing, and decreasing) were replicated in the ALSPAC cohort (6096 participants; 3091 female [51%]) and ABCD cohort (8016 participants; 4274 male [53%]) between ages 10 and 17 years. Most univariate PRSs showed significant uniform associations with persistent trajectories, but fewer were significantly associated with intermediate (increasing and decreasing) trajectories. Multitrait PRSs—derived from a hierarchical factor model—showed the strongest associations for persistent trajectories (ABCD cohort: OR, 1.46; 95% CI, 1.26-1.68; ALSPAC cohort: OR, 1.34; 95% CI, 1.20-1.49), surpassing the effect size of univariate PRS in both cohorts. Multitrait PRSs were associated with intermediate trajectories but to a lesser extent (ABCD cohort: hierarchical increasing, OR, 1.27; 95% CI, 1.13-1.43; decreasing, OR, 1.23; 95% CI, 1.09-1.40; ALSPAC cohort: hierarchical increasing, OR, 1.16; 95% CI, 1.04-1.28; decreasing, OR, 1.32; 95% CI, 1.18-1.47). Transancestral genetic risk for depression showed no evidence for association with trajectories. Conclusions and Relevance: Results of this cohort study revealed a high multitrait genetic loading of persistent symptom trajectories, consistent across traits and cohorts. Variability in univariate genetic association with intermediate trajectories may stem from environmental factors. Multitrait genetics may strengthen depression prediction models, but more diverse data are needed for generalizability. [ABSTRACT FROM AUTHOR]

Background: In the tumor microenvironment (TME), a bidirectional relationship exists between hypoxia and lactate metabolism, with each component exerting a reciprocal influence on the other, forming an inextricable link. The aim of the present investigation was to develop a prognostic model by amalgamating genes associated with hypoxia and lactate metabolism. This model is intended to serve as a tool for predicting patient outcomes, including survival rates, the status of the immune microenvironment, and responsiveness to therapy in patients with lung adenocarcinoma (LUAD). Methods: Transcriptomic sequencing data and patient clinical information specific to LUAD were obtained from comprehensive repositories of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). A compendium of genes implicated in hypoxia and lactate metabolism was assembled from an array of accessible datasets. Univariate and multivariate Cox regression analyses were employed. Additional investigative procedures, including tumor mutational load (TMB), microsatellite instability (MSI), functional enrichment assessments and the ESTIMATE, CIBERSORT, and TIDE algorithms, were used to evaluate drug sensitivity and predict the efficacy of immune-based therapies. Results: A novel prognostic signature comprising five lactate and hypoxia-related genes (LHRGs), PKFP, SLC2A1, BCAN, CDKN3, and ANLN, was established. This model demonstrated that LUAD patients with elevated LHRG-related risk scores exhibited significantly reduced survival rates. Both univariate and multivariate Cox analyses confirmed that the risk score was a robust prognostic indicator of overall survival. Immunophenotyping revealed increased infiltration of memory CD4 + T cells, dendritic cells and NK cells in patients classified within the high-risk category compared to their low-risk counterparts. Higher probability of mutations in lung adenocarcinoma driver genes in high-risk groups, and the MSI was associated with the risk-score. Functional enrichment analyses indicated a predominance of cell cycle-related pathways in the high-risk group, whereas metabolic pathways were more prevalent in the low-risk group. Moreover, drug sensitivity analyses revealed increased sensitivity to a variety of drugs in the high-risk group, especially inhibitors of the PI3K-AKT, EGFR, and ELK pathways. Conclusions: This prognostic model integrates lactate metabolism and hypoxia parameters, offering predictive insights regarding survival, immune cell infiltration and functionality, as well as therapeutic responsiveness in LUAD patients. This model may facilitate personalized treatment strategies, tailoring interventions to the unique molecular profile of each patient's disease. [ABSTRACT FROM AUTHOR]

Islands are crucial evolutionary hotspots, providing unique opportunities for differentiation of novel biodiversity and long-term segregation of endemic species. Islands are also fragile ecosystems, where biodiversity is more exposed to environmental and anthropogenic pressures than on continents. The Ponza grayling, Hipparchia sbordonii , is an endemic butterfly species that is currently found only in two tiny islands of the Pontine archipelago, off the coast of Italy, occupying an area smaller than 10 km2. It has been classified as Endangered (IUCN) because of the extremely limited area of occurrence, population fragmentation, and the recent demographic decline. Thanks to a combination of different assemblers of long and short genomic reads, bulk transcriptome RNAseq, and synteny analysis with phylogenetically close butterflies, we produced a highly contiguous, chromosome-scale annotated reference genome for the Ponza grayling, including 28 autosomes and the Z sexual chromosomes. The final assembly spanned 388.61 Gb with a contig N50 of 14.5 Mb and a BUSCO completeness score of 98.5%. Synteny analysis using four other butterfly species revealed high collinearity with Hipparchia semele and highlighted 10 intrachromosomal inversions longer than 10 kb, of which two appeared on the lineage leading to H. sbordonii. Our results show that a chromosome-scale reference genome is attainable also when chromatin conformation data may be impractical or present specific technical challenges. The high-quality genomic resource for H. sbordonii opens up new opportunities for the accurate assessment of genetic diversity and genetic load and for the investigations of the genomic novelties characterizing the evolutionary path of this endemic island species. [ABSTRACT FROM AUTHOR]

The Seychelles magpie‐robin's (SMR) five island populations exhibit some of the lowest recorded levels of genetic diversity among endangered birds, and high levels of inbreeding. These populations collapsed during the 20th century, and the species was listed as Critically Endangered in the IUCN Red List in 1994. An assisted translocation‐for‐recovery program initiated in the 1990s increased the number of mature individuals, resulting in its downlisting to Endangered in 2005. Here, we explore the temporal genomic erosion of the SMR based on a dataset of 201 re‐sequenced whole genomes that span the past ~150 years. Our sample set includes individuals that predate the bottleneck by up to 100 years, as well as individuals from contemporary populations established during the species recovery program. Despite the SMR's recent demographic recovery, our data reveal a marked increase in both the genetic load and realized load in the extant populations when compared to the historical samples. Conservation management may have reduced the intensity of selection by increasing juvenile survival and relaxing intraspecific competition between individuals, resulting in the accumulation of loss‐of‐function mutations (i.e. severely deleterious variants) in the rapidly recovering population. In addition, we found a 3‐fold decrease in genetic diversity between temporal samples. While the low genetic diversity in modern populations may limit the species' adaptability to future environmental changes, future conservation efforts (including IUCN assessments) may also need to assess the threats posed by their high genetic load. Our computer simulations highlight the value of translocations for genetic rescue and show how this could halt genomic erosion in threatened species such as the SMR. [ABSTRACT FROM AUTHOR]

