A kinetic dichotomy between mitochondrial and nuclear gene expression processes.

Oxidative phosphorylation (OXPHOS) complexes, encoded by both mitochondrial and nuclear DNA, are essential producers of cellular ATP, but how nuclear and mitochondrial gene expression steps are coordinated to achieve balanced OXPHOS subunit biogenesis remains unresolved. Here, we present a parallel quantitative analysis of the human nuclear and mitochondrial messenger RNA (mt-mRNA) life cycles, including transcript production, processing, ribosome association, and degradation. The kinetic rates of nearly every stage of gene expression differed starkly across compartments. Compared with nuclear mRNAs, mt-mRNAs were produced 1,100-fold more, degraded 7-fold faster, and accumulated to 160-fold higher levels. Quantitative modeling and depletion of mitochondrial factors LRPPRC and FASTKD5 identified critical points of mitochondrial regulatory control, revealing that the mitonuclear expression disparities intrinsically arise from the highly polycistronic nature of human mitochondrial pre-mRNA. We propose that resolving these differences requires a 100-fold slower mitochondrial translation rate, illuminating the mitoribosome as a nexus of mitonuclear co-regulation.

MYCN recruits the nuclear exosome complex to RNA polymerase II to prevent transcription-replication conflicts.

The MYCN oncoprotein drives the development of numerous neuroendocrine and pediatric tumors. Here we show that MYCN interacts with the nuclear RNA exosome, a 3'-5' exoribonuclease complex, and recruits the exosome to its target genes. In the absence of the exosome, MYCN-directed elongation by RNA polymerase II (RNAPII) is slow and non-productive on a large group of cell-cycle-regulated genes. During the S phase of MYCN-driven tumor cells, the exosome is required to prevent the accumulation of stalled replication forks and of double-strand breaks close to the transcription start sites. Upon depletion of the exosome, activation of ATM causes recruitment of BRCA1, which stabilizes nuclear mRNA decapping complexes, leading to MYCN-dependent transcription termination. Disruption of mRNA decapping in turn activates ATR, indicating transcription-replication conflicts. We propose that exosome recruitment by MYCN maintains productive transcription elongation during S phase and prevents transcription-replication conflicts to maintain the rapid proliferation of neuroendocrine tumor cells.

Functional Diversification of Chromatin on Rapid Evolutionary Timescales.

Repeat-enriched genomic regions evolve rapidly and yet support strictly conserved functions like faithful chromosome transmission and the preservation of genome integrity. The leading resolution to this paradox is that DNA repeat-packaging proteins evolve adaptively to mitigate deleterious changes in DNA repeat copy number, sequence, and organization. Exciting new research has tested this model of coevolution by engineering evolutionary mismatches between adaptively evolving chromatin proteins of one species and the DNA repeats of a close relative. Here, we review these innovative evolution-guided functional analyses. The studies demonstrate that vital, chromatin-mediated cellular processes, including transposon suppression, faithful chromosome transmission, and chromosome retention depend on species-specific versions of chromatin proteins that package species-specific DNA repeats. In many cases, the ever-evolving repeats are selfish genetic elements, raising the possibility that chromatin is a battleground of intragenomic conflict.

Toxin-Antidote Elements Across the Tree of Life.

In life's constant battle for survival, it takes one to kill but two to conquer. Toxin-antitoxin or toxin-antidote (TA) elements are genetic dyads that cheat the laws of inheritance to guarantee their transmission to the next generation. This seemingly simple genetic arrangement-a toxin linked to its antidote-is capable of quickly spreading and persisting in natural populations. TA elements were first discovered in bacterial plasmids in the 1980s and have recently been characterized in fungi, plants, and animals, where they underlie genetic incompatibilities and sterility in crosses between wild isolates. In this review, we provide a unified view of TA elements in both prokaryotic and eukaryotic organisms and highlight their similarities and differences at the evolutionary, genetic, and molecular levels. Finally, we propose several scenarios that could explain the paradox of the evolutionary origin of TA elements and argue that these elements may be key evolutionary players and that the full scope of their roles is only beginning to be uncovered.

Fork Cleavage-Religation Cycle and Active Transcription Mediate Replication Restart after Fork Stalling at Co-transcriptional R-Loops.

