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Jacobs, Bette, Jason Roffenbender, Jeff Collmann, Kate Cherry, LeManuel Lee Bitsói, Kim Bassett, and Charles H. Evans. "Bridging the Divide between Genomic Science and Indigenous Peoples." Journal of Law, Medicine & Ethics 38, no. 3 (September 2010): 684–96. http://dx.doi.org/10.1111/j.1748-720x.2010.00521.x.
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The new science of genomics endeavors to chart the genomes of individuals around the world, with the dual goals of understanding the role genetic factors play in human health and solving problems of disease and disability. From the perspective of indigenous peoples and developing countries, the promises and perils of genomic science appear against a backdrop of global health disparity and political vulnerability. These conditions pose a dilemma for many communities when attempting to decide about participating in genomic research or any other biomedical research. Genomic research offers the possibility of improved technologies for managing the acute and chronic diseases that plague their members. Yet, the history of biomedical research among people in indigenous and developing nations offers salient examples of unethical practice, misuse of data and failed promises. This dilemma creates risks for communities who decide either to participate or not to participate in genomic science research.
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Feulner, Philine G. D., and Ole Seehausen. "Genomic insights into the vulnerability of sympatric whitefish species flocks." Molecular Ecology 28, no. 3 (January 29, 2019): 615–29. http://dx.doi.org/10.1111/mec.14977.
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Grauke, L. J., Bruce W. Wood, and Marvin K. Harris. "Crop Vulnerability: Carya." HortScience 51, no. 6 (June 2016): 653–63. http://dx.doi.org/10.21273/hortsci.51.6.653.
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Long-established native tree populations reflect local adaptations. Representation of diverse populations in accessible ex situ collections that link information on phenotypic expression to information on spatial and temporal origination is the most efficient means of preserving and exploring genetic diversity, which is the foundation of breeding and crop improvement. Throughout North America, sympatric Carya species sharing the same ploidy level tend to hybridize, permitting gene flow that contributes to regional diversity and adaptation. The topographic isolation of many fragmented populations, some of which are small, places native Carya populations of United States, Mexico, and Asia in a vulnerable position and justifies systematic collection and characterization. The characterization of indigenous Mexican pecan and other Carya populations will facilitate use for rootstocks and scion breeding and will contribute to pecan culture. The Asian species, as a group, are not only geographically isolated from North American species, but also occur in disjunct, fragmented populations isolated from other Asian species. Section Sinocarya includes the members of the genus most vulnerable to genetic loss. With all species, recognition of utility based on characterization of ex situ collections may contribute to the establishment of in situ reserves. Global Carya genetic resources should be cooperatively collected, maintained, characterized, and developed. The integration of crop wild relatives into characterization and breeding efforts represents a challenging opportunity for both domestic and international cooperation. Genomic tools used on the accessible collections of the National Collection of Genetic Resources for Pecans and Hickories (NCGR-Carya) offer great potential to elucidate genetic adaptation in relation to geographic distribution. The greatest progress will be made by integrating the disciplines of genetics, botany, pathology, entomology, ecology, and horticulture into internationally cooperative efforts. International germplasm exchange is becoming increasingly complicated by a combination of protectionist policies and legitimate phytosanitary concerns. Cooperative international evaluation of in situ autochthonous germplasm provides a valuable safeguard to unintended pathogen exchange associated with certain forms of germplasm distribution, while enabling beneficial communal exploration and directed exchange. This is threatened by the “proprietary” focus on intellectual property. The greatest risk to the productive development of the pecan industry might well be a myopic focus on pecan production through the lens of past practice. The greatest limitation to pecan culture in the western United States is reduced water quantity and quality; in the eastern United States the challenge is disease susceptibility; and insufficient cold hardiness in the northern United States. The greatest benefit for the entire industry might be achieved by tree size reduction through both improved rootstocks and scions, which will improve both nut production and tree management, impacting all areas of culture. This achievement will likely necessitate incorporation of crop wild relatives in breeding, broad cooperation in the testing leading to selection, and development of improved methods linking phenotypic expression to genomic characterization. The development of a database to appropriately house information available to a diverse research community will facilitate cooperative research. The acquisition of funds to pursue development of those tools will require the support of the pecan industry, which in the United States, is regionally fragmented and focused on marketing rather than crop development.
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Hettmer, Simone, Anna C. Schinzel, Daria Tchessalova, Nigel Richards, William C. Hahn, and Amy J. Wagers. "Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma." Molecular and Cellular Pediatrics 2, Suppl 1 (2015): A3. http://dx.doi.org/10.1186/2194-7791-2-s1-a3.
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Schmidt-Kastner, Rainald. "Genomic approach to selective vulnerability of the hippocampus in brain ischemia–hypoxia." Neuroscience 309 (November 2015): 259–79. http://dx.doi.org/10.1016/j.neuroscience.2015.08.034.
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Chan, Sock Hoai, and Joanne Ngeow. "Germline mutation contribution to chromosomal instability." Endocrine-Related Cancer 24, no. 9 (September 2017): T33—T46. http://dx.doi.org/10.1530/erc-17-0062.
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Genomic instability is a feature of cancer that fuels oncogenesis through increased frequency of genetic disruption, leading to loss of genomic integrity and promoting clonal evolution as well as tumor transformation. A form of genomic instability prevalent across cancer types is chromosomal instability, which involves karyotypic changes including chromosome copy number alterations as well as gross structural abnormalities such as transversions and translocations. Defects in cellular mechanisms that are in place to govern fidelity of chromosomal segregation, DNA repair and ultimately genomic integrity are known to contribute to chromosomal instability. In this review, we discuss the association of germline mutations in these pathways with chromosomal instability in the background of related cancer predisposition syndromes. We will also reflect on the impact of genetic predisposition to clinical management of patients and how we can exploit this vulnerability to promote catastrophic genomic instability as a therapeutic strategy.
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Dwyer, Donard S. "Genomic Chaos Begets Psychiatric Disorder." Complex Psychiatry 6, no. 1-2 (2020): 20–29. http://dx.doi.org/10.1159/000507988.
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The processes that created the primordial genome are inextricably linked to current day vulnerability to developing a psychiatric disorder as summarized in this review article. Chaos and dynamic forces including duplication, transposition, and recombination generated the protogenome. To survive early stages of genome evolution, self-organization emerged to curb chaos. Eventually, the human genome evolved through a delicate balance of chaos/instability and organization/stability. However, recombination coldspots, silencing of transposable elements, and other measures to limit chaos also led to retention of variants that increase risk for disease. Moreover, ongoing dynamics in the genome creates various new mutations that determine liability for psychiatric disorders. Homologous recombination, long-range gene regulation, and gene interactions were all guided by spooky action-at-a-distance, which increased variability in the system. A probabilistic system of life was required to deal with a changing environment. This ensured the generation of outliers in the population, which enhanced the probability that some members would survive unfavorable environmental impacts. Some of the outliers produced through this process in man are ill suited to cope with the complex demands of modern life. Genomic chaos and mental distress from the psychological challenges of modern living will inevitably converge to produce psychiatric disorders in man.
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Razgour, Orly, Brenna Forester, John B. Taggart, Michaël Bekaert, Javier Juste, Carlos Ibáñez, Sébastien J. Puechmaille, Roberto Novella-Fernandez, Antton Alberdi, and Stéphanie Manel. "Considering adaptive genetic variation in climate change vulnerability assessment reduces species range loss projections." Proceedings of the National Academy of Sciences 116, no. 21 (May 6, 2019): 10418–23. http://dx.doi.org/10.1073/pnas.1820663116.