Inbred populations often suffer from increased mutational load and reduced fitness due to lower efficacy of purifying selection in groups with small effective population sizes. Genetic rescue (GR) is a conservation tool that is studied and deployed with the aim of increasing the fitness of such inbred populations by assisted migration of individuals from closely related outbred populations. The success of GR depends on several factors—such as their demographic history and distribution of dominance effects of mutations—that may vary across populations. While we understand the impact of these factors on the dynamics of GR, their impact on local adaptations remains unclear. To this end, we conduct a population genetics simulation study to evaluate the impact of trait complexity (Mendelian vs. polygenic), dominance effects, and demographic history on the efficacy of GR. We find that the impact on local adaptations depends highly on the mutational load at the time of GR, which is in turn shaped dynamically by interactions between demographic history and dominance effects of deleterious variation. Over time local adaptations are generally restored post-GR, though in the short term they are often compromised in the process of purging deleterious variation. We also show that while local adaptations are almost always fully restored, the degree to which ancestral genetic variation affecting the trait is replaced by donor variation can vary drastically and is especially high for complex traits. Our results provide insights on the impact of GR on trait evolution and considerations for the practical implementation of GR. [ABSTRACT FROM AUTHOR]

Background The predominance of sex in eukaryotes, despite the high costs of meiosis and mating, remains an evolutionary enigma. Many theories have been proposed, none of them being conclusive on its own, and they are, in part, not well applicable to land plants. Sexual reproduction is obligate in embryophytes for the great majority of species. Scope This review compares the main forms of sexual and asexual reproduction in ferns and angiosperms, based on the generation cycling of sporophyte and gametophyte (leaving vegetative propagation aside). The benefits of sexual reproduction for maintenance of genomic integrity in comparison to asexuality are discussed in the light of developmental, evolutionary, genetic and phylogenetic studies. Conclusions Asexual reproduction represents modifications of the sexual pathway, with various forms of facultative sexuality. For sexual land plants, meiosis provides direct DNA repair mechanisms for oxidative damage in reproductive tissues. The ploidy alternations of meiosis–syngamy cycles and prolonged multicellular stages in the haploid phase in the gametophytes provide a high efficiency of purifying selection against recessive deleterious mutations. Asexual lineages might buffer effects of such mutations via polyploidy and can purge the mutational load via facultative sexuality. The role of organelle–nuclear genome compatibility for maintenance of genome integrity is not well understood. In plants in general, the costs of mating are low because of predominant hermaphroditism. Phylogenetic patterns in the archaeplastid clade suggest that high frequencies of sexuality in land plants are concomitant with a stepwise increase of intrinsic and extrinsic stress factors. Furthermore, expansion of genome size in land plants would increase the potential mutational load. Sexual reproduction appears to be essential for keeping long-term genomic integrity, and only rare combinations of extrinsic and intrinsic factors allow for shifts to asexuality. [ABSTRACT FROM AUTHOR]

Local adaptation frequently evolves in patches or environments that are connected via migration. In these cases, genomic regions that are linked to a locally adapted locus experience reduced effective migration rates. Via individual-based simulations of a two-patch system, we show that this reduced effective migration results in the accumulation of conditionally deleterious mutations, but not universally deleterious mutations, adjacent to adaptive loci. When there is redundancy in the genetic basis of local adaptation (i.e., genotypic redundancy), turnover of locally adapted polymorphisms allows conditionally deleterious mutation load to be purged. The amount of mutational load that accumulates adjacent to locally adapted loci is dependent on redundancy, recombination rate, migration rate, population size, strength of selection, and the phenotypic effect size of adaptive alleles. Our results highlight the need to be cautious when interpreting patterns of local adaptation at the level of phenotype or fitness, as the genetic basis of local adaptation can be transient, and evolution may confer a degree of maladaptation to nonlocal environments. [ABSTRACT FROM AUTHOR]

The feral cattle of the subantarctic island of Amsterdam provide an outstanding case study of a large mammalian population that was established by a handful of founders and thrived within a few generations in a seemingly inhospitable environment. Here, we investigated the genetic history and composition of this population using genotyping and sequencing data. Our inference showed an intense but brief founding bottleneck around the late 19th century and revealed contributions from European taurine and Indian Ocean Zebu in the founder ancestry. Comparative analysis of whole-genome sequences further revealed a moderate reduction in genetic diversity despite high levels of inbreeding. The brief and intense bottleneck was associated with high levels of drift, a flattening of the site frequency spectrum and a slight relaxation of purifying selection on mildly deleterious variants. Unlike some populations that have experienced prolonged reductions in effective population size, we did not observe any significant purging of highly deleterious variants. Interestingly, the population's success in the harsh environment can be attributed to preadaptation from their European taurine ancestry, suggesting no strong bioclimatic challenge, and also contradicting evidence for insular dwarfism. Genome scan for footprints of selection uncovered a majority of candidate genes related to nervous system function, likely reflecting rapid feralization driven by behavioral changes and complex social restructuring. The Amsterdam Island cattle offers valuable insights into rapid population establishment, feralization, and genetic adaptation in challenging environments. It also sheds light on the unique genetic legacies of feral populations, raising ethical questions according to conservation efforts. [ABSTRACT FROM AUTHOR]

Background: Neural progenitor cells (NPCs) can be cultivated from developing brains, reproducing many of the processes that occur during neural development. They can be isolated from a variety of animal models, such as transgenic mice carrying mutations in amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN 1 and 2), characteristic of familial Alzheimer's disease (fAD). Modulating the development of these cells with inflammation-related peptides, such as bradykinin (BK) and its antagonist HOE-140, enables the understanding of the impact of such molecules in a relevant AD model. Results: We performed a global gene expression analysis on transgenic neurospheres treated with BK and HOE-140. To validate the microarray data, quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) was performed on 8 important genes related to the immune response in AD such as CCL12, CCL5, CCL3, C3, CX3CR1, TLR2 and TNF alpha and Iba-1. Furthermore, comparative analysis of the transcriptional profiles was performed between treatments, including gene ontology and reactome enrichment, construction and analysis of protein-protein interaction networks and, finally, comparison of our data with human dataset from AD patients. The treatments affected the expression levels of genes mainly related to microglia-mediated neuroinflammatory responses, with BK promoting an increase in the expression of genes that enrich processes, biological pathways, and cellular components related to immune dysfunction, neurodegeneration and cell cycle. B2 receptor inhibition by HOE-140 resulted in the reduction of AD-related anomalies caused in this system. Conclusions: BK is an important immunomodulatory agent and enhances the immunological changes identified in transgenic neurospheres carrying the genetic load of AD. Bradykinin treatments modulate the expression rates of genes related to microglia-mediated neuroinflammation. Inhibiting bradykinin activity in Alzheimer's disease may slow disease progression. [ABSTRACT FROM AUTHOR]