Formation of co-transcriptional R-loops underlies replication fork stalling upon head-on transcription-replication encounters. Here, we demonstrate that RAD51-dependent replication fork reversal induced by R-loops is followed by the restart of semiconservative DNA replication mediated by RECQ1 and RECQ5 helicases, MUS81/EME1 endonuclease, RAD52 strand-annealing factor, the DNA ligase IV (LIG4)/XRCC4 complex, and the non-catalytic subunit of DNA polymerase δ, POLD3. RECQ5 disrupts RAD51 filaments assembled on stalled forks after RECQ1-mediated reverse branch migration, preventing a new round of fork reversal and facilitating fork cleavage by MUS81/EME1. MUS81-dependent DNA breaks accumulate in cells lacking RAD52 or LIG4 upon induction of R-loop formation, suggesting that RAD52 acts in concert with LIG4/XRCC4 to catalyze fork religation, thereby mediating replication restart. The resumption of DNA synthesis after R-loop-associated fork stalling also requires active transcription, the restoration of which depends on MUS81, RAD52, LIG4, and the transcription elongation factor ELL. These findings provide mechanistic insights into transcription-replication conflict resolution.

Decoupled evolution of the Sex Peptide gene family and Sex Peptide Receptor in Drosophilidae.

Across internally fertilising species, males transfer ejaculate proteins that trigger wide-ranging changes in female behaviour and physiology. Much theory has been developed to explore the drivers of ejaculate protein evolution. The accelerating availability of high-quality genomes now allows us to test how these proteins are evolving at fine taxonomic scales. Here, we use genomes from 264 species to chart the evolutionary history of Sex Peptide (SP), a potent regulator of female post-mating responses in Drosophila melanogaster. We infer that SP first evolved in the Drosophilinae subfamily and has since followed markedly different evolutionary trajectories in different lineages. Outside of the Sophophora-Lordiphosa, SP exists largely as a single-copy gene with independent losses in several lineages. Within the Sophophora-Lordiphosa, the SP gene family has repeatedly and independently expanded. Up to seven copies, collectively displaying extensive sequence variation, are present in some species. Despite these changes, SP expression remains restricted to the male reproductive tract. Alongside, we document considerable interspecific variation in the presence and morphology of seminal microcarriers that, despite the critical role SP plays in microcarrier assembly in D. melanogaster, appears to be independent of changes in the presence/absence or sequence of SP. We end by providing evidence that SP's evolution is decoupled from that of its receptor, Sex Peptide Receptor, in which we detect no evidence of correlated diversifying selection. Collectively, our work describes the divergent evolutionary trajectories that a novel gene has taken following its origin and finds a surprisingly weak coevolutionary signal between a supposedly sexually antagonistic protein and its receptor.

Spatial spillovers of violent conflict amplify the impacts of climate variability on malaria risk in sub-Saharan Africa.

Africa carries a disproportionately high share of the global malaria burden, accounting for 94% of malaria cases and deaths worldwide in 2019. It is also a politically unstable region and the most vulnerable continent to climate change in recent decades. Knowledge about the modifying impacts of violent conflict on climate-malaria relationships remains limited. Here, we quantify the associations between violent conflict, climate variability, and malaria risk in sub-Saharan Africa using health surveys from 128,326 individuals, historical climate data, and 17,429 recorded violent conflicts from 2006 to 2017. We observe that spatial spillovers of violent conflict (SSVCs) have spatially distant effects on malaria risk. Malaria risk induced by SSVCs within 50 to 100 km from the households gradually increases from 0.1% (not significant, P>0.05) to 6.5% (95% CI: 0 to 13.0%). SSVCs significantly promote malaria risk within the average 20.1 to 26.9 °C range. At the 12-mo mean temperature of 22.5 °C, conflict deaths have the largest impact on malaria risk, with an approximately 5.8% increase (95% CI: 1.0 to 11.0%). Additionally, a pronounced association between SSVCs and malaria risk exists in the regions with 9.2 wet days per month. The results reveal that SSVCs increase population exposure to harsh environments, amplifying the effect of warm temperature and persistent precipitation on malaria transmission. Violent conflict therefore poses a substantial barrier to mosquito control and malaria elimination efforts in sub-Saharan Africa. Our findings support effective targeting of treatment programs and vector control activities in conflict-affected regions with a high malaria risk.

Eviction-driven infanticide and sexually selected adoption and infanticide in a neotropical parrot.