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Local adaptations can determine the potential of populations to respond to environmental changes, yet adaptive genetic variation is commonly ignored in models forecasting species vulnerability and biogeographical shifts under future climate change. Here we integrate genomic and ecological modeling approaches to identify genetic adaptations associated with climate in two cryptic forest bats. We then incorporate this information directly into forecasts of range changes under future climate change and assessment of population persistence through the spread of climate-adaptive genetic variation (evolutionary rescue potential). Considering climate-adaptive potential reduced range loss projections, suggesting that failure to account for intraspecific variability can result in overestimation of future losses. On the other hand, range overlap between species was projected to increase, indicating that interspecific competition is likely to play an important role in limiting species’ future ranges. We show that although evolutionary rescue is possible, it depends on a population’s adaptive capacity and connectivity. Hence, we stress the importance of incorporating genomic data and landscape connectivity in climate change vulnerability assessments and conservation management.
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Lee, Tae-Hee, Xuan C. Qiao, Tongyu Wu, Vladislav Kuzin, Xianzhen Zhou, Vijayalalitha Ramanarayanan, Laura Baranello, and Philipp Oberdoerffer. "Abstract A024: Epigenetic control of topoisomerase 1 activity presents a cancer vulnerability." Cancer Research 84, no. 1_Supplement (January 9, 2024): A024. http://dx.doi.org/10.1158/1538-7445.dnarepair24-a024.
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Abstract Genome integrity is inherently at risk due to the torsional constraints imposed by DNA transactions. Topoisomerase 1 (TOP1) is essential for genomic stability by removing DNA supercoils generated during replication and transcription. Aberrant stabilization of TOP1:DNA cleavage complexes (TOP1ccs), however, result in DNA lesions that drive transcription-associated mutation burden and are a cytotoxic consequence of many clinically used chemotherapeutic agents. What protects genomic regions prone to elevated torsional stress from the cytotoxic potential of TOP1 enzymes remains unknown. Here, we identify macroH2A1.1, the only nucleosome component with an inherent ability to bind the TOP1cc repair-essential poly(ADP-ribose) (PAR) protein modification, as an essential means to establish a TOP1-permissive chromatin environment. MacroH2A1.1 is one of two alternatively spliced isoforms of the macro-histone variant macroH2A1, and comparative proteomics between the two isoforms uncovered a macroH2A1.1-specific and PARP activity-dependent interaction with the TOP1cc repair effector TDP1 as well as downstream base excision repair (BER) factors XRCC1 and LIG3. Consequently, macroH2A1.1 loss or inactivation of its PAR-binding domain resulted in impaired XRCC1 recruitment to damaged DNA and defective TOP1cc turnover, while the macroH2A1.2 splice isoform is unable to bind PAR or protect from TOP1ccs. Genome-wide mapping of macroH2A1.1, TOP1 and TOP1-DNA adducts identified macroH2A1.1 as a regulatory hub for TOP1 activity that ensures transcriptional integrity by preventing excessive TOP1cc accumulation at transcription start sites. Impaired macroH2A1.1 splicing, a frequent cancer feature, correlated with sensitivity to TOP1 poisons in a pharmaco-genomic screen in breast cancer cells, and macroH2A1.1 inactivation mirrored this effect. Finally, we find that aberrant macroH2A1 alternative splicing in cancer correlates with BER-related mutation signatures. We propose that macroH2A1 alternative splicing serves as an epigenetic modulator of TOP1-associated genome maintenance and a potential cancer vulnerability. Citation Format: Tae-Hee Lee, Xuan C. Qiao, Tongyu Wu, Vladislav Kuzin, Xianzhen Zhou, Vijayalalitha Ramanarayanan, Laura Baranello, Philipp Oberdoerffer. Epigenetic control of topoisomerase 1 activity presents a cancer vulnerability [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A024.
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Akimkin, V. G., T. A. Semenenko, K. F. Khafizov, S. V. Ugleva, D. V. Dubodelov, E. D. Sverdlov, A. S. Cherkashina, et al. "Biosafety and Genomic Epidemiological Surveillance." Epidemiology and Vaccinal Prevention 23, no. 5 (November 6, 2024): 4–12. http://dx.doi.org/10.31631/2073-3046-2024-23-5-4-12.
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The problem of biological safety is extremely relevant today for all countries of the world because of the real and potential threats caused by biological agents that are dangerous to public health and the environment. Modern microorganisms are becoming increasingly aggressive towards humans, as clearly demonstrated by the COVID-19 pandemic, which has affected all aspects of people's lives and exposed the vulnerability of the healthcare system. According to the Decree of the President of the Russian Federation «On the Fundamentals of the State policy of the Russian Federation in the field of chemical and biological safety for the period up to 2025 and beyond» and the Federal Law «On Biological Safety in the Russian Federation», the main objectives of state policy are to reduce the risks of negative effects of biological factors on the population and the environment. Antimicrobial resistance, the emergence of new infections and the overcoming of interspecific barriers by microorganisms are of particular concern. Infectious disease agents with epidemic potential, such as Ebola, Zika, Marburg, Lassa, MERS-CoV and SARS-CoV viruses, continue to pose a high threat. To counteract new biological threats, Russia has created a scientific concept of future biosafety, focusing on the development of genomic epidemiological surveillance, digital transformation and mobile technologies. Effective management of epidemic processes requires constant monitoring of genetic changes in infectious agents and prompt response to new threats, which allows the VGARus platform created in Russia to monitor virus mutations. Thus, genomic epidemiological surveillance is becoming a key element of ensuring biological safety and scientific and technological development in Russia.
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Trent, Jeffrey, John Carpten, Michael Reich, Ted Liefeld, Jonathan Keats, Spyro Mousses, William Hahn, et al. "The Multiple Myeloma Research Consortium Genomics Initiative." Blood 110, no. 11 (November 16, 2007): 2498. http://dx.doi.org/10.1182/blood.v110.11.2498.2498.
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Abstract The Multiple Myeloma Research Consortium (MMRC) Genomics Initiative is a three-year program to analyze tumor tissue from hundreds of multiple myeloma (MM) patients via gene expression profiling (GEP), comparative genomic hybridization (aCGH), and exon re-sequencing. In addition, RNAi knockdown of selected genes in MM tumor cell lines is being evaluated to identify potential new targets. All genomic data generated is scheduled for placement in an open-access Multiple Myeloma Genomics Portal pre-publication and in near real-time (www.broad.mit.edu/mmgp). Additionally, samples are also destined for drug validation and correlative science on clinical protocols as this study moves forward. This comprehensive project is spearheaded by the MMRC and conducted via collaboration with the Eli and Edythe L. Broad Institute of MIT and Harvard, the Translational Genomics Research Institute (TGen), Mayo Clinic Arizona, and The Dana-Farber Cancer Center. The study is supported by the collection from member institutions of the MMRC of bone marrow aspirates and matched peripheral blood samples from over 1000 patients. Specific genomic technologies that are currently being employed across this sample set include GEP using Affymetrix Human Genome U133A 2.0 Plus Arrays, and, in parallel, efforts to identify regions of genomic gain and loss are using Agilent Human Genome CGH arrays. In contrast to other large-scale genomic projects based on exon-sequencing of targeted gene sets, this project will be the first to perform genome-scale single molecule sequencing (SMS) of DNA from patient specimens. Results will be targeted against candidate classes of genes (e.g. kinases, phosphatases, known oncogenes and tumor suppressors), and genes from GEP or within candidate regions of copy gain or loss identified by the aCGH experiments. Mutations will be further validated in an independent set of patient specimens. Finally we will attempt to identify points of vulnerability of MM through systematic loss-of-function screens in myeloma cell lines using high-throughput RNA interference (using both shRNA and siRNA platforms). Importantly, data generated from this genomics initiative will ultimately be made public pre-publication through the established MMRC Multiple Myeloma Genomics Portal. Data from all aspects of this project (sample collection and analyte isolation, GEP, aCGH, SMS, RNAi and bioinformatics) will be described in this presentation. The power of this study is the comprehensive collection of gene expression, CGH, and genome sequencing on a single reference set of clinically annotated samples. The addition of RNAi screens makes this a very important and unique data resource, which we hope will help expedite the discovery of novel targeted agents for MM scientific community.