Mitochondrial quality control is essential in mitochondrial function. To examine the importance of Parkin-dependent mechanisms in mitochondrial quality control, we assessed the impact of modulating Parkin on proteome flux and mitochondrial function in a context of reduced mtDNA fidelity. To accomplish this, we crossed either the Parkin knockout mouse or ParkinW402A knock-in mouse lines to the Polg mitochondrial mutator line to generate homozygous double mutants. In vivo longitudinal isotopic metabolic labeling was followed by isolation of liver mitochondria and synaptic terminals from the brain, which are rich in mitochondria. Mass spectrometry and bioenergetics analysis were assessed. We demonstrate that slower mitochondrial protein turnover is associated with loss of mtDNA fidelity in liver mitochondria but not synaptic terminals, and bioenergetic function in both tissues is impaired. Pathway analysis revealed loss of mtDNA fidelity is associated with disturbances of key metabolic pathways, consistent with its association with metabolic disorders and neurodegeneration. Furthermore, we find that loss of Parkin leads to exacerbation of Polg-driven proteomic consequences, though it may be bioenergetically protective in tissues exhibiting rapid mitochondrial turnover. Finally, we provide evidence that, surprisingly, dis-autoinhibition of Parkin (ParkinW402A) functionally resembles Parkin knockout and fails to rescue deleterious Polg-driven effects. Our study accomplishes three main outcomes: (1) it supports recent studies suggesting that Parkin dependence is low in response to an increased mtDNA mutational load, (2) it provides evidence of a potential protective role of Parkin insufficiency, and (3) it draws into question the therapeutic attractiveness of enhancing Parkin function. [ABSTRACT FROM AUTHOR]

Facultative parthenogenesis (FP) has historically been regarded as rare in vertebrates, but in recent years incidences have been reported in a growing list of fish, reptile, and bird species. Despite the increasing interest in the phenomenon, the underlying mechanism and evolutionary implications have remained unclear. A common finding across many incidences of FP is either a high degree of homozygosity at microsatellite loci or low levels of heterozygosity detected in next-generation sequencing data. This has led to the proposal that second polar body fusion following the meiotic divisions restores diploidy and thereby mimics fertilization. Here, we show that FP occurring in the gonochoristic Aspidoscelis species A. marmoratus and A. arizonae results in genome-wide homozygosity, an observation inconsistent with polar body fusion as the underlying mechanism of restoration. Instead, a high-quality reference genome for A. marmoratus and analysis of whole-genome sequencing from multiple FP and control animals reveals that a post-meiotic mechanism gives rise to homozygous animals from haploid, unfertilized oocytes. Contrary to the widely held belief that females need to be isolated from males to undergo FP, females housed with conspecific and heterospecific males produced unfertilized eggs that underwent spontaneous development. In addition, offspring arising from both fertilized eggs and parthenogenetic development were observed to arise from a single clutch. Strikingly, our data support a mechanism for facultative parthenogenesis that removes all heterozygosity in a single generation. Complete homozygosity exposes the genetic load and explains the high rate of congenital malformations and embryonic mortality associated with FP in many species. Conversely, for animals that develop normally, FP could potentially exert strong purifying selection as all lethal recessive alleles are purged in a single generation. [ABSTRACT FROM AUTHOR]

Human populations harbor a high concentration of deleterious genetic variants. Here, we tested the hypothesis that non-random mating practices affect the distribution of these variants, through exposure in the homozygous state, leading to their purging from the population gene pool. To do so, we produced whole-genome sequencing data for two pairs of Asian populations exhibiting different alliance rules and rates of inbreeding, but with similar effective population sizes. The results show that populations with higher rates of inbred matings do not purge deleterious variants more efficiently. Purging therefore has a low efficiency in human populations, and different mating practices lead to a similar mutational load. [ABSTRACT FROM AUTHOR]

High mountains harbor a considerable proportion of biodiversity, but we know little about how diverse plants adapt to the harsh environment. Here we finished a high-quality genome assembly for Dasiphora fruticosa , an ecologically important plant distributed in the Qinghai-Tibetan Plateau and lowland of the Northern Hemisphere, and resequenced 592 natural individuals to address how this horticulture plant adapts to highland. Demographic analysis revealed D. fruticosa underwent a bottleneck after Naynayxungla Glaciation. Selective sweep analysis of two pairs of lowland and highland populations identified 63 shared genes related to cell wall organization or biogenesis, cellular component organization, and dwarfism, suggesting parallel adaptation to highland habitats. Most importantly, we found that stronger purging of estimated genetic load due to inbreeding in highland populations apparently contributed to their adaptation to the highest mountain. Our results revealed how plants could tolerate the extreme plateau, which could provide potential insights for species conservation and crop breeding. [ABSTRACT FROM AUTHOR]

Global climate change has increased concerns regarding biodiversity loss. However, many key conservation issues still required further research, including demographic history, deleterious mutation load, adaptive evolution, and putative introgression. Here we generated the first chromosome-level genome of the endangered Chinese hazelnut, Corylus chinensis, and compared the genomic signatures with its sympatric widespread C. kwechowensis–C. yunnanensis complex. We found large genome rearrangements across all Corylus species and identified species-specific expanded gene families that may be involved in adaptation. Population genomics revealed that both C. chinensis and the C. kwechowensis–C. yunnanensis complex had diverged into two genetic lineages, forming a consistent pattern of southwestern-northern differentiation. Population size of the narrow southwestern lineages of both species have decreased continuously since the late Miocene, whereas the widespread northern lineages have remained stable (C. chinensis) or have even recovered from population bottlenecks (C. kwechowensis–C. yunnanensis complex) during the Quaternary. Compared with C. kwechowensis–C. yunnanensis complex, C. chinensis showed significantly lower genomic diversity and higher inbreeding level. However, C. chinensis carried significantly fewer deleterious mutations than C. kwechowensis–C. yunnanensis complex, as more effective purging selection reduced the accumulation of homozygous variants. We also detected signals of positive selection and adaptive introgression in different lineages, which facilitated the accumulation of favorable variants and formation of local adaptation. Hence, both types of selection and exogenous introgression could have mitigated inbreeding and facilitated survival and persistence of C. chinensis. Overall, our study provides critical insights into lineage differentiation, local adaptation, and the potential for future recovery of endangered trees.