Infanticide and adoption have been attributed to sexual selection, where an individual later reproduces with the parent whose offspring it killed or adopted. While sexually selected infanticide is well known, evidence for sexually selected adoption is anecdotal. We report on both behaviors at 346 nests over 27 y in green-rumped parrotlets (Forpus passerinus) in Venezuela. Parrotlets are monogamous with long-term pair bonds, exhibit a strongly male-biased adult sex ratio, and nest in cavities that are in short supply, creating intense competition for nest sites and mates. Infanticide attacks occurred at 256 nests in two distinct contexts: 1) Attacks were primarily committed by nonbreeding pairs (69%) attempting to evict parents from the cavity. Infanticide attacks per nest were positively correlated with population size and evicting pairs never adopted abandoned offspring. Competition for limited nest sites was a primary cause of eviction-driven infanticide, and 2) attacks occurred less frequently at nests where one mate died (31%), was perpetrated primarily by stepparents of both sexes, and was independent of population size. Thus, within a single species and mating system, infanticide occurred in multiple contexts due to multiple drivers. Nevertheless, 48% of stepparents of both sexes adopted offspring, and another 23% of stepfathers exhibited both infanticide and long-term care. Stepfathers were often young males who subsequently nested with widows, reaching earlier ages of first breeding than competitors and demonstrating sexually selected adoption. Adoption and infanticide conferred similar fitness benefits to stepfathers and appeared to be equivalent strategies driven by limited breeding opportunities, male-biased sex ratios, and long-term monogamy.

Negotiating discord in sustainability transformations.

Policy action for sustainability transformation faces inherent and ever-present sources of conflict, pushback, and resistance (i.e., discord). However, conceptual frameworks and policy prescriptions for sustainability transformations often reflect an undue image of accord. This involves simplified assumptions about consensus, steering, friction, discreteness, and additiveness of policy action, conferring an unrealistic view of the potential to deliberately realize transformation. Instead, negotiating discord through continuously finding partial political settlements among divided actors needs to become a key focus of policy action for sustainability transformations. Doing so can help to navigate deeply political settings through imperfect but workable steps that loosen deadlock, generate momentum for further policy action, and avoid complete derailment of transformation agendas when discord arises.

Private management of African protected areas improves wildlife and tourism outcomes but with security concerns in conflict regions.

Protected areas can conserve wildlife and benefit people when managed effectively. African governments increasingly delegate the management of protected areas to private, nongovernmental organizations, hoping that private organizations' significant resources and technical capacities actualize protected areas' potential. Does private sector management improve outcomes compared to a counterfactual of government management? We leverage the transfer of management authority from governments to African Parks (AP)-the largest private manager of protected areas in Africa-to show that private management significantly improves wildlife outcomes via reduced elephant poaching and increased bird abundances. Our results also suggest that AP's management augments tourism, while the effect on rural wealth is inconclusive. However, AP's management increases the risk of armed groups targeting civilians, which could be an unintended outcome of AP's improved monitoring and enforcement systems. These findings reveal an intricate interplay between conservation, economic development, and security under privately managed protected areas in Africa.

Effects of climate, land use, and human population change on human-elephant conflict risk in Africa and Asia.

Human-wildlife conflict is an important factor in the modern biodiversity crisis and has negative effects on both humans and wildlife (such as property destruction, injury, or death) that can impede conservation efforts for threatened species. Effectively addressing conflict requires an understanding of where it is likely to occur, particularly as climate change shifts wildlife ranges and human activities globally. Here, we examine how projected shifts in cropland density, human population density, and climatic suitability-three key drivers of human-elephant conflict-will shift conflict pressures for endangered Asian and African elephants to inform conflict management in a changing climate. We find that conflict risk (cropland density and/or human population density moving into the 90th percentile based on current-day values) increases in 2050, with a larger increase under the high-emissions "regional rivalry" SSP3 - RCP 7.0 scenario than the low-emissions "sustainability" SSP1 - RCP 2.6 scenario. We also find a net decrease in climatic suitability for both species along their extended range boundaries, with decreasing suitability most often overlapping increasing conflict risk when both suitability and conflict risk are changing. Our findings suggest that as climate changes, the risk of conflict with Asian and African elephants may shift and increase and managers should proactively mitigate that conflict to preserve these charismatic animals.

Genetic conflicts in budding yeast: The 2µ plasmid as a model selfish element.

Antagonistic coevolution, arising from genetic conflict, can drive rapid evolution and biological innovation. Conflict can arise both between organisms and within genomes. This review focuses on budding yeasts as a model system for exploring intra- and inter-genomic genetic conflict, highlighting in particular the 2-micron (2µ) plasmid as a model selfish element. The 2µ is found widely in laboratory strains and industrial isolates of Saccharomyces cerevisiae and has long been known to cause host fitness defects. Nevertheless, the plasmid is frequently ignored in the context of genetic, fitness, and evolution studies. Here, I make a case for further exploring the evolutionary impact of the 2µ plasmid as well as other selfish elements of budding yeasts, discuss recent advances, and, finally, future directions for the field.

