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The DNA damage response is essential to safeguard genome integrity. Although the contribution of chromatin in DNA repair has been investigated1,2, the contribution of chromosome folding to these processes remains unclear3. Here we report that, after the production of double-stranded breaks (DSBs) in mammalian cells, ATM drives the formation of a new chromatin compartment (D compartment) through the clustering of damaged topologically associating domains, decorated with γH2AX and 53BP1. This compartment forms by a mechanism that is consistent with polymer-polymer phase separation rather than liquid-liquid phase separation. The D compartment arises mostly in G1 phase, is independent of cohesin and is enhanced after pharmacological inhibition of DNA-dependent protein kinase (DNA-PK) or R-loop accumulation. Importantly, R-loop-enriched DNA-damage-responsive genes physically localize to the D compartment, and this contributes to their optimal activation, providing a function for DSB clustering in the DNA damage response. However, DSB-induced chromosome reorganization comes at the expense of an increased rate of translocations, also observed in cancer genomes. Overall, we characterize how DSB-induced compartmentalization orchestrates the DNA damage response and highlight the critical impact of chromosome architecture in genomic instability.

Plastic pollution is distributed patchily around the worlds oceans. Likewise, marine organisms that are vulnerable to plastic ingestion or entanglement have uneven distributions. Understanding where wildlife encounters plastic is crucial for targeting research and mitigation. Oceanic seabirds, particularly petrels, frequently ingest plastic, are highly threatened, and cover vast distances during foraging and migration. However, the spatial overlap between petrels and plastics is poorly understood. Here we combine marine plastic density estimates with individual movement data for 7137 birds of 77 petrel species to estimate relative exposure risk. We identify high exposure risk areas in the Mediterranean and Black seas, and the northeast Pacific, northwest Pacific, South Atlantic and southwest Indian oceans. Plastic exposure risk varies greatly among species and populations, and between breeding and non-breeding seasons. Exposure risk is disproportionately high for Threatened species. Outside the Mediterranean and Black seas, exposure risk is highest in the high seas and Exclusive Economic Zones (EEZs) of the USA, Japan, and the UK. Birds generally had higher plastic exposure risk outside the EEZ of the country where they breed. We identify conservation and research priorities, and highlight that international collaboration is key to addressing the impacts of marine plastic on wide-ranging species.

Our understanding of Earth's paleogeography relies heavily on paleomagnetic apparent polar wander paths (APWPs), which represent the time-dependent position of Earth's spin axis relative to a given block of lithosphere. However, conventional approaches to APWP construction have significant limitations. First, the paleomagnetic record contains substantial noise that is not integrated into APWPs. Second, parametric assumptions are adopted to represent spatial and temporal uncertainties even where the underlying data do not conform to the assumed distributions. The consequences of these limitations remain largely unknown. Here, we address these challenges with a bottom-up Monte Carlo uncertainty propagation scheme that operates on site-level paleomagnetic data. To demonstrate our methodology, we present an extensive compilation of site-level Cenozoic paleomagnetic data from North America, which we use to generate a high-resolution APWP. Our results demonstrate that even in the presence of substantial noise, polar wandering can be assessed with unprecedented temporal and spatial resolution.

In the published version of this paper, the list of members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium and their affiliations contained minor errors in the affiliations. The original Article has been corrected to include the corrected list.