Genetic changes that enabled the evolution of eusociality have long captivated biologists. More recently, attention has focussed on the consequences of eusociality on genome evolution. Studies have reported higher molecular evolutionary rates in eusocial hymenopteran insects compared with their solitary relatives. To investigate the genomic consequences of eusociality in termites, we analysed nine genomes, including newly sequenced genomes from three non-eusocial cockroaches. Using a phylogenomic approach, we found that termite genomes have experienced lower rates of synonymous substitutions than those of cockroaches, possibly as a result of longer generation times. We identified higher rates of non-synonymous substitutions in termite genomes than in cockroach genomes, and identified pervasive relaxed selection in the former (24–31% of the genes analysed) compared with the latter (2–4%). We infer that this is due to reductions in effective population size, rather than gene-specific effects (e.g. indirect selection of caste-biased genes). We found no obvious signature of increased genetic load in termites, and postulate efficient purging of deleterious alleles at the colony level. Additionally, we identified genomic adaptations that may underpin caste differentiation, such as genes involved in post-translational modifications. Our results provide insights into the evolution of termites and the genomic consequences of eusociality more broadly. [ABSTRACT FROM AUTHOR]

Introduction: In recent years, there has been a strong association between transient receptor potential (TRP) channels and the development of various malignancies, drug resistance, and resistance to radiotherapy. Consequently, we have investigated the relationship between transient receptor potential channels and cervical cancer from multiple angles. Methods: Patients' mRNA expression profiles and gene variants were obtained from the TCGA database. Key genes in transient receptor potential channel prognosis-related genes (TRGs) were screened using the least absolute shrinkage and selection operator (LASSO) regression method, and a risk signature was constructed based on the expression of key genes. Various analyses were performed to evaluate the prognostic significance, biological functions, immune infiltration, and response to immunotherapy based on the risk signature. Results: Our research reveals substantial differences between high and low-risk groups in prognosis, tumor microenvironment, tumor mutational load, immune infiltration, and response to immunotherapy. Patients in the high-risk group exhibited poorer prognosis, lower tumor microenvironment scores and reduced response to immunotherapy while showing increased sensitivity to specific targeted drugs. In vitro experiments further illustrated that inhibiting transient receptor potential channels effectively decreased the proliferation, invasion, and migration of cervical cancer cells. Discussion: This study highlights the significant potential of transient receptor potential channels in cervical cancer, emphasizing their crucial role in prognostic prediction and personalized treatment strategies. The combination of TRP inhibitors with immunotherapy and targeted drugs may offer promise for individuals affected by cervical cancer. [ABSTRACT FROM AUTHOR]

Zoo populations of threatened species are a valuable resource for the restoration of wild populations. However, their small effective population size poses a risk to long‐term viability, especially in species with high genetic load. Recent bioinformatic developments can identify harmful genetic variants in genome data. Here, we advance this approach, analysing the genetic load in the threatened pink pigeon (Nesoenas mayeri). We lifted the mutation‐impact scores that had been calculated for the chicken (Gallus gallus) to estimate the genetic load in six pink pigeons. Additionally, we perform in silico crossings to predict the genetic load and realized load of potential offspring. We thus identify the optimal mate pairs that are theoretically expected to produce offspring with the least inbreeding depression. We use computer simulations to show how genomics‐informed conservation can reduce the genetic load whilst reducing the loss of genome‐wide diversity. Genomics‐informed management is likely to become instrumental in maintaining the long‐term viability of zoo populations. [ABSTRACT FROM AUTHOR]

Genetic diversity underpins evolutionary potential that is essential for the long‐term viability of wildlife populations. Captive populations harbor genetic diversity potentially lost in the wild, which could be valuable for release programs and genetic rescue. The Critically Endangered Arabian leopard (Panthera pardus nimr) has disappeared from most of its former range across the Arabian Peninsula, with fewer than 120 individuals left in the wild, and an additional 64 leopards in captivity. We (i) examine genetic diversity in the wild and captive populations to identify global patterns of genetic diversity and structure; (ii) estimate the size of the remaining leopard population across the Dhofar mountains of Oman using spatially explicit capture–recapture models on DNA and camera trap data, and (iii) explore the impact of genetic rescue using three complementary computer modeling approaches. We estimated a population size of 51 (95% CI 32–79) in the Dhofar mountains and found that 8 out of 25 microsatellite alleles present in eight loci in captive leopards were undetected in the wild. This includes two alleles present only in captive founders known to have been wild‐sourced from Yemen, which suggests that this captive population represents an important source for genetic rescue. We then assessed the benefits of reintroducing novel genetic diversity into the wild population as well as the risks of elevating the genetic load through the release of captive‐bred individuals. Simulations indicate that genetic rescue can improve the long‐term viability of the wild population by reducing its genetic load and realized load. The model also suggests that the genetic load has been partly purged in the captive population, potentially making it a valuable source population for genetic rescue. However, the greater loss of its genetic diversity could exacerbate genomic erosion of the wild population during a rescue program, and these risks and benefits should be carefully evaluated. An important next step in the recovery of the Arabian leopard is to empirically validate these conclusions, implement and monitor a genomics‐informed management plan, and optimize a strategy for genetic rescue as a tool to recover Arabia's last big cat. [ABSTRACT FROM AUTHOR]

Premise: Global anthropogenic change threatens the health and productivity of forest ecosystems. Assisted migration and reforestation are tools to help mitigate these impacts. However, questions remain about how to approach sourcing seeds to ensure high establishment and future adaptability. Methods: Using exome‐capture sequencing, we demonstrate a computational approach to finding the best n‐sets from a candidate list of seed sources that collectively achieve high genetic diversity (GD) and minimal genetic load (GL), while also increasing evolvability in quantitative traits. The benefits of this three‐part strategy (diversity‐load‐evolvability) are to increase near‐term establishment success while also boosting evolutionary potential to respond to future stressors. Members of The Nature Conservancy and the Central Appalachian Spruce Restoration Initiative planted 58,000 seedlings across 255 acres. A subset of seedlings was monitored for establishment success and variation in growth. Results: The results show gains in GD relative to GL and increases in quantitative genetic variation in seedling growth for pooled vs. single‐source restoration. No single "super source" was observed across planting sites; rather, monitoring results demonstrate that pooling of multiple sources helps achieve higher GD:GL and evolvability. Discussion: Our study shows the potential for integrating genomics into local‐scale restoration and the importance of building partnerships between academic researchers and applied conservation managers. [ABSTRACT FROM AUTHOR]