Diverse genetic conflicts mediated by molecular mimicry and computational approaches to detect them.

In genetic conflicts between intergenomic and selfish elements, driver and killer elements achieve biased survival, replication, or transmission over sensitive and targeted elements through a wide range of molecular mechanisms, including mimicry. Driving mechanisms manifest at all organismal levels, from the biased propagation of individual genes, as demonstrated by transposable elements, to the biased transmission of genomes, as illustrated by viruses, to the biased transmission of cell lineages, as in cancer. Targeted genomes are vulnerable to molecular mimicry through the conserved motifs they use for their own signaling and regulation. Mimicking these motifs enables an intergenomic or selfish element to control core target processes, and can occur at the sequence, structure, or functional level. Molecular mimicry was first appreciated as an important phenomenon more than twenty years ago. Modern genomics technologies, databases, and machine learning approaches offer tremendous potential to study the distribution of molecular mimicry across genetic conflicts in nature. Here, we explore the theoretical expectations for molecular mimicry between conflicting genomes, the trends in molecular mimicry mechanisms across known genetic conflicts, and outline how new examples can be gleaned from population genomic datasets. We discuss how mimics involving short sequence-based motifs or gene duplications can evolve convergently from new mutations. Whereas, processes that involve divergent domains or fully-folded structures occur among genomes by horizontal gene transfer. These trends are largely based on a small number of organisms and should be reevaluated in a general, phylogenetically independent framework. Currently, publicly available databases can be mined for genotypes driving non-Mendelian inheritance patterns, epistatic interactions, and convergent protein structures. A subset of these conflicting elements may be molecular mimics. We propose approaches for detecting genetic conflict and molecular mimicry from these datasets.

PSRs: Selfish chromosomes that manipulate reproductive development.

B chromosomes are intriguing "selfish" genetic elements, many of which exhibit higher-than-Mendelian transmission. This perspective highlights a group of B chromosomes known as Paternal Sex Ratio chromosomes (PSRs), which are found in several insects with haplo-diploid reproduction. PSRs harshly alter the organism's reproduction to facilitate their own inheritance. A manifestation of this effect is the conversion of female destined individuals into males. Key to this conversion is the mysterious ability of PSRs to cause elimination of the sperm-inherited half of the genome during zygote formation. Here we discuss how PSRs were discovered, what is known about how they alter paternal chromatin dynamics to cause sex conversion, and how PSR-induced genome elimination is different from other forms of programmed genome elimination in different insects. PSRs also stand out because their DNA sequence compositions differ in remarkable ways from their insect's essential chromosomes, a characteristic suggestive of interspecies origins. Broadly, we also highlight poorly understood aspects of PSR dynamics that need to be investigated.

Genetic conflicts and the origin of self/nonself-discrimination in the vertebrate immune system.

Genetic conflicts shape the genomes of prokaryotic and eukaryotic organisms. Here, we argue that some of the key evolutionary novelties of adaptive immune systems of vertebrates are descendants of prokaryotic toxin-antitoxin (TA) systems. Cytidine deaminases and RAG recombinase have evolved from genotoxic enzymes to programmable editors of host genomes, supporting the astounding discriminatory capability of variable lymphocyte receptors of jawless vertebrates, as well as immunoglobulins and T cell receptors of jawed vertebrates. The evolutionarily recent lymphoid lineage is uniquely sensitive to mutations of the DNA maintenance methylase, which is an orphaned distant relative of prokaryotic restriction-modification systems. We discuss how the emergence of adaptive immunity gave rise to higher order genetic conflicts between genetic parasites and their vertebrate host.

Disease burden among Ukrainians forcibly displaced by the 2022 Russian invasion.

The Russian invasion of Ukraine on February 24, 2022, has displaced more than a quarter of the population. Assessing disease burdens among displaced people is instrumental in informing global public health and humanitarian aid efforts. We estimated the disease burden in Ukrainians displaced both within Ukraine and to other countries by combining a spatiotemporal model of forcible displacement with age- and gender-specific estimates of cardiovascular disease (CVD), diabetes, cancer, HIV, and tuberculosis (TB) in each of Ukraine's 629 raions (i.e., districts). Among displaced Ukrainians as of May 13, we estimated that more than 2.63 million have CVDs, at least 615,000 have diabetes, and over 98,500 have cancer. In addition, more than 86,000 forcibly displaced individuals are living with HIV, and approximately 13,500 have TB. We estimated that the disease prevalence among refugees was lower than the national disease prevalence before the invasion. Accounting for internal displacement and healthcare facilities impacted by the conflict, we estimated that the number of people per hospital has increased by more than two-fold in some areas. As regional healthcare systems come under increasing strain, these estimates can inform the allocation of critical resources under shifting disease burdens.