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Ayoz, Kerem, Erman Ayday, and A. Ercument Cicek. "Genome Reconstruction Attacks Against Genomic Data-Sharing Beacons." Proceedings on Privacy Enhancing Technologies 2021, no. 3 (April 27, 2021): 28–48. http://dx.doi.org/10.2478/popets-2021-0036.
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Abstract Sharing genome data in a privacy-preserving way stands as a major bottleneck in front of the scientific progress promised by the big data era in genomics. A community-driven protocol named genomic data-sharing beacon protocol has been widely adopted for sharing genomic data. The system aims to provide a secure, easy to implement, and standardized interface for data sharing by only allowing yes/no queries on the presence of specific alleles in the dataset. However, beacon protocol was recently shown to be vulnerable against membership inference attacks. In this paper, we show that privacy threats against genomic data sharing beacons are not limited to membership inference. We identify and analyze a novel vulnerability of genomic data-sharing beacons: genome reconstruction. We show that it is possible to successfully reconstruct a substantial part of the genome of a victim when the attacker knows the victim has been added to the beacon in a recent update. In particular, we show how an attacker can use the inherent correlations in the genome and clustering techniques to run such an attack in an efficient and accurate way. We also show that even if multiple individuals are added to the beacon during the same update, it is possible to identify the victim’s genome with high confidence using traits that are easily accessible by the attacker (e.g., eye color or hair type). Moreover, we show how a reconstructed genome using a beacon that is not associated with a sensitive phenotype can be used for membership inference attacks to beacons with sensitive phenotypes (e.g., HIV+). The outcome of this work will guide beacon operators on when and how to update the content of the beacon and help them (along with the beacon participants) make informed decisions.
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Smith, Thomas B., Trevon L. Fuller, Ying Zhen, Virginia Zaunbrecher, Henri A. Thomassen, Kevin Njabo, Nicola M. Anthony, et al. "Genomic vulnerability and socio‐economic threats under climate change in an African rainforest bird." Evolutionary Applications 14, no. 5 (January 28, 2021): 1239–47. http://dx.doi.org/10.1111/eva.13193.
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Perry, Jennifer A., Adam Kiezun, Peter Tonzi, Eliezer M. Van Allen, Scott L. Carter, Sylvan C. Baca, Glenn S. Cowley, et al. "Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma." Proceedings of the National Academy of Sciences 111, no. 51 (December 15, 2014): E5564—E5573. http://dx.doi.org/10.1073/pnas.1419260111.
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Sharma, Samantha, Tao Yu, Abhinav Achreja, Xinna Zhang, Deepak Nagrath, and Xiongbin Lu. "Abstract 3913: Genomic loss of UQCR11 creates therapeutic vulnerability in triple-negative breast cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3913. http://dx.doi.org/10.1158/1538-7445.am2023-3913.
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Abstract Recurrent loss-of-function deletions are prevalent genomic alterations in tumors; nonetheless, these deletions occasionally create conditional therapeutic vulnerabilities in tumors. Our previous study used The Cancer Genome Atlas High-Grade Serous Ovarian Carcinoma (TCGA-HGSOC) dataset to identify the 19p13.3 locus as the most pervasive deletion in the high-grade serous ovarian carcinoma (HGSOC). Subsequently, the machine learning integrated-precision oncology platform identified that the loss of UQCR11, a gene located within the chromosome 19p13.3 locus, created a therapeutic collateral target, the MTHFD2. Furthermore, pharmacological inhibition of MTHFD2 in the UQCR11-deleted cells led to complete tumor remission in our in vivo mouse model (Nature metabolism, 2022). Encouraged by the promising anti-tumor effect of the MTHFD2 inhibitor, we extended our research to other tumor types. By analyzing the TGCA datasets, we found that UQCR11 deletion was a common occurrence among humans' most prevalent solid tumors, especially in pan breast and lung cancer. Within the pan breast cancer dataset, we found that over 50% of patients with triple-negative breast cancer (TNBC), the most difficult-to-treat breast cancer subtype in women, displayed either heterozygous or homozygous deletions in the UQCR11 gene. Moreover, the TGCA-TNBC dataset analysis revealed that the genomic copy loss of UQCR11 positively correlates with the deceased mRNA expression of the gene, bringing our interest to validate the collateral lethal targets in this breast cancer subtype. We first analyzed The Cancer Cell Line Encyclopedia (CCLE) database and further explored the correlation between the copy number alteration and mRNA expression of UQCR11 in several breast cancer cell lines. Then, we selected seven human TNBC cells with copy number neutral or deletion UQCR11 and validated the copy number and gene expression of UQCR11 and MTHFD2 using qPCR and western blot. We next treated these cells with a selective MTHFD2 inhibitor, DS18561882, and found that UQCR11-deleted cells showed a more favorable response than the UQCR11-intact cells. Finally, to test the therapeutic potential of targeting MTHFD2-null tumors in vivo, we generated isogenic mouse breast cancer cell lines using shRNA-mediated UQCR11 knockdown. Consistent with our previous findings, the MTHFD2 expression level was upregulated upon UQCR11 knockdown, suggesting a compensation function of MTHFD2 in UQCR11-deleted cells. Furthermore, the UQCR11 knocked-down cells showed better responses to MTHFD2 inhibitor treatment than the parental control cells. In summary, our study provides evidence that targeting MTHFD2 holds strong therapeutic potential in over 50% of the TNBC patients with UQCR11 deletion and highlights the broad efficacy of targeting MTHFD2 for individualized therapeutic strategy in different tumor types co-occurring with UQCR11 deletion. Citation Format: Samantha Sharma, Tao Yu, Abhinav Achreja, Xinna Zhang, Deepak Nagrath, Xiongbin Lu. Genomic loss of UQCR11 creates therapeutic vulnerability in triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3913.
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Kamath, Tushar, Abdulraouf Abdulraouf, S. J. Burris, Jonah Langlieb, Vahid Gazestani, Naeem M. Nadaf, Karol Balderrama, Charles Vanderburg, and Evan Z. Macosko. "Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson’s disease." Nature Neuroscience 25, no. 5 (May 2022): 588–95. http://dx.doi.org/10.1038/s41593-022-01061-1.
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AbstractThe loss of dopamine (DA) neurons within the substantia nigra pars compacta (SNpc) is a defining pathological hallmark of Parkinson’s disease (PD). Nevertheless, the molecular features associated with DA neuron vulnerability have not yet been fully identified. Here, we developed a protocol to enrich and transcriptionally profile DA neurons from patients with PD and matched controls, sampling a total of 387,483 nuclei, including 22,048 DA neuron profiles. We identified ten populations and spatially localized each within the SNpc using Slide-seq. A single subtype, marked by the expression of the gene AGTR1 and spatially confined to the ventral tier of SNpc, was highly susceptible to loss in PD and showed the strongest upregulation of targets of TP53 and NR2F2, nominating molecular processes associated with degeneration. This same vulnerable population was specifically enriched for the heritable risk associated with PD, highlighting the importance of cell-intrinsic processes in determining the differential vulnerability of DA neurons to PD-associated degeneration.
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Haig, David. "Maternal–fetal conflict, genomic imprinting and mammalian vulnerabilities to cancer." Philosophical Transactions of the Royal Society B: Biological Sciences 370, no. 1673 (July 19, 2015): 20140178. http://dx.doi.org/10.1098/rstb.2014.0178.
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Antagonistic coevolution between maternal and fetal genes, and between maternally and paternally derived genes may have increased mammalian vulnerability to cancer. Placental trophoblast has evolved to invade maternal tissues and evade structural and immunological constraints on its invasion. These adaptations can be co-opted by cancer in intrasomatic selection. Imprinted genes of maternal and paternal origin favour different degrees of proliferation of particular cell types in which they reside. As a result, the set of genes favouring greater proliferation will be selected to evade controls on cell-cycle progression imposed by the set of genes favouring lesser proliferation. The dynamics of stem cell populations will be a particular focus of this intragenomic conflict. Gene networks that are battlegrounds of intragenomic conflict are expected to be less robust than networks that evolve in the absence of conflict. By these processes, maternal–fetal and intragenomic conflicts may undermine evolved defences against cancer.