The fungus Ustilago maydis produces galls or tumors on corn ears called corn smut or huitlacoche. Used for human consumption in several countries for its nutritional and sensory traits, huitlacoche is considered a delicacy in Mexican cuisine and has a significant economic value. Hybrid U. maydis strains are regularly used for the large-scale production of huitlacoche; however, depending on the genetic characteristics of the parent strains, the pathogenicity and infection rate of hybrid fungi are often suboptimal due to compatibility issues between different strains. Using double-loaded organisms is common in agriculture to improve product characteristics, performance, and shelf-life. A methodology to obtain unicellular U. maydis strains with a double genetic load (n + n) capable of producing galls on corn ears without mating (hybridization) is reported herein. This methodology resulted in 206 U. maydis isolates. Screening showed that 147 corn plants (>70%) underwent infection and gall production. Of the 147 gall-producing U. maydis strains, those with the highest field performance were selected. Three strains, Um-UAEMor-78 (yielding 21.65 ton/ha), Um-UAEMor-120 (22.31 ton/ha), and Um-UAEMor-187 (22.99 ton/ha), showed higher yields than the control strain, CP-436(a1b1) × CP-437(a2b2) (17.80 ton/ha). A specific methodology to obtain unicellular U. maydis strains with a double genetic load capable of infecting baby corn ears and forming galls is described for the first time, providing a novel alternative for producing huitlacoche and helping to improve the yields and morphological traits of galls. [ABSTRACT FROM AUTHOR]

As biodiversity loss outpaces recovery, conservationists are increasingly turning to novel tools for preventing extinction, including cloning and in vitro gametogenesis of biobanked cells. However, restoration of populations can be hindered by low genetic diversity and deleterious genetic load. The persistence of the northern white rhino (Ceratotherium simum cottoni) now depends on the cryopreserved cells of 12 individuals. These banked genomes have higher genetic diversity than southern white rhinos (C. s. simum), a sister subspecies that successfully recovered from a severe bottleneck, but the potential impact of genetic load is unknown. We estimated how demographic history has shaped genome‐wide genetic load in nine northern and 13 southern white rhinos. The bottleneck left southern white rhinos with more fixed and homozygous deleterious alleles and longer runs of homozygosity, whereas northern white rhinos retained more deleterious alleles masked in heterozygosity. To gauge the impact of genetic load on the fitness of a northern white rhino population restored from biobanked cells, we simulated recovery using fitness of southern white rhinos as a benchmark for a viable population. Unlike traditional restoration, cell‐derived founders can be reintroduced in subsequent generations to boost lost genetic diversity and relieve inbreeding. In simulations with repeated reintroduction of founders into a restored population, the fitness cost of genetic load remained lower than that borne by southern white rhinos. Without reintroductions, rapid growth of the restored population (>20–30% per generation) would be needed to maintain comparable fitness. Our results suggest that inbreeding depression from genetic load is not necessarily a barrier to recovery of the northern white rhino and demonstrate how restoration from biobanked cells relieves some constraints of conventional restoration from a limited founder pool. Established conservation methods that protect healthy populations will remain paramount, but emerging technologies hold promise to bolster these tools to combat the extinction crisis. [ABSTRACT FROM AUTHOR]

Background: Tryptophan (Trp) is an essential amino acid. Increasing evidence suggests that tryptophan metabolism plays a complex role in immune escape from Lung adenocarcinoma (LUAD). However, the role of long non-coding RNAs (lncRNAs) in tryptophan metabolism remains to be investigated. Methods: This study uses The Cancer Genome Atlas (TCGA)-LUAD dataset as the training cohort, and several datasets from the Gene Expression Omnibus (GEO) database are merged into the validation cohort. Genes related to tryptophan metabolism were identified from the Molecular Signatures Database (MSigDB) database and further screened for lncRNAs with Trp-related expression. Subsequently, a prognostic signature of lncRNAs related to tryptophan metabolism was constructed using Cox regression analysis, (Least absolute shrinkage and selection operator regression) and LASSO analysis. The predictive performance of this risk score was validated by Kaplan–Meier (KM) survival analysis, (receiver operating characteristic) ROC curves, and nomograms. We also explored the differences in immune cell infiltration, immune cell function, tumor mutational load (TMB), tumor immune dysfunction and exclusion (TIDE), and anticancer drug sensitivity between high- and low-risk groups. Finally, we used real-time fluorescence quantitative PCR, CCK-8, colony formation, wound healing, transwell, flow cytometry, and nude mouse xenotransplantation models to elucidate the role of ZNF8-ERVK3-1 in LUAD. Results: We constructed 16 tryptophan metabolism-associated lncRNA prognostic models in LUAD patients. The risk score could be used as an independent prognostic indicator for the prognosis of LUAD patients. Kaplan–Meier survival analysis, ROC curves, and risk maps validated the prognostic value of the risk score. The high-risk and low-risk groups showed significant differences in phenotypes, such as the percentage of immune cell infiltration, immune cell function, gene mutation frequency, and anticancer drug sensitivity. In addition, patients with high-risk scores had higher TMB and TIDE scores compared to patients with low-risk scores. Finally, we found that ZNF8-ERVK3-1 was highly expressed in LUAD tissues and cell lines. A series of in vitro experiments showed that knockdown of ZNF8-ERVK3-1 inhibited cell proliferation, migration, and invasion, leading to cell cycle arrest in the G0/G1 phase and increased apoptosis. In vivo experiments with xenografts have shown that knocking down ZNF8-ERVK3-1 can significantly inhibit tumor size and tumor proliferation. Conclusion: We constructed a new prognostic model for tryptophan metabolism-related lncRNA. The risk score was closely associated with common clinical features such as immune cell infiltration, immune-related function, TMB, and anticancer drug sensitivity. Knockdown of ZNF8-ERVK3-1 inhibited LUAD cell proliferation, migration, invasion, and G0/G1 phase blockade and promoted apoptosis. [ABSTRACT FROM AUTHOR]

Schizophrenia (SCZ) has a known neurodevelopmental etiology, but limited access to human prenatal brain tissue hampers the investigation of basic disease mechanisms in early brain development. Here, we elucidate the molecular mechanisms contributing to SCZ risk in a disease-relevant model of the prenatal human brain. We generated induced pluripotent stem cell–derived organoids, termed human cortical spheroids (hCSs), from a large, genetically stratified sample of 14 SCZ cases and 14 age- and sex-matched controls. The hCSs were differentiated for 150 days, and comprehensive molecular characterization across 4 time points was carried out. The transcriptional and cellular architecture of hCSs closely resembled that of fetal brain tissue at 10 to 24 postconception weeks, showing strongest spatial overlap with frontal regions of the cerebral cortex. A total of 3520 genes were differentially modulated between SCZ and control hCSs across organoid maturation, displaying a significant contribution of genetic loading, an overrepresentation of risk genes for autism spectrum disorder and SCZ, and the strongest enrichment for axonal processes in all hCS stages. The two axon guidance genes SEMA7A and SEMA5A , the first a promoter of synaptic functions and the second a repressor, were downregulated and upregulated, respectively, in SCZ hCSs. This expression pattern was confirmed at the protein level and replicated in a large postmortem sample. Applying a disease-relevant model of the developing fetal brain, we identified consistent dysregulation of axonal genes as an early risk factor for SCZ, providing novel insights into the effects of genetic predisposition on the neurodevelopmental origins of the disorder. [ABSTRACT FROM AUTHOR]