BackgroundMagnetic resonance imaging (MRI) measurements of gray matter (GM) atrophy and magnetization transfer ratio (MTR; correlate of myelination) may provide better insights than conventional MRI regarding brain tissue integrity/myelination in multiple sclerosis (MS).ObjectiveTo examine the effect of siponimod in the EXPAND trial on whole-brain and GM atrophy, newly formed normalized magnetization transfer ratio (nMTR) lesions, and nMTR-assessed integrity of normal-appearing brain tissue (NABT), cortical GM (cGM), and normal-appearing white matter (NAWM).MethodsPatients with secondary progressive multiple sclerosis (SPMS) received siponimod (2 mg/day; n =1037) or placebo (n = 523). Endpoints included percentage change from baseline to months 12/24 in whole-brain, cGM, and thalamic volumes; change in nMTR from baseline to months 12/24 in NABT, cGM, and NAWM; MTR recovery in newly formed lesions.ResultsCompared with placebo, siponimod significantly reduced progression of whole-brain and GM atrophy over 12/24 months, and was associated with improvements in brain tissue integrity/myelination within newly formed nMTR lesions and across NABT, cGM, and NAWM over 24 months. Effects were consistent across age, disease duration, inflammatory activity subgroups, and disease severity.ConclusionSiponimod reduced brain tissue damage in patients with SPMS as evidenced by objective measures of brain tissue integrity/myelination. This is consistent with central nervous system (CNS) effects observed in preclinical models. ClinicalTrials.gov number: NCT01665144.

Transcriptionally active loci are particularly prone to breakage and mounting evidence suggests that DNA Double-Strand Breaks arising in active genes are handled by a dedicated repair pathway, Transcription-Coupled DSB Repair (TC-DSBR), that entails R-loop accumulation and dissolution. Here, we uncover a function for the Bloom RecQ DNA helicase (BLM) in TC-DSBR in human cells. BLM is recruited in a transcription dependent-manner at DSBs where it fosters resection, RAD51 binding and accurate Homologous Recombination repair. However, in an R-loop dissolution-deficient background, we find that BLM promotes cell death. We report that upon excessive RNA:DNA hybrid accumulation, DNA synthesis is enhanced at DSBs, in a manner that depends on BLM and POLD3. Altogether our work unveils a role for BLM at DSBs in active chromatin, and highlights the toxic potential of RNA:DNA hybrids that accumulate at transcription-associated DSBs.

Substantial variation in foraging strategies can exist within populations, even those typically regarded as generalists. Specializations arise from the consistent exploitation of a narrow behavioral, spatial or dietary niche over time, which may reduce intraspecific competition and influence adaptability to environmental change. However, few studies have investigated whether behavioral consistency confers benefits at the individual and/or population level. While still recovering from commercial sealing overexploitation, Australian fur seals (AUFS; Arctocephalus pusillus doriferus) represent the largest marine predator biomass in south-eastern Australia. During lactation, female AUFS adopt a central-place foraging strategy and are, thus, vulnerable to changes in prey availability. The present study investigated the population-level repeatability and individual consistency in foraging behavior of 34 lactating female AUFS at a south-east Australian breeding colony between 2006 and 2019. Additionally, the influence of individual-level behavioral consistency on indices of foraging success and efficiency during benthic diving was determined. Low to moderate population-level repeatability was observed across foraging behaviors, with the greatest repeatability in the mean bearing and modal dive depth. Individual-level consistency was greatest for the proportion of benthic diving, total distance travelled, and trip duration. Indices of benthic foraging success and efficiency were positively influenced by consistency in the proportion of benthic diving, trip duration and dive rate but not influenced by consistency in bearing to most distal point, dive depth or foraging site fidelity. The results of the present study provide evidence of the benefits of consistency for individuals, which may have flow-on effects at the population level.

Substantial variation in foraging strategies can exist within populations, even those typically regarded as generalists. Specializations arise from the consistent exploitation of a narrow behavioral, spatial or dietary niche over time, which may reduce intraspecific competition and influence adaptability to environmental change. However, few studies have investigated whether behavioral consistency confers benefits at the individual and/or population level. While still recovering from commercial sealing overexploitation, Australian fur seals (AUFS; Arctocephalus pusillus doriferus) represent the largest marine predator biomass in south-eastern Australia. During lactation, female AUFS adopt a central-place foraging strategy and are, thus, vulnerable to changes in prey availability. The present study investigated the population-level repeatability and individual consistency in foraging behavior of 34 lactating female AUFS at a south-east Australian breeding colony between 2006 and 2019. Additionally, the influence of individual-level behavioral consistency on indices of foraging success and efficiency during benthic diving was determined. Low to moderate population-level repeatability was observed across foraging behaviors, with the greatest repeatability in the mean bearing and modal dive depth. Individual-level consistency was greatest for the proportion of benthic diving, total distance travelled, and trip duration. Indices of benthic foraging success and efficiency were positively influenced by consistency in the proportion of benthic diving, trip duration and dive rate but not influenced by consistency in bearing to most distal point, dive depth or foraging site fidelity. The results of the present study provide evidence of the benefits of consistency for individuals, which may have flow-on effects at the population level.