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Wu, He Qi, Zheng Hong Li, Xuan Zhou, Hong Dao Zhang, Ji Lin Li, Yu Xin Li, and Yan Ming Zhang. "Development of Plant Genetic Diversity by Biotechnology and Genomics." Applied Mechanics and Materials 522-524 (February 2014): 1047–50. http://dx.doi.org/10.4028/www.scientific.net/amm.522-524.1047.
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Interactions between civilizations and ethnic groups have generated a fusion of customs and lifestyles, with an important effect on plant genetic diversity. The loss of local species and varieties usually results in irreversible loss of the genetic diversity they contain, this has dangerously shrunk the genetic pool that is available for natural selection and art selection, and has consequently increased the vulnerability of agricultural crops to sudden changes in climate, and to the appearance of new pests. Currently, biotechnology and genomic selection have enabled the genetic alteration of crops, improved soil productivity, and enhanced weed and pest control, and benefit to the development of plant genetic diversity. For example, next generation sequencing (NGS) and bioinformatics, as the gold standard, they provide a powerful tool for discovery of domestication genes in crop plants and their wild relatives.The objectives of this article are to review the development of plant genetic diversity and summarize the research of biotechnology and genomics for plant. Then, we look forward and consider the significant of development of plant genetic diversity by biotechnology and genomics.
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de Nigris, Filomena, Concetta Meo, and Wulf Palinski. "Combination of Genomic Landsscape and 3D Culture Functional Assays Bridges Sarcoma Phenotype to Target and Immunotherapy." Cells 12, no. 17 (September 4, 2023): 2204. http://dx.doi.org/10.3390/cells12172204.
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Genomic-based precision medicine has not only improved tumour therapy but has also shown its weaknesses. Genomic profiling and mutation analysis have identified alterations that play a major role in sarcoma pathogenesis and evolution. However, they have not been sufficient in predicting tumour vulnerability and advancing treatment. The relative rarity of sarcomas and the genetic heterogeneity between subtypes also stand in the way of gaining statistically significant results from clinical trials. Personalized three-dimensional tumour models that reflect the specific histologic subtype are emerging as functional assays to test anticancer drugs, complementing genomic screening. Here, we provide an overview of current target therapy for sarcomas and discuss functional assays based on 3D models that, by recapitulating the molecular pathways and tumour microenvironment, may predict patient response to treatments. This approach opens new avenues to improve precision medicine when genomic and pathway alterations are not sufficient to guide the choice of the most promising treatment. Furthermore, we discuss the aspects of the 3D culture assays that need to be improved, such as the standardisation of growth conditions and the definition of in vitro responses that can be used as a cut-off for clinical implementation.
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Wood, Georgina, Ezequiel M. Marzinelli, Alexandra H. Campbell, Peter D. Steinberg, Adriana Vergés, and Melinda A. Coleman. "Genomic vulnerability of a dominant seaweed points to future‐proofing pathways for Australia's underwater forests." Global Change Biology 27, no. 10 (February 16, 2021): 2200–2212. http://dx.doi.org/10.1111/gcb.15534.
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Alloza, Iraide, Andrea Salegi, Jorge Mena, Raquel Tulloch Navarro, César Martin, Patricia Aspichueta, Lucía Martínez Salazar, et al. "BIRC6 Is Associated with Vulnerability of Carotid Atherosclerotic Plaque." International Journal of Molecular Sciences 21, no. 24 (December 9, 2020): 9387. http://dx.doi.org/10.3390/ijms21249387.
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Carotid atherosclerotic plaque rupture can lead to cerebrovascular accident (CVA). By comparing RNA-Seq data from vascular smooth muscle cells (VSMC) extracted from carotid atheroma surgically excised from a group of asymptomatic and symptomatic subjects, we identified more than 700 genomic variants associated with symptomatology (p < 0.05). From these, twelve single nucleotide polymorphisms (SNPs) were selected for further validation. Comparing genotypes of a hospital-based cohort of asymptomatic with symptomatic patients, an exonic SNP in the BIRC6 (BRUCE/Apollon) gene, rs35286811, emerged as significantly associated with CVA symptomatology (p = 0.002; OR = 2.24). Moreover, BIRC6 mRNA levels were significantly higher in symptomatic than asymptomatic subjects upon measurement by qPCR in excised carotid atherosclerotic tissue (p < 0.0001), and significantly higher in carriers of the rs35286811 risk allele (p < 0.0001). rs35286811 is a proxy of a GWAS SNP reported to be associated with red cell distribution width (RDW); RDW was increased in symptomatic patients (p < 0.03), but was not influenced by the rs35286811 genotype in our cohort. BIRC6 is a negative regulator of both apoptosis and autophagy. This work introduces BIRC6 as a novel genetic risk factor for stroke, and identifies autophagy as a genetically regulated mechanism of carotid plaque vulnerability.
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Botrugno, Oronza A., and Giovanni Tonon. "Genomic Instability and Replicative Stress in Multiple Myeloma: The Final Curtain?" Cancers 14, no. 1 (December 22, 2021): 25. http://dx.doi.org/10.3390/cancers14010025.
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Multiple Myeloma (MM) is a genetically complex and heterogeneous hematological cancer that remains incurable despite the introduction of novel therapies in the clinic. Sadly, despite efforts spanning several decades, genomic analysis has failed to identify shared genetic aberrations that could be targeted in this disease. Seeking alternative strategies, various efforts have attempted to target and exploit non-oncogene addictions of MM cells, including, for example, proteasome inhibitors. The surprising finding that MM cells present rampant genomic instability has ignited concerted efforts to understand its origin and exploit it for therapeutic purposes. A credible hypothesis, supported by several lines of evidence, suggests that at the root of this phenotype there is intense replicative stress. Here, we review the current understanding of the role of replicative stress in eliciting genomic instability in MM and how MM cells rely on a single protein, Ataxia Telangiectasia-mutated and Rad3-related protein, ATR, to control and survive the ensuing, potentially fatal DNA damage. From this perspective, replicative stress per se represents not only an opportunity for MM cells to increase their evolutionary pool by increasing their genomic heterogeneity, but also a vulnerability that could be leveraged for therapeutic purposes to selectively target MM tumor cells.
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Sweet-Cordero, E. Alejandro. "Abstract IA026: Epigenetic and genomic features define distinct cellular states with possible therapeutic relevance in osteosarcoma." Clinical Cancer Research 28, no. 18_Supplement (September 15, 2022): IA026. http://dx.doi.org/10.1158/1557-3265.sarcomas22-ia026.
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Abstract The Osteosarcoma (OS) genome is characterized by aneuploidy and dramatic structural rearrangements often leading to copy number gain and loss. Currently, all patients with osteoblastic OS at diagnosis are treated with the same highly toxic chemotherapy and no clinically relevant subtypes have been identified. While there is significant heterogeneity at the genome level between patients, less is known regarding epigenetic heterogeneity and how this may impact critical phenotypes such as therapy response and metastasis. To characterize the osteosarcoma epigenome, we integrated ATAC-seq and RNA-seq across a unique set of patient samples, PDXs and PDX-derived cell lines obtained across the disease continuum and including biopsies, resections, and metastasis. ATACseq analysis revealed the presence of two distinct epigenetic cell states (C1 and C2). Associating the differential genomic regions to likely regulated genes, the enriched pathways of Cluster 1 (C1) are related to mesenchymal cell proliferation, skeletal system morphogenesis, osteoblast differentiation, and Wnt signaling pathway. In contrast, Cluster 2 (C2) enriched pathways are related to cell motility and migration, extracellular matrix organization and regulation of protein serine/threonine kinase activity. Furthermore, accessible chromatin regions were enriched for a distinct set of transcription factor binding sites. We then assessed whether these epigenetic states were associated with response to targeted therapies. We identified unique vulnerability of C1 cell lines to AURK inhibitors whereas C2 cell lines had evidence for upregulation of MAPK and were vulnerable to treatment with trametinib. ATACseq analysis of PDX and a limited number of patient samples confirmed that these subtypes of OS also likely exist in patient tumors. In parallel to these studies, we have also carried out extensive additional analysis of vulnerability of OS cell ines to a wide range of targeted therapies. We find evidence for significant response to several inhibitors of the ATR-WEE1-CHK1 pathway nominating this as a potential novel vulnerability for OS. Therapeutic relevance of these findings is currently being explores in an orthotopic metastasis model of OS. Overall, our findings may define new subtypes of osteosarcoma with unique therapeutic vulnerabilities. Citation Format: E. Alejandro Sweet-Cordero. Epigenetic and genomic features define distinct cellular states with possible therapeutic relevance in osteosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr IA026.