Genetic load refers to the accumulated and potentially life-threatening deleterious mutations in populations. Understanding the mechanisms underlying genetic load variation of transposable element (TE) insertion, a major large-effect mutation, during range expansion is an intriguing question in biology. Here, we used 1,115 global natural accessions of Arabidopsis (Arabidopsis thaliana) to study the driving forces of TE load variation during its range expansion. TE load increased with range expansion, especially in the recently established Yangtze River basin population. Effective population size, which explains 62.0% of the variance in TE load, high transposition rate, and selective sweeps contributed to TE accumulation in the expanded populations. We genetically mapped and identified multiple candidate causal genes and TEs, and revealed the genetic architecture of TE load variation. Overall, this study reveals the variation in TE genetic load during Arabidopsis expansion and highlights the causes of TE load variation from the perspectives of both population genetics and quantitative genetics. The genetic load of transposable elements accumulated during Arabidopsis range expansion and effective population size could explain 62.0% of the variance in genetic load of transposable elements. [ABSTRACT FROM AUTHOR]

California, USA, is home to 3 subspecies of North American elk (Cervus canadensis): Roosevelt (C. c. roosevelti), Rocky Mountain (C. c. nelsoni), and tule (C. c. nannodes). Effective management requires a baseline understanding of each subspecies' range, admixture zones, and geographic patterns of genetic diversity. To address these questions, we genotyped 1,271 individual elk from California (n = 1,204) and reference populations of Rocky Mountain and Roosevelt elk from Nevada (n = 32) and Oregon (n = 35), USA. Using 19 polymorphic microsatellite loci, we detected admixture between Roosevelt and Rocky Mountain elk at a contact zone in northern California, and between Roosevelt and tule elk in north-coastal California and centralcoastal California. We identified a genetically distinct population of Roosevelt elk in northwestern California, likely reflecting the remnant population that survived a large demographic decline from overhunting during the 1800s. Tule elk exhibited lower levels of heterozygosity (0.44 ± 0.03 [SD]) and allelic richness (2.9±0.2) than Rocky Mountain (0.58±0.05, 4.9±0.4, respectively) and Roosevelt (0.50 ± 0.06, 4.4 ± 0.6, respectively) elk. Among tule elk populations, heterozygosity varied, with the lowest heterozygosity (0.23 ± 0.05) corresponding to the oldest enclosed herd used over the past century as a source of translocations. Among tule elk populations, genetic structure revealed several cases of successful and unsuccessful reintroduction or augmentation attempts. Results provide an essential baseline for future monitoring and decisions about harvest management, translocations to preserve genetic diversity, and landscape-level conservation planning to maintain, enhance, or obstruct connectivity of elk populations. Genome-wide sequencing and analyses are needed to quantify inbreeding absolutely and assess genetic load and the age of admixture where subspecies currently exchange genes. [ABSTRACT FROM AUTHOR]

Anthropogenic impact is causing the decline of a large proportion of species worldwide and reduces their genetic diversity. Island species typically have smaller ranges than continental species. As a consequence, island species are particularly liable to undergo population bottlenecks, giving rise to conservation challenges such as inbreeding and unmasking of deleterious genetic load. Such challenges call for more detailed assessments of the genetic make‐up of threatened island populations. The Mascarene islands (Indian Ocean) present many prime examples, being unusual in having been pristine until first human arrival ~400 years ago, following which anthropogenic pressure was unusually intense. A threatened harrier (Circus maillardi) endemic to the westernmost island of the archipelago is a good example of the challenges faced by species that have declined to small population size following intense anthropogenic pressure. In this study, we use an extensive set of population genomic tools to quantify variation at near‐neutral and coding loci, in order to test the historical impact of human activity on this species, and evaluate the species' (mal)adaptive potential. We observed low but significant genetic differentiation between populations on the West and North‐East sides of the island, echoing observations in other endemic species. Inbreeding was significant, with a substantial fraction of samples being first or second‐degree relatives. Historical effective population sizes have declined from ~3000 to 300 individuals in the past 1000 years, with a more recent drop ~100 years ago consistent with human activity. Based on our simulations and comparisons with a close relative (Circus melanoleucos), this demographic history may have allowed purging of the most deleterious variants but is unlikely to have allowed the purging of mildly deleterious variants. Our study shows how using relatively affordable methods can reveal the massive impact that human activity may have on the genetic diversity and adaptive potential of island populations, and calls for urgent action to closely monitor the reproductive success of such endemic populations, in association with genetic studies. [ABSTRACT FROM AUTHOR]

Most species will not be able to migrate fast enough to cope with climate change, nor evolve quickly enough with current levels of genetic variation. Exacerbating the problem are anthropogenic influences on adaptive potential, including the prevention of gene flow through habitat fragmentation and the erosion of genetic diversity in small, bottlenecked populations. Facilitated adaptation, or assisted evolution, offers a way to augment adaptive genetic variation via artificial selection, induced hybridization, or genetic engineering. One key source of genetic variation, particularly for climatic adaptation, are the core metabolic genes encoded by the mitochondrial genome. These genes influence environmental tolerance to heat, drought, and hypoxia, but must interact intimately and co‐evolve with a suite of important nuclear genes. These coadapted mitonuclear genes form some of the important reproductive barriers between species. Mitochondrial genomes can and do introgress between species in an adaptive manner, and they may co‐introgress with nuclear genes important for maintaining mitonuclear compatibility. Managers should consider the relevance of mitonuclear genetic variability in conservation decision‐making, including as a tool for facilitating adaptation. I propose a novel technique dubbed Conservation Mitonuclear Replacement (CmNR), which entails replacing the core metabolic machinery of a threatened species—the mitochondrial genome and key nuclear loci—with those from a closely related species or a divergent population, which may be better‐adapted to climatic changes or carry a lower genetic load. The most feasible route to CmNR is to combine CRISPR‐based nuclear genetic editing with mitochondrial replacement and assisted reproductive technologies. This method preserves much of an organism's phenotype and could allow populations to persist in the wild when no other suitable conservation options exist. The technique could be particularly important on mountaintops, where rising temperatures threaten an alarming number of species with almost certain extinction in the next century. [ABSTRACT FROM AUTHOR]