The endangered Galapagos sea lion (GSL, Zalophus wollebaeki) exhibits a range of foraging strategies utilising various dive types including benthic, epipelagic and mesopelagic dives. In the present study, potential prey captures (PPC), prey energy consumption and energy expenditure in lactating adult female GSLs (n = 9) were examined to determine their foraging efficiency relative to the foraging strategy used. Individuals displayed four dive types: (a) epipelagic (100 m; MP) with a characteristic V-shape or U-shape diving profile; and (c) shallow benthic (100 m; DB) with square or flat-bottom dive profiles. These dive types varied in the number of PPC, assumed prey types, and the energy expended. Prey items and their energetic value were assumed from previous GSL diet studies in combination with common habitat and depth ranges of the prey. In comparison to pelagic dives occurring at similar depths, when diving benthically, GSLs had both higher prey energy consumption and foraging energy expenditure whereas PPC rate was lower. Foraging efficiency varied across dive types, with benthic dives being more profitable than pelagic dives. Three foraging trip strategies were identified and varied relative to prey energy consumed, energy expended, and dive behaviour. Foraging efficiency did not significantly vary among the foraging trip strategies suggesting that, while individuals may diverge into different foraging habitats, they are optimal within them. These findings indicate that these three strategies will have different sensitivities to habitat-specific fluctuations due to environmental change.

Understanding the factors which influence foraging behaviour and success in marine mammals is crucial to predicting how their populations may respond to environmental change. The Australian fur seal (Arctocephalus pusillus doriferus, AUFS) is a predominantly benthic forager on the shallow continental shelf of Bass Strait, and represents the greatest biomass of marine predators in south-eastern Australia. The south-east Australian region is experiencing rapid oceanic warming, predicted to lead to substantial alterations in prey diversity, distribution and abundance. In the present study, foraging effort and indices of foraging success and efficiency were investigated in 138 adult female AUFS (970 foraging trips) during the winters of 1998-2019. Large scale climate conditions had a strong influence on foraging effort, foraging success and efficiency. Foraging effort and foraging success were also strongly influenced by winter chlorophyll-a concentrations and sea-surface height anomalies in Bass Strait. The results suggest increasing foraging effort and decreasing foraging success and efficiency under anticipated environmental conditions, which may have population-level impacts.

Telomere dysfunction is associated with multiple fibrotic lung processes, including chronic lung allograft dysfunction (CLAD)-the major limitation to long-term survival following lung transplantation. Although shorter donor telomere lengths are associated with an increased risk of CLAD, it is unknown whether short telomeres are a cause or consequence of CLAD pathology. Our objective was to test whether telomere dysfunction contributes to the pathologic changes observed in CLAD. Histopathologic and molecular analysis of human CLAD lungs demonstrated shortened telomeres in lung epithelial cells quantified by teloFISH, increased numbers of surfactant protein C immunoreactive type II alveolar epithelial cells, and increased expression of senescence markers (β-galactosidase, p16, p53, and p21) in lung epithelial cells. TRF1F/F (telomere repeat binding factor 1 flox/flox) mice were crossed with tamoxifen-inducible SCGB1a1-cre mice to generate SCGB1a1-creTRF1F/F mice. Following 9 months of tamoxifen-induced deletion of TRF1 in club cells, mice developed mixed obstructive and restrictive lung physiology, small airway obliteration on microcomputed tomography, a fourfold decrease in telomere length in airway epithelial cells, collagen deposition around bronchioles and adjacent lung parenchyma, increased type II aveolar epithelial cell numbers, expression of senescence-associated β-galactosidase in epithelial cells, and decreased SCGB1a1 expression in airway epithelial cells. These findings demonstrate that telomere dysfunction isolated to airway epithelial cells leads to airway-centric lung remodeling and fibrosis similar to that observed in patients with CLAD and suggest that lung epithelial cell telomere dysfunction may be a molecular driver of CLAD.