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Shammas, Masood A., Leutz Buon, Subodh Kumar, Mehmet K. Samur, David Alagpulinsa, Purushothama Nanjappa, and Nikhil C. Munshi. "Flap Structure-Specific Endonuclease 1 (FEN1) May be a Key Mediator of Genome Instability in Myeloma: A Cellular Vulnerability with Potential Therapeutic Significance." Blood 128, no. 22 (December 2, 2016): 4440. http://dx.doi.org/10.1182/blood.v128.22.4440.4440.
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Abstract Multiple myeloma is associated with a marked genomic instability which leads to acquisition of mutational changes, some of which underlie disease progression including development of drug resistance and poor clinical outcome. Understanding mechanisms of genomic instability is, therefore, extremely important to develop novel improved therapeutic strategies. Since dysregulated nuclease activity can induce DNA breaks and genetic recombination eventually disrupting genomic integrity, we have evaluated nuclease activity and specific nucleases for their role in genomic instability in MM. We previously identified a nuclease gene signature correlating with genomic instability in a myeloma patient dataset and tested it for correlation with survival in two other datasets. We showed that expression of these genes associated with poor overall as well as event free survival in both datasets, IFM172 (P< 0.00005) and gse24080 (P< 0.0008). We have now further refined this signature to a nine gene signature and tested it for correlation with survival in three different MM patient datasets in which gene expression was evaluated either by microarray (GSE39754, n=170; gse24080; n=559) or RNASeq (n=300). Elevated expression of nine gene signature significantly correlated with poor overall survival in all three datasets (P ≤ 1e-06 for IFM70 and gse24080 and P = 0.002 for RNASeq). To biologically and molecularly validate this signature, we conducted an shRNA screen and evaluated impact of all nine genes in signature as well as four additional nucleases on homologous recombination (HR) activity, using a plasmid based assay in which HR produces a functional luciferase gene. Of thirteen nucleases tested, knockdown of seven was associated with ≥50% inhibition of HR activity; the strongest (~80%) inhibition of HR activity was observed by FEN1 knockdown. To further investigate FEN1, we confirmed the role of this nuclease in HR using a different (DRGFP) assay in which homology-based recombination between two mutated genes, generates a functional GFP gene. Using this assay, we showed that FEN1-knockdown in U2OS cells was also associated with a strong (71%) inhibition of HR activity, confirming the role of this nuclease in dysregulation of HR. Evaluation by Western blotting in three different normal PBMC samples and eleven MM cell lines showed that FEN1 was not detected in normal cells, whereas highly expressed in MM cells. Expression profile using microarray also showed that FEN1 is elevated in a subset of MM patient samples. Knockdown of FEN1 in two MM cell lines, RPMI and H929, led to reduction in overall nuclease activity (by ~40%) as assessed by a fluorescence based nuclease activity assay and a similar (~50%) reduction in the levels of gamma-H2AX, a marker of DNA breaks. These data indicate that FEN1 nuclease activity contributes to increased DNA breaks as well as elevated HR activity in MM cells. To further understand the role of FEN1 in dysregulated HR and genome stability in MM, using mass spectrometry, we have identified the interacting proteins. Role of FEN1 in acquisition of new genomic changes over time in MM cells is cuurently being investigated in our laboratory. In summary, we show that FEN1 is an important component of machinery maintaining genomic integrity and plays a significant role in genome dysregulation in myeloma. The FEN1 dysfunction may provide a cellular vulnerability that can be therapeutically exploited. Disclosures No relevant conflicts of interest to declare.
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Bekele, Raie, Amruta Samant, Timothy Hanlon, and Kent Mouw. "Abstract 1709: MAPK pathway alterations are a targetable vulnerability in bladder cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1709. http://dx.doi.org/10.1158/1538-7445.am2023-1709.
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Abstract Bladder cancer (BC) is the fourth most common cancer in males and accounts for about 80,000 new cases in the US. Approximately 25% patients with BC will present with muscle-invasive bladder cancer (MIBC) and for the past several decades the standard-of-care for MIBC and metastatic bladder cancer has been cisplatin-based chemotherapy. More recently, multiple immunotherapeutic agents have been approved but only a subset of patients respond to these treatments and therefore novel therapeutic strategies are needed to expand treatment options and improve clinical outcomes for BC patients. Large-scale genomic studies of MIBC have identified numerous recurrent genomic alterations including mutations, copy number alterations, and chromosomal translocations. Using publicly available patient datasets, we identified ~20% of MIBC patients harboring alterations in genes involved in the mitogen-activated protein kinase (MAPK) pathway and their upstream activators. RAF1 copy number amplification was the most predominant alteration followed by activating HRAS mutations. Leveraging our institutional cohorts of bladder cancer specimens, we defined the frequency of these alterations and validated RAF1 amplification in a subset of cases using fluorescence in situ hybridization. To functionally define the role of MAPK pathway alterations in BC, we tested activity of RAF and MEK inhibitors in BC cell line models with diverse MAPK pathway alterations including RAF1 amplification and HRAS/NRAS mutations. We found that these MAPK pathway altered models displayed increased sensitivity to RAF/MEK inhibition compared to MAPK-unaltered models. We further demonstrated the feasibility of preclinically targeting these alterations in mouse models of BC using cell line and patient-derived-xenografts. Additionally, we tested the impact of MAPK pathway modulation on tumor extrinsic properties including changes in the tumor microenvironment that could potentially affect responses to immunotherapeutic agents. Taken together, we have identified MAPK pathway alterations as a novel dependency in BC that can be targeted with emerging RAF inhibitors. Citation Format: Raie Bekele, Amruta Samant, Timothy Hanlon, Kent Mouw. MAPK pathway alterations are a targetable vulnerability in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1709.
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Sa, Jason K., Sung Heon Kim, Jin-Ku Lee, Hee Jin Cho, Yong Jae Shin, Hyemi Shin, Harim Koo, et al. "Identification of genomic and molecular traits that present therapeutic vulnerability to HGF-targeted therapy in glioblastoma." Neuro-Oncology 21, no. 2 (June 23, 2018): 222–33. http://dx.doi.org/10.1093/neuonc/noy105.
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Ashton, Jack, and Robert Bristow. "Bad neighbours: hypoxia and genomic instability in prostate cancer." British Journal of Radiology 93, no. 1115 (November 1, 2020): 20200087. http://dx.doi.org/10.1259/bjr.20200087.