Background selection describes the reduction in neutral diversity caused by selection against deleterious alleles at other loci. It is typically assumed that the purging of deleterious alleles affects linked neutral variants, and indeed simulations typically only treat a genomic window. However, background selection at unlinked loci also depresses neutral diversity. In agreement with previous analytical approximations, in our simulations of a human-like genome with a realistically high genome-wide deleterious mutation rate, the effects of unlinked background selection exceed those of linked background selection. Background selection reduces neutral genetic diversity by a factor that is independent of census population size. Outside of genic regions, the strength of background selection increases with the mean selection coefficient, contradicting the linked theory but in agreement with the unlinked theory. Neutral diversity within genic regions is fairly independent of the strength of selection. Deleterious genetic load among haploid individuals is underdispersed, indicating nonindependent evolution of deleterious mutations. Empirical evidence for underdispersion was previously interpreted as evidence for global epistasis, but we recover it from a non-epistatic model. [ABSTRACT FROM AUTHOR]

Retinal homeostasis, a tightly regulated process maintaining the functional integrity of the retina, is vital for visual function. Emerging research has unveiled the critical role of epigenetic regulation in controlling gene expression patterns during retinal development, maintenance, and response to mutational loads and injuries. Epigenetic switches, including DNA methylation, histone modifications, and non-coding RNAs, play pivotal roles in orchestrating retinal gene expression and cellular responses through various intracellular, extracellular, and environmental modulators. This review compiles the current knowledge on epigenetic switches in retinal homeostasis, providing a deeper understanding of their impact on retinal structural integrity and function and using them as potential targets for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Models of range expansion have independently explored fitness consequences of life history trait evolution and increased rates of genetic drift—or "allele surfing"—during spatial spread, but no previous model has examined the interactions between these two processes. Here, using spatially explicit simulations, we explore an ecologically complex range expansion scenario that combines density-dependent selection with allele surfing to asses the genetic and fitness consequences of density-dependent selection on the evolution of life history traits. We demonstrate that density-dependent selection on the range edge acts differently depending on the life history trait and can either diminish or enhance allele surfing. Specifically, we show that selection at the range edge is always weaker at sites affecting competitive ability (K -selected traits) than at sites affecting birth rate (r -selected traits). We then link differences in the frequency of deleterious mutations to differences in the efficacy of selection and rate of mutation accumulation across distinct life history traits. Finally, we demonstrate that the observed fitness consequences of allele surfing depend on the population density in which expansion load is measured. Our work highlights the complex relationship between ecology and expressed genetic load, which will be important to consider when interpreting both experimental and field studies of range expansion. [ABSTRACT FROM AUTHOR]

The reinvention of potato, from a tetraploid clonal crop into a diploid seed-based hybrid crop, requires insight in the mutational load, recombination landscape, and the genetic basis of fertility. Genomics-based breeding and QTL discovery rely on efficient genotyping strategies such as skim sequencing, to gather genotypic information. The application of skim sequencing to full-sib population of non-inbred parents remains challenging. Here, we report on an R implementation of the OutcrossSeq pipeline for diploids. We applied this pipeline to a large diploid skim sequenced potato population. We used the resulting bin-markers for the construction of high-density parent specific linkage maps, highlighting variation in parental recombination rate and structural variations. We subsequently explored transmission ratio distortion and non-independent assortment of alleles, indicative of large-effect deleterious mutations. Finally, we identified QTLs for seedling tuber yield in pots and pollen shed. This study showcases the range of genetic analyses, from marker inference, identification of transmission ratio distortion, and linkage map construction to QTL mapping, resulting in new insights that contribute to breeding diploid potato. [ABSTRACT FROM AUTHOR]

Island ecosystems provide natural laboratories to assess the impacts of isolation on population persistence. However, most studies of persistence have focused on a single species, without comparisons to other organisms they interact with in the ecosystem. The case study of moose and gray wolves on Isle Royale allows for a direct contrast of genetic variation in isolated populations that have experienced dramatically differing population trajectories over the past decade. Whereas the Isle Royale wolf population recently declined nearly to extinction due to severe inbreeding depression, the moose population has thrived and continues to persist, despite having low genetic diversity and being isolated for ∼120 years. Here, we examine the patterns of genomic variation underlying the continued persistence of the Isle Royale moose population. We document high levels of inbreeding in the population, roughly as high as the wolf population at the time of its decline. However, inbreeding in the moose population manifests in the form of intermediate-length runs of homozygosity suggestive of historical inbreeding and purging, contrasting with the long runs of homozygosity observed in the smaller wolf population. Using simulations, we confirm that substantial purging has likely occurred in the moose population. However, we also document notable increases in genetic load, which could eventually threaten population viability over the long term. Overall, our results demonstrate a complex relationship between inbreeding, genetic diversity, and population viability that highlights the use of genomic datasets and computational simulation tools for understanding the factors enabling persistence in isolated populations.

Deleterious mutations decrease reproductive fitness and are ubiquitous in genomes. Given that many organisms face ongoing threats of extinction, there is interest in elucidating the impact of deleterious variation on extinction risk and optimizing management strategies accounting for such mutations. Quantifying deleterious variation and understanding the effects of population history on deleterious variation are complex endeavors because we do not know the strength of selection acting on each mutation. Further, the effect of demographic history on deleterious mutations depends on the strength of selection against the mutation and the degree of dominance. Here we clarify how deleterious variation can be quantified and studied in natural populations. We then discuss how different demographic factors, such as small population size, nonequilibrium population size changes, inbreeding, and gene flow, affect deleterious variation. Lastly, we provide guidance on studying deleterious variation in nonmodel populations of conservation concern.

Endangered species generally have small populations with low genetic diversity and a high genetic load. Thuja sutchuenensis is an endangered conifer endemic to southwestern China. It was once considered extinct in the wild, but in 1999 was rediscovered. However, little is known about its genetic load. We collected 67 individuals from five wild, isolated T. sutchuenensis populations, and used 636,151 SNPs to analyze the level of genetic diversity and genetic load in T. sutchuenensis to delineate the conservation units of T. sutchuenensis, based on whole transcriptome sequencing data, as well as target capture sequencing data. We found that populations of T. sutchuenensis could be divided into three groups. These groups had low levels genetic diversity and were moderately genetically differentiated. Our findings also indicate that T. sutchuenensis suffered two severe bottlenecks around the Last Glaciation Period and Last Glacial Maximum. Among Thuja species, T. sutchuenensis presented the lowest genetic load and hence might have purged deleterious mutations efficiently through purifying selection. However, distribution of fitness effects analysis indicated a high extinction risk for T. sutchuenensis. Multiple lines of evidence identified three management units for T. sutchuenensis. Although T. sutchuenensis possesses a low genetic load, low genetic diversity, suboptimal fitness, and anthropogenic pressures all present an extinction risk for this rare conifer. This might also hold true for many endangered plant species in the mountains all over the world.