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1-3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10-18.

While marine top predators can play a critical role in ecosystem structure and dynamics through their effects on prey populations, how the predators function in this role is often not well understood. In the Benguela region of southern Africa, the Cape fur seal (Arctocephalus pusillus pusillus) population constitutes the largest marine top predator biomass, but little is known of its foraging ecology other than its diet and some preliminary dive records. Dive information was obtained from 32 adult females instrumented with dive recorders at the Kleinsee colony (29°34.17' S, 16°59.80' E) in South Africa during 2006-2008. Most dives were in the depth range of epipelagic prey species (less than 50 m deep) and at night, reflecting the reliance of Cape fur seals on small, vertically migrating, schooling prey. However, most females also performed benthic dives, and benthic diving was prevalent in some individuals. Benthic diving was significantly associated with the frequency with which females exceeded their aerobic dive limit. The greater putative costs of benthic diving highlight the potential detrimental effects to Cape fur seals of well-documented changes in the availability of epipelagic prey species in the Benguela.

While marine top predators can play a critical role in ecosystem structure and dynamics through their effects on prey populations, how the predators function in this role is often not well understood. In the Benguela region of southern Africa, the Cape fur seal (Arctocephalus pusillus pusillus) population constitutes the largest marine top predator biomass, but little is known of its foraging ecology other than its diet and some preliminary dive records. Dive information was obtained from 32 adult females instrumented with dive recorders at the Kleinsee colony (29°34.17 S, 16°59.80 E) in South Africa during 2006-2008. Most dives were in the depth range of epipelagic prey species (less than 50 m deep) and at night, reflecting the reliance of Cape fur seals on small, vertically migrating, schooling prey. However, most females also performed benthic dives, and benthic diving was prevalent in some individuals. Benthic diving was significantly associated with the frequency with which females exceeded their aerobic dive limit. The greater putative costs of benthic diving highlight the potential detrimental effects to Cape fur seals of well-documented changes in the availability of epipelagic prey species in the Benguela.

While marine top predators can play a critical role in ecosystem structure and dynamics through their effects on prey populations, how the predators function in this role is often not well understood. In the Benguela region of southern Africa, the Cape fur seal (Arctocephalus pusillus pusillus) population constitutes the largest marine top predator biomass, but little is known of its foraging ecology other than its diet and some preliminary dive records. Dive information was obtained from 32 adult females instrumented with dive recorders at the Kleinsee colony (29°34.17' S, 16°59.80' E) in South Africa during 2006-2008. Most dives were in the depth range of epipelagic prey species (less than 50 m deep) and at night, reflecting the reliance of Cape fur seals on small, vertically migrating, schooling prey. However, most females also performed benthic dives, and benthic diving was prevalent in some individuals. Benthic diving was significantly associated with the frequency with which females exceeded their aerobic dive limit. The greater putative costs of benthic diving highlight the potential detrimental effects to Cape fur seals of well-documented changes in the availability of epipelagic prey species in the Benguela.