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Prostate cancer (PCa) is a clinically heterogeneous disease and has poor patient outcome when tumours progress to castration-resistant and metastatic states. Understanding the mechanistic basis for transition to late stage aggressive disease is vital for both assigning patient risk status in the localised setting and also identifying novel treatment strategies to prevent progression. Subregions of intratumoral hypoxia are found in all solid tumours and are associated with many biologic drivers of tumour progression. Crucially, more recent findings show the co-presence of hypoxia and genomic instability can confer a uniquely adverse prognosis in localised PCa patients. In-depth informatic and functional studies suggests a role for hypoxia in co-operating with oncogenic drivers (e.g. loss of PTEN) and suppressing DNA repair capacity to alter clonal evolution due to an aggressive mutator phenotype. More specifically, hypoxic suppression of homologous recombination represents a “contextual lethal“ vulnerability in hypoxic prostate tumours which could extend the application of existing DNA repair targeting agents such as poly-ADP ribose polymerase inhibitors. Further investigation is now required to assess this relationship on the background of existing genomic alterations relevant to PCa, and also characterise the role of hypoxia in driving early metastatic spread. On this basis, PCa patients with hypoxic tumours can be better stratified into risk categories and treated with appropriate therapies to prevent progression.
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Phair, Nikki Leanne, Robert John Toonen, Ingrid Knapp, and Sophie von der Heyden. "Shared genomic outliers across two divergent population clusters of a highly threatened seagrass." PeerJ 7 (April 29, 2019): e6806. http://dx.doi.org/10.7717/peerj.6806.
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The seagrass, Zostera capensis, occurs across a broad stretch of coastline and wide environmental gradients in estuaries and sheltered bays in southern and eastern Africa. Throughout its distribution, habitats are highly threatened and poorly protected, increasing the urgency of assessing the genomic variability of this keystone species. A pooled genomic approach was employed to obtain SNP data and examine neutral genomic variation and to identify potential outlier loci to assess differentiation across 12 populations across the ∼9,600 km distribution of Z. capensis. Results indicate high clonality and low genomic diversity within meadows, which combined with poor protection throughout its range, increases the vulnerability of this seagrass to further declines or local extinction. Shared variation at outlier loci potentially indicates local adaptation to temperature and precipitation gradients, with Isolation-by-Environment significantly contributing towards shaping spatial variation in Z. capensis. Our results indicate the presence of two population clusters, broadly corresponding to populations on the west and east coasts, with the two lineages shaped only by frequency differences of outlier loci. Notably, ensemble modelling of suitable seagrass habitat provides evidence that the clusters are linked to historical climate refugia around the Last Glacial Maxi-mum. Our work suggests a complex evolutionary history of Z. capensis in southern and eastern Africa that will require more effective protection in order to safeguard this important ecosystem engineer into the future.
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Xue, Caroline, Eva Corey, and Taranjit S. Gujral. "Proteomic and Transcriptomic Profiling Reveals Mitochondrial Oxidative Phosphorylation as Therapeutic Vulnerability in Androgen Receptor Pathway Active Prostate Tumors." Cancers 14, no. 7 (March 29, 2022): 1739. http://dx.doi.org/10.3390/cancers14071739.
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Metastatic prostate cancer (PC) is the second leading cause of cancer deaths in males and has limited therapeutic options. The lack of preclinical models for advanced stage PC represents one of the primary barriers in understanding the key genetic drivers of aggressive subsets, including androgen receptor (AR) pathway active and AR-null castration-resistant prostate cancers (CRPC). In our studies, we described a series of LuCaP patient-derived xenograft (PDX) models representing the major genomic and phenotypic features of human disease. To fully exploit the potential of these preclinical models, we carried out a comprehensive transcriptomic and proteomic profiling of 42 LuCaP PDX prostate tumors. The collected proteomic data (~6000 data points) based on 71 antibodies revealed many of the previously known molecular markers associated with AR-positive and AR-null CRPC. Genomic analysis indicated subtype-specific activation of pathways such as Wnt/beta-catenin signaling, mTOR, and oxidative phosphorylation for AR-positive CRPC and upregulation of carbohydrate metabolism and glucose metabolism for AR-null CRPC. Of these, we functionally confirmed the role of mitochondrial metabolism in AR-positive CRPC cell lines. Our data highlight how the integration of transcriptomic and proteomic approaches and PDX systems as preclinical models can potentially map the connectivity of poorly understood signaling pathways in metastatic prostate cancer.
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Burkart, Sebastian, Christopher Weusthof, Karam Khorani, Sonja Steen, Fabian Stögbauer, Kristian Unger, Julia Hess, et al. "A Novel Subgroup of UCHL1-Related Cancers Is Associated with Genomic Instability and Sensitivity to DNA-Damaging Treatment." Cancers 15, no. 6 (March 8, 2023): 1655. http://dx.doi.org/10.3390/cancers15061655.
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Purpose: Identification of molecularly-defined cancer subgroups and targeting tumor-specific vulnerabilities have a strong potential to improve treatment response and patient outcomes but remain an unmet challenge of high clinical relevance, especially in head and neck squamous cell carcinoma (HNSC). Experimental design: We established a UCHL1-related gene set to identify and molecularly characterize a UCHL1-related subgroup within TCGA-HNSC by integrative analysis of multi-omics data. An extreme gradient boosting model was trained on TCGA-HNSC based on GSVA scores for gene sets of the MSigDB to robustly predict UCHL1-related cancers in other solid tumors and cancer cell lines derived thereof. Potential vulnerabilities of UCHL1-related cancer cells were elucidated by an in-silico drug screening approach. Results: We established a 497-gene set, which stratified the TCGA-HNSC cohort into distinct subgroups with a UCHL1-related or other phenotype. UCHL1-related HNSC were characterized by higher frequencies of genomic alterations, which was also evident for UCHL1-related cancers of other solid tumors predicted by the classification model. These data indicated an impaired maintenance of genomic integrity and vulnerability for DNA-damaging treatment, which was supported by a favorable prognosis of UCHL1-related tumors after radiotherapy, and a higher sensitivity of UCHL1-related cancer cells to irradiation or DNA-damaging compounds (e.g., Oxaliplatin). Conclusion: Our study established UCHL1-related cancers as a novel subgroup across most solid tumor entities with a unique molecular phenotype and DNA-damaging treatment as a specific vulnerability, which requires further proof-of-concept in pre-clinical models and future clinical trials.
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Aoki, Yuka, Masanori Nojima, Hiromu Suzuki, Hiroshi Yasui, Reo Maruyama, Eiichiro Yamamoto, Masami Ashida, et al. "Genomic vulnerability to LINE-1 hypomethylation is a potential determinant of the clinicogenetic features of multiple myeloma." Genome Medicine 4, no. 12 (2012): 101. http://dx.doi.org/10.1186/gm402.
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Arendt, Thomas, Martina K. Brückner, and Andreas Lösche. "Regional mosaic genomic heterogeneity in the elderly and in Alzheimer’s disease as a correlate of neuronal vulnerability." Acta Neuropathologica 130, no. 4 (August 23, 2015): 501–10. http://dx.doi.org/10.1007/s00401-015-1465-5.
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Grohar, Patrick J., Suntae Kim, Guillermo O. Rangel Rivera, Nirmalya Sen, Sara Haddock, Matt L. Harlow, Nichole K. Maloney, et al. "Functional Genomic Screening Reveals Splicing of the EWS-FLI1 Fusion Transcript as a Vulnerability in Ewing Sarcoma." Cell Reports 14, no. 3 (January 2016): 598–610. http://dx.doi.org/10.1016/j.celrep.2015.12.063.
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De Nonneville, A., P. Finetti, A. Gonçalves, E. Mamessier, and F. Bertucci. "61P Genomic risk and gene expression-based inference of anti-cancer drugs vulnerability in early breast cancer." ESMO Open 8, no. 1 (May 2023): 101285. http://dx.doi.org/10.1016/j.esmoop.2023.101285.
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Mayeur, Chloé, Heidi Mertes, and Wannes Van Hoof. "Do genomic passports leave us more vulnerable or less vulnerable? Perspectives from an online citizen engagement." Humanities and Social Sciences Communications 10, no. 1 (March 4, 2023). http://dx.doi.org/10.1057/s41599-023-01580-7.