After the outbreak of COVID-19, additional protocols have been established to prevent the transmission of the SARS-CoV-2 from the patient to the health personnel and vice versa in health care settings. However, in the case of emergency surgeries, it is not always possible to ensure that the patient is not infected with SARS-CoV-2, assuming a potential source of transmission of the virus to health personnel. This work aimed to evaluate the presence of the SARS-CoV-2 and quantify the viral load in indoor air samples collected inside operating rooms, where emergency and scheduled operations take place. Samples were collected for 3 weeks inside two operating rooms for 24 h at 38 L/min in quartz filters. RNA was extracted from the filters and analyzed using RT-qPCR targeting SARS-CoV-2 genes E, N1 and N2 regions. SARS-CoV-2 RNA was detected in 11.3% of aerosol samples collected in operating rooms, despite with low concentrations (not detected at 13.5 cg/m3 and 10.5 cg/m3 in the scheduled and emergency operating rooms, respectively). Potential sources of airborne SARS-CoV-2 could be aerosolization of the virus during aerosol-generating procedures and in open surgery from patients that might have been recently infected with the virus, despite presenting a negative COVID-19 test. Another source could be related to health care workers unknowingly infected with the virus and exhaling SARS-CoV-2 virions into the air. These results highlight the importance of reinforcing preventive measures against COVID-19 in operating rooms, such as the correct use of protective equipment, screening programs for health care workers, and information campaigns. IMPORTANCE Operating rooms are critical environments in which asepsis must be ensured. The COVID-19 pandemic entailed the implementation of additional preventative measures in health care settings, including operating theaters. Although one of the measures is to operate only COVID-19 free patients, this measure cannot be always implemented, especially in emergency interventions. Therefore, a surveillance campaign was conducted during 3 weeks in two operating rooms to assess the level of SARS-CoV-2 genetic material detected in operating theaters with the aim to assess the risk of COVID-19 transmission during operating procedures. SARS-CoV-2 genetic material was detected in 11% of aerosol samples collected in operating rooms, despite with low concentrations. Plausible SARS-CoV-2 sources have been discussed, including patients and health care personnel infected with the virus. These results highlight the importance of reinforcing preventive measures against COVID-19 in operating rooms, such as the correct use of protective equipment, screening programs for health care workers and information campaigns.

Background: Covert cerebral small vessel disease (cCSVD) is associated with many age-related morbidities with little available data regarding the pathophysiology and role of genetics in it. This study aims to investigate the genetic load in a sample of Egyptian patients with cCSVD. Results: Thirty patients with cCSVD were recruited and underwent cognitive, gait, sphincter assessment, magnetic resonance imaging (MRI) brain, and blood sampling for whole exome sequencing. The mean age for the patients was 65.93 ± 8.8 with male patients representing 63.33% of the studied sample. The major risk factor was hypertension followed by diabetes mellitus, dyslipidaemia, and smoking. The main presenting symptom was cognitive impairment, found in 60% of the patients and the mean duration of symptoms was 2.1 ± 1.12 years. Two out of thirty patients were positive for a known pathogenic gene (NOTCH3 and COL4A1) despite the absence of family history in one representing 6.7% of the entire studied sample. Meanwhile, three patients had variant genes not previously linked to cCSVD. Conclusions: Whole exome sequencing and genetic studying of patients with cCSVD is of utmost importance as the genetic load is underestimated in the Egyptian population. [ABSTRACT FROM AUTHOR]

The success of efficiently delivering genetic material to target cells depends on developing an appropriate vector. Among the variety of nanocarriers used for gene therapy, cationic liposomes are the most investigated for delivering genetic material in different forms of cancer. Cationic liposomes contain lipids with positively charged head groups that form electrostatic bonds with the negatively charged phosphate group of nucleic acids, ensuring efficient loading of the genetic material. The aim of this study was the development and in vitro characterization of liposomal formulations for genetic material delivery using the Quality by Design (QbD) approach. We have employed the Design of Experiments (DoE) methodology to study the impact of selected formulation factors on the quality of the proposed non‐viral vectors. Among the varied factors, the ones that had an impact on the responses were the total lipid concentration and cationic lipid concentration. Two liposomal formulations with adequate critical quality attributes (CQAs) were selected for miRNA‐21 inhibitor encapsulation. We continued with the in vitro evaluation on lung cancer cell line. Fluorescence microscopy helped visualize the internalization of all liposomal formulations and apoptotic effects. Finally, we evaluated the cellular viability and migration events after treatment with the cationic liposomes. [ABSTRACT FROM AUTHOR]

While haplotype‐specific genetic load shapes the evolutionary trajectory of natural and captive populations, mixed‐haplotype assembly and genotyping hindered its characterization in diploids. Herein, we produced two phased genome assemblies of the critically endangered fish Chinese Bahaba (Bahaba taipingensis, Sciaenidae, Teleostei) and resequenced 20 whole genomes to quantify population genetic load at a haplotype level. We identified frame‐shifting variants as the most deleterious type, followed by mutations in the 5′‐UTR, 3′‐UTR and missense mutations at conserved amino acids. Phased haplotypes revealed gene deletions and high‐impact deleterious variants. We estimated ~1.12% of genes missing or interrupted per haplotype, with a significant overlap of disrupted genes (30.35%) between haplotype sets. Relative proportions of deleterious variant categories differed significantly between haplotypes. Simulations suggested that purifying selection struggled to purge slightly deleterious genetic load in captive breeding compared to genotyping interventions, and that higher inter‐haplotypic variance of genetic load predicted more efficient purging by artificial selection. Combining the knowledge of haplotype‐resolved genetic load with predictive modelling will be immensely useful for understanding the evolution of deleterious variants and guiding conservation planning. [ABSTRACT FROM AUTHOR]

Populations of many bumblebee species are declining, with distributions shifting northwards to track suitable climates. Climate change is considered a major contributing factor. Arctic species are particularly vulnerable as they cannot shift further north, making assessment of their population viability important. Analysis of levels of whole‐genome variation is a powerful way to analyse population declines and fragmentation. Here, we use genome sequencing to analyse genetic variation in seven species of bumblebee from the Scandinavian mountains, including two classified as vulnerable. We sequenced 333 samples from across the ranges of these species in Sweden. Estimates of effective population size (NE) vary from ~55,000 for species with restricted high alpine distributions to 220,000 for more widespread species. Population fragmentation is generally very low or undetectable over large distances in the mountains, suggesting an absence of barriers to gene flow. The relatively high NE and low population structure indicate that none of the species are at immediate risk of negative genetic effects caused by high levels of genetic drift. However, reconstruction of historical fluctuations in NE indicates that the arctic specialist species Bombus hyperboreus has experienced population declines since the last ice age and we detected one highly inbred diploid male of this species close to the southern limit of its range, potentially indicating elevated genetic load. Although the levels of genetic variation in montane bumblebee populations are currently relatively high, their ranges are predicted to shrink drastically due to the effects of climate change and monitoring is essential to detect future population declines. [ABSTRACT FROM AUTHOR]