BackgroundPatients with hypersensitivity pneumonitis are at risk of developing pulmonary fibrosis, which is associated with reduced survival. In families with multiple affected members, individuals might be diagnosed as having idiopathic pulmonary fibrosis (IPF) or chronic (fibrotic) hypersensitivity pneumonitis, which suggests these disorders share risk factors. We aimed to test whether the genomic risk factors associated with the development and progression of IPF are also associated with the development of fibrosis and reduced survival in people with chronic hypersensitivity pneumonitis.MethodsWe did an observational study of two independent cohorts of patients with chronic hypersensitivity pneumonitis, one from the University of California San Francisco, CA, USA (UCSF), and one from the University of Texas Southwestern, TX, USA (UTSW). We measured two common single-nucleotide polymorphisms associated with IPF (MUC5B rs35705950 and TOLLIP rs5743890) and telomere length in peripheral blood leucocytes, and assessed their associations with chronic hypersensitivity pneumonitis risk, survival, and clinical, radiographic, and pathological features. We compared findings with those in patients with IPF from the UCSF and UTSW cohorts, and healthy controls from the European population of the 1000 Genomes Project Phase 3, version 1.FindingsThe cohorts included 145 patients from UCSF and 72 from UTSW. The minor allele frequency (MAF) was greater for MUC5B rs35705950 in patients with chronic hypersensitivity pneumonitis than in healthy controls (24·4% in UCSF and 32·3% in UTSW vs 10·7%, both p

BackgroundPatients with hypersensitivity pneumonitis are at risk of developing pulmonary fibrosis, which is associated with reduced survival. In families with multiple affected members, individuals might be diagnosed as having idiopathic pulmonary fibrosis (IPF) or chronic (fibrotic) hypersensitivity pneumonitis, which suggests these disorders share risk factors. We aimed to test whether the genomic risk factors associated with the development and progression of IPF are also associated with the development of fibrosis and reduced survival in people with chronic hypersensitivity pneumonitis.MethodsWe did an observational study of two independent cohorts of patients with chronic hypersensitivity pneumonitis, one from the University of California San Francisco, CA, USA (UCSF), and one from the University of Texas Southwestern, TX, USA (UTSW). We measured two common single-nucleotide polymorphisms associated with IPF (MUC5B rs35705950 and TOLLIP rs5743890) and telomere length in peripheral blood leucocytes, and assessed their associations with chronic hypersensitivity pneumonitis risk, survival, and clinical, radiographic, and pathological features. We compared findings with those in patients with IPF from the UCSF and UTSW cohorts, and healthy controls from the European population of the 1000 Genomes Project Phase 3, version 1.FindingsThe cohorts included 145 patients from UCSF and 72 from UTSW. The minor allele frequency (MAF) was greater for MUC5B rs35705950 in patients with chronic hypersensitivity pneumonitis than in healthy controls (24·4% in UCSF and 32·3% in UTSW vs 10·7%, both p

Within a heterogeneous environment, animals must efficiently locate and utilise foraging patches. One way animals can achieve this is by increasing residency times in areas where foraging success is highest (area-restricted search). For air-breathing diving predators, increased patch residency times can be achieved by altering both surface movements and diving patterns. The current study aimed to spatially identify the areas where female Australian fur seals allocated the most foraging effort, while simultaneously determining the behavioural changes that occur when they increase their foraging intensity. To achieve this, foraging behaviour was successfully recorded with a FastLoc GPS logger and dive behaviour recorder from 29 individual females provisioning pups. Females travelled an average of 118 ± 50 km from their colony during foraging trips that lasted 7.3 ± 3.4 days. Comparison of two methods for calculating foraging intensity (first-passage time and first-passage time modified to include diving behaviour) determined that, due to extended surface intervals where individuals did not travel, inclusion of diving behaviour into foraging analyses was important for this species. Foraging intensity 'hot spots' were found to exist in a mosaic of patches within the Bass Basin, primarily to the south-west of the colony. However, the composition of benthic habitat being targeted remains unclear. When increasing their foraging intensity, individuals tended to perform dives around 148 s or greater, with descent/ascent rates of approximately 1.9 m•s-1 or greater and reduced postdive durations. This suggests individuals were maximising their time within the benthic foraging zone. Furthermore, individuals increased tortuosity and decreased travel speeds while at the surface to maximise their time within a foraging location. These results suggest Australian fur seals will modify both surface movements and diving behaviour to maximise their time within a foraging patch.