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AbstractSince genomics is becoming commonplace in healthcare for the diagnosis, treatment, and prevention, the prospect of generating a genomic passport for all citizens is gaining traction. While this would have many advantages, it raises ethical issues requiring societal debate alongside academic reflection. Hence, Sciensano—the Belgian scientific Institute of Public Health—organised an online citizen engagement on genomic information usage, including a question on a genomic passport for all. The inductive thematic analysis of participants’ contributions highlighted vulnerability as a fundamental concern, while this has not received sufficient attention so far in genomics. Participants expressed their vulnerability in two ways. First, the genomic passport would inform them about their ontological vulnerability. By revealing their constitutional weaknesses (predisposition to diseases), it reminds them that everyone is unavoidably and perennially at risk of being harmed. Second, the misuse of the genomic passport can add situational vulnerabilities (e.g., discrimination causing psychological and economic harm). Moreover, the fundamental uncertainty in genomics—how will such sensitive information be used, and how will the science evolve?—exacerbates these vulnerabilities. This article ends with recommendations to alleviate these vulnerabilities in genomics now and in the future in which the genomic passport may become a reality.
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Schmidt, Danielle A., and Michael A. Russello. "Genomic Vulnerability of a Sentinel Mammal Under Climate Change." Molecular Ecology, February 19, 2025. https://doi.org/10.1111/mec.17688.
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ABSTRACTClimate change poses a significant threat to biodiversity, particularly in alpine ecosystems where species have already undergone elevational range shifts. Genomics can be used to estimate the adaptive potential of species, as well as the shift in adaptive genomic composition necessary for populations to adjust to climate change (e.g., genomic offset). Here, we investigated patterns of climate‐mediated adaptive genetic variation and predicted the degree of genomic offset under multiple climate change scenarios for a sentinel alpine mammal, the American pika (Ochotona princeps). We collected genome‐wide data (29,709 SNPs) from 363 individuals spanning the entire range in western North America and employed genotype‐environment association analyses to identify 924 robust outlier SNPs, several of which were linked to genes previously associated with high elevation and hypoxia responses in various pika species (Ochotonidae). Adaptive genomic variation was most strongly influenced by mean warmest month temperature, followed by precipitation of the coldest quarter. Spatial patterns of genomic offset were heterogeneous, significantly predicted by levels of adaptive genetic variation, elevation and latitude. Sites within the Northern Rocky Mountains exhibited the highest genomic offset under projected climate change despite possessing high levels of adaptive genetic variation. As such, while our study provides an example of how genomic data can be used to explore the potential consequences of climate change, it further highlights the need for careful consideration of genomic offset values within their proper ecological context.
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Forester, Brenna R., Amanda S. Cicchino, Alisha A. Shah, Austin B. Mudd, Eric C. Anderson, Jessen V. Bredeson, Andrew J. Crawford, et al. "Population Genomics Reveals Local Adaptation Related to Temperature Variation in Two Stream Frog Species: Implications for Vulnerability to Climate Warming." Molecular Ecology, January 17, 2025. https://doi.org/10.1111/mec.17651.
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ABSTRACTIdentifying populations at highest risk from climate change is a critical component of conservation efforts. However, vulnerability assessments are usually applied at the species level, even though intraspecific variation in exposure, sensitivity and adaptive capacity play a crucial role in determining vulnerability. Genomic data can inform intraspecific vulnerability by identifying signatures of local adaptation that reflect population‐level variation in sensitivity and adaptive capacity. Here, we address the question of local adaptation to temperature and the genetic basis of thermal tolerance in two stream frogs (Ascaphus truei and A. montanus). Building on previous physiological and temperature data, we used whole‐genome resequencing of tadpoles from four sites spanning temperature gradients in each species to test for signatures of local adaptation. To support these analyses, we developed the first annotated reference genome for A. truei. We then expanded the geographic scope of our analysis using targeted capture at an additional 11 sites per species. We found evidence of local adaptation to temperature based on physiological and genomic data in A. montanus and genomic data in A. truei, suggesting similar levels of sensitivity (i.e., susceptibility) among populations regardless of stream temperature. However, invariant thermal tolerances across temperatures in A. truei suggest that populations occupying warmer streams may be most sensitive. We identified high levels of evolutionary potential in both species based on genomic and physiological data. While further integration of these data is needed to comprehensively evaluate spatial variation in vulnerability, this work illustrates the value of genomics in identifying spatial patterns of climate change vulnerability.
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Brauer, Chris J., Jonathan Sandoval-Castillo, Katie Gates, Michael P. Hammer, Peter J. Unmack, Louis Bernatchez, and Luciano B. Beheregaray. "Natural hybridization reduces vulnerability to climate change." Nature Climate Change, January 30, 2023. http://dx.doi.org/10.1038/s41558-022-01585-1.
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AbstractUnder climate change, species unable to track their niche via range shifts are largely reliant on genetic variation to adapt and persist. Genomic vulnerability predictions are used to identify populations that lack the necessary variation, particularly at climate-relevant genes. However, hybridization as a source of novel adaptive variation is typically ignored in genomic vulnerability studies. We estimated environmental niche models and genomic vulnerability for closely related species of rainbowfish (Melanotaenia spp.) across an elevational gradient in the Australian Wet Tropics. Hybrid populations between a widespread generalist and several narrow range endemic species exhibited reduced vulnerability to projected climates compared to pure narrow endemics. Overlaps between introgressed and adaptive genomic regions were consistent with a signal of adaptive introgression. Our findings highlight the often-underappreciated conservation value of hybrid populations and indicate that adaptive introgression may contribute to evolutionary rescue of species with narrow environmental ranges.
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Barratt, Christopher D., Renske E. Onstein, Malin L. Pinsky, Sebastian Steinfartz, Hjalmar S. Kühl, Brenna R. Forester, and Orly Razgour. "Life on the edge: A new toolbox for population‐level climate change vulnerability assessments." Methods in Ecology and Evolution, October 7, 2024. http://dx.doi.org/10.1111/2041-210x.14429.
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Abstract Global change is impacting biodiversity across all habitats on earth. New selection pressures from changing climatic conditions and other anthropogenic activities are creating heterogeneous ecological and evolutionary responses across many species' geographic ranges. Yet we currently lack standardised and reproducible tools to effectively predict the resulting patterns in species vulnerability to declines or range changes. We developed an informatic toolbox that integrates ecological, environmental and genomic data and analyses (environmental dissimilarity, species distribution models, landscape connectivity, neutral and adaptive genetic diversity, genotype‐environment associations and genomic offset) to estimate population vulnerability. In our toolbox, functions and data structures are coded in a standardised way so that it is applicable to any species or geographic region where appropriate data are available, for example individual or population sampling and genomic datasets (e.g. RAD‐seq, ddRAD‐seq, whole genome sequencing data) representing environmental variation across the species geographic range. To demonstrate multi‐species applicability, we apply our toolbox to three georeferenced genomic datasets for co‐occurring East African spiny reed frogs (Afrixalus fornasini, A. delicatus and A. sylvaticus) to predict their population vulnerability, as well as demonstrating that range loss projections based on adaptive variation can be accurately reproduced from a previous study using data for two European bat species (Myotis escalerai and M. crypticus). Our framework sets the stage for large scale, multi‐species genomic datasets to be leveraged in a novel climate change vulnerability framework to quantify intraspecific differences in genetic diversity, local adaptation, range shifts and population vulnerability based on exposure, sensitivity and landscape barriers.
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Booth, Emily J., Chris J. Brauer, Jonathan Sandoval‐Castillo, Katherine Harrisson, Meaghan L. Rourke, Catherine R. M. Attard, Dean M. Gilligan, et al. "Genomic Vulnerability to Climate Change of an Australian Migratory Freshwater Fish, the Golden Perch (Macquaria ambigua)." Molecular Ecology, November 4, 2024. http://dx.doi.org/10.1111/mec.17570.