Male harm offsets the demographic benefits of good genes.

Sexual conflict can arise when males evolve traits that improve their mating success but in doing so harm females. By reducing female fitness, male harm can diminish offspring production in a population and even drive extinction. Current theory on harm is based on the assumption that an individual's phenotype is solely determined by its genotype. But the expression of most sexually selected traits is also influenced by variation in biological condition (condition-dependent expression), such that individuals in better condition can express more extreme phenotypes. Here, we developed demographically explicit models of sexual conflict evolution where individuals vary in their condition. Because condition-dependent expression readily evolves for traits underlying sexual conflict, we show that conflict is more intense in populations where individuals are in better condition. Such intensified conflict reduces mean fitness and can thus generate a negative association between condition and population size. The impact of condition on demography is especially likely to be detrimental when the genetic basis of condition coevolves with sexual conflict. This occurs because sexual selection favors alleles that improve condition (the so-called good genes effect), producing feedback between condition and sexual conflict that drives the evolution of intense male harm. Our results indicate that in presence of male harm, the good genes effect in fact easily becomes detrimental to populations.

Educating for inclusion: Diversity education programs can reduce prejudice toward outgroups in Israel.

Intergroup prejudice is pervasive in many contexts worldwide, leading to discrimination and conflict. Existing research suggests that prejudice is acquired at an early age and that durably improving intergroup relations is extremely challenging, often requiring intense interventions. Building on existing research in social psychology and inspired by the Israeli TV series "You Can't Ask That," which depicts charismatic children from minority groups broaching sensitive topics at the core of intergroup relations, we develop a month-long diversity education program. Our program exposed students to the TV series and facilitated follow-up classroom discussions in which students constructively addressed various sensitive topics at the core of intergroup relations and learned about intergroup similarities, intragroup heterogeneity, and the value of taking others' perspectives. Through two field experiments implemented in Israeli schools, we show that integrating our intervention into school curricula improved Jewish students' attitudes toward minorities and increased some pro-diversity behavior up to 13 wk posttreatment. We further provide suggestive evidence that the intervention was effective by encouraging students to take their outgroups' perspectives and address an element of scalability by delegating implementation responsibilities to classroom teachers in our second study. Our findings suggest that theoretically informed intensive education programs are a promising route to reducing prejudice at a young age.

How contact can promote societal change amid conflict: An intergroup contact field experiment in Nigeria.

Intergroup contact, originally designed as a tool for prejudice reduction, offers a promising means to resolve intergroup conflict. Evidence for contact-based interventions to improve intergroup relations is sparse, however, with most studies focusing only on the individuals who directly engage in contact. We test the ability of a contact-based intervention to promote peace between conflicting groups with a field experiment in Nigeria, where farmer and pastoralist communities are embroiled in a deadly conflict over land use. We examine the effectiveness of the contact intervention on the wider population-not just those directly engaged in contact-using surveys, direct observation of behavior in markets and social events, and a behavioral game. We find those who lived in the communities that received the intervention had more positive intergroup attitudes and feelings of physical security, as well as were more likely to engage in voluntary intergroup contact measured through self-reports and observed behavior in markets. Exploratory analyses show that those who directly participated in the program and those who were exposed to it by living in the communities where activities were taking place changed similarly with regard to attitudes and perceptions of security, but not with regard to behaviors, indicating the spread to the wider community was likely due to norm change. These results suggest that contact interventions can have wider societal change and reduce the barriers to peace between conflicting groups.

Individual costs and societal benefits of interventions during the COVID-19 pandemic.

Individual and societal reactions to an ongoing pandemic can lead to social dilemmas: In some cases, each individual is tempted to not follow an intervention, but for the whole society, it would be best if they did. Now that in most countries, the extent of regulations to reduce SARS-CoV-2 transmission is very small, interventions are driven by individual decision-making. Assuming that individuals act in their best own interest, we propose a framework in which this situation can be quantified, depending on the protection the intervention provides to a user and to others, the risk of getting infected, and the costs of the intervention. We discuss when a tension between individual and societal benefits arises and which parameter comparisons are important to distinguish between different regimes of intervention use.