Human-induced changes to habitats can have deleterious effects on many species that occupy them. However, some species can adapt and even benefit from such modifications. Artificial reefs have long been used to provide habitat for invertebrate communities and promote local fish populations. With the increasing demand for energy resources within ocean systems, there has been an expansion of infrastructure in near-shore benthic environments which function as de facto artificial reefs. Little is known of their use by marine mammals. In this study, the influence of anthropogenic sea floor structures (pipelines, cable routes, wells and shipwrecks) on the foraging locations of 36 adult female Australian fur seals (Arctocephalus pusillus doriferus) was investigated. For 9 (25%) of the individuals, distance to anthropogenic sea floor structures was the most important factor in determining the location of intensive foraging activity. Whereas the influence of anthropogenic sea floor structures on foraging locations was not related to age and mass, it was positively related to flipper length/standard length (a factor which can affect manoeuvrability). A total of 26 (72%) individuals tracked with GPS were recorded spending time in the vicinity of structures (from 75% of the foraging trip duration) with pipelines and cable routes being the most frequented. No relationships were found between the amount of time spent frequenting anthropogenic structures and individual characteristics. More than a third (35%) of animals foraging near anthropogenic sea floor structures visited more than one type of structure. These results further highlight potentially beneficial ecological outcomes of marine industrial development.

Within a heterogeneous environment, animals must efficiently locate and utilise foraging patches. One way animals can achieve this is by increasing residency times in areas where foraging success is highest (area-restricted search). For air-breathing diving predators, increased patch residency times can be achieved by altering both surface movements and diving patterns. The current study aimed to spatially identify the areas where female Australian fur seals allocated the most foraging effort, while simultaneously determining the behavioural changes that occur when they increase their foraging intensity. To achieve this, foraging behaviour was successfully recorded with a FastLoc GPS logger and dive behaviour recorder from 29 individual females provisioning pups. Females travelled an average of 118 ± 50 km from their colony during foraging trips that lasted 7.3 ± 3.4 days. Comparison of two methods for calculating foraging intensity (first-passage time and first-passage time modified to include diving behaviour) determined that, due to extended surface intervals where individuals did not travel, inclusion of diving behaviour into foraging analyses was important for this species. Foraging intensity 'hot spots' were found to exist in a mosaic of patches within the Bass Basin, primarily to the south-west of the colony. However, the composition of benthic habitat being targeted remains unclear. When increasing their foraging intensity, individuals tended to perform dives around 148 s or greater, with descent/ascent rates of approximately 1.9 m•s-1 or greater and reduced postdive durations. This suggests individuals were maximising their time within the benthic foraging zone. Furthermore, individuals increased tortuosity and decreased travel speeds while at the surface to maximise their time within a foraging location. These results suggest Australian fur seals will modify both surface movements and diving behaviour to maximise their time within a foraging patch.

Human-induced changes to habitats can have deleterious effects on many species that occupy them. However, some species can adapt and even benefit from such modifications. Artificial reefs have long been used to provide habitat for invertebrate communities and promote local fish populations. With the increasing demand for energy resources within ocean systems, there has been an expansion of infrastructure in near-shore benthic environments which function as de facto artificial reefs. Little is known of their use by marine mammals. In this study, the influence of anthropogenic sea floor structures (pipelines, cable routes, wells and shipwrecks) on the foraging locations of 36 adult female Australian fur seals (Arctocephalus pusillus doriferus) was investigated. For 9 (25%) of the individuals, distance to anthropogenic sea floor structures was the most important factor in determining the location of intensive foraging activity. Whereas the influence of anthropogenic sea floor structures on foraging locations was not related to age and mass, it was positively related to flipper length/standard length (a factor which can affect manoeuvrability). A total of 26 (72%) individuals tracked with GPS were recorded spending time in the vicinity of structures (from 75% of the foraging trip duration) with pipelines and cable routes being the most frequented. No relationships were found between the amount of time spent frequenting anthropogenic structures and individual characteristics. More than a third (35%) of animals foraging near anthropogenic sea floor structures visited more than one type of structure. These results further highlight potentially beneficial ecological outcomes of marine industrial development.