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ABSTRACTGenomic vulnerability is a measure of how much evolutionary change is required for a population to maintain optimal genotype‐environment associations under projected climates. Aquatic species, and in particular migratory ectotherms, are largely underrepresented in studies of genomic vulnerability. Such species might be well equipped for tracking suitable habitat and spreading diversity that could promote adaptation to future climates. We characterised range‐wide genomic diversity and genomic vulnerability in the migratory and fisheries‐important golden perch (Macquaria ambigua) from Australia's expansive Murray–Darling Basin (MDB). The MDB has a steep hydroclimatic gradient and is one of the world's most variable regions in terms of climate and streamflow. Golden perch are threatened by fragmentation and obstruction of waterways, alteration of flow regimes, and a progressively hotter and drying climate. We gathered a genomic dataset of 1049 individuals from 186 MDB localities. Despite high range‐wide gene flow, golden perch in the warmer, northern catchments had higher predicted vulnerability than those in the cooler, southern catchments. A new cross‐validation approach showed that these predictions were insensitive to the exclusion of individual catchments. The results raise concern for populations at warm range edges, which may already be close to their thermal limits. However, a population with functional variants beneficial for climate adaptation found in the most arid and hydrologically variable catchment was predicted to be less vulnerable. Native fish management plans, such as captive breeding and stocking, should consider spatial variation in genomic vulnerability to improve conservation outcomes under climate change, even for dispersive species with high connectivity.
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Chen, Yilin, Zhiyong Jiang, Ping Fan, Per G. P. Ericson, Gang Song, Xu Luo, Fumin Lei, and Yanhua Qu. "The combination of genomic offset and niche modelling provides insights into climate change-driven vulnerability." Nature Communications 13, no. 1 (August 16, 2022). http://dx.doi.org/10.1038/s41467-022-32546-z.
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AbstractGlobal warming is increasingly exacerbating biodiversity loss. Populations locally adapted to spatially heterogeneous environments may respond differentially to climate change, but this intraspecific variation has only recently been considered when modelling vulnerability under climate change. Here, we incorporate intraspecific variation in genomic offset and ecological niche modelling to estimate climate change-driven vulnerability in two bird species in the Sino-Himalayan Mountains. We found that the cold-tolerant populations show higher genomic offset but risk less challenge for niche suitability decline under future climate than the warm-tolerant populations. Based on a genome-niche index estimated by combining genomic offset and niche suitability change, we identified the populations with the least genome-niche interruption as potential donors for evolutionary rescue, i.e., the populations tolerant to climate change. We evaluated potential rescue routes via a landscape genetic analysis. Overall, we demonstrate that the integration of genomic offset, niche suitability modelling, and landscape connectivity can improve climate change-driven vulnerability assessments and facilitate effective conservation management.
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Wang, Yihan, Lin Zhang, Yuchao Zhou, Wenxin Ma, Manyu Li, Peng Guo, Li Feng, and Chengxin Fu. "Using landscape genomics to assess local adaptation and genomic vulnerability of a perennial herb Tetrastigma hemsleyanum (Vitaceae) in subtropical China." Frontiers in Genetics 14 (April 18, 2023). http://dx.doi.org/10.3389/fgene.2023.1150704.
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Understanding adaptive genetic variation of plant populations and their vulnerabilities to climate change are critical to preserve biodiversity and subsequent management interventions. To this end, landscape genomics may represent a cost-efficient approach for investigating molecular signatures underlying local adaptation. Tetrastigma hemsleyanum is, in its native habitat, a widespread perennial herb of warm-temperate evergreen forest in subtropical China. Its ecological and medicinal values constitute a significant revenue for local human populations and ecosystem. Using 30,252 single nucleotide polymorphisms (SNPs) derived from reduced-representation genome sequencing in 156 samples from 24 sites, we conducted a landscape genomics study of the T. hemsleyanum to elucidate its genomic variation across multiple climate gradients and genomic vulnerability to future climate change. Multivariate methods identified that climatic variation explained more genomic variation than that of geographical distance, which implied that local adaptation to heterogeneous environment might represent an important source of genomic variation. Among these climate variables, winter precipitation was the strongest predictor of the contemporary genetic structure. FST outlier tests and environment association analysis totally identified 275 candidate adaptive SNPs along the genetic and environmental gradients. SNP annotations of these putatively adaptive loci uncovered gene functions associated with modulating flowering time and regulating plant response to abiotic stresses, which have implications for breeding and other special agricultural aims on the basis of these selection signatures. Critically, modelling revealed that the high genomic vulnerability of our focal species via a mismatch between current and future genotype-environment relationships located in central-northern region of the T. hemsleyanum’s range, where populations require proactive management efforts such as assistant adaptation to cope with ongoing climate change. Taken together, our results provide robust evidence of local climate adaption for T. hemsleyanum and further deepen our understanding of adaptation basis of herbs in subtropical China.
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Fitzpatrick, Matthew C., Stephen R. Keller, and Katie E. Lotterhos. "Comment on “Genomic signals of selection predict climate-driven population declines in a migratory bird”." Science 361, no. 6401 (August 3, 2018). http://dx.doi.org/10.1126/science.aat7279.
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Bay et al . (Reports, 5 January 2018, p. 83) combine genomics, spatial modeling, and future climate scenarios to examine yellow warbler population trends in response to climate change, and they suggest that their methods can inform conservation. We discuss problems in their statistical analyses and explain why the concept of “genomic vulnerability” needs further validation before application to real-world conservation problems.
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Yang, Yi-Xin, Meng Wang, Xuan-Ye Wu, Ya-Ni Zhou, Jie Qiu, Xia Cai, and Zhong-Hu Li. "The chromosome-level genome assembly of an endangered herb Bergenia scopulosa provides insights into local adaptation and genomic vulnerability under climate change." GigaScience 13 (2024). http://dx.doi.org/10.1093/gigascience/giae091.
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Abstract Background Global climate change poses severe threats to biodiversity and ecosystem stability. Rapid climate oscillations potentially lead to species geographic range shifts, population declines, and even extinctions. The rare and endangered species, being critical components of regional biodiversity, hold the key to understanding local adaptation and evolutionary processes shaping species distributions. Therefore, assessing the evolutionary mechanisms of local adaptation and population vulnerability under climate change is crucial for developing conservation strategies of endangered species. Results In this study, we assembled a high-quality, chromosome-level genome of the rare and endangered herb Bergenia scopulosa in the Qinling Mountains in East Asia and resequenced 37 individual genomes spanning its entire geographic distributional ranges. By integrating population genetics, landscape genomics, and climate datasets, a substantial number of adaptive single-nucleotide polymorphism loci associated with climate variables were identified. The genotype–environment association analysis showed that some cold-tolerant genes have played pivotal roles in cold environmental adaptation of B. scopulosa. These findings are further corroborated through evolutionary analysis of gene family and quantitative PCR validation. Population genomic analysis revealed 2 distinct genetic lineages in B. scopulosa. The western lineage showed higher genomic vulnerability and more rare cold-tolerance alleles, suggesting its heightened sensitivity to impending climate shifts, and should be given priority conservation in the management practices. Conclusions These findings provide novel insights into local adaptation and genomic vulnerability of B. scopulosa under climate change in the Qinling Mountains in East Asia. Additionally, the study also offers valuable guidance for formulating conservation strategies for the rare and endangered plants.
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Tigano, Anna, Tyler Weir, Hillary G. M. Ward, Marika Kirstin Gale, Carmen M. Wong, Erika J. Eliason, Kristina M. Miller, Scott G. Hinch, and Michael A. Russello. "Genomic vulnerability of a freshwater salmonid under climate change." Evolutionary Applications, October 27, 2023. http://dx.doi.org/10.1111/eva.13602.
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AbstractUnderstanding the adaptive potential of populations and species is pivotal for minimizing the loss of biodiversity in this era of rapid climate change. Adaptive potential has been estimated in various ways, including based on levels of standing genetic variation, presence of potentially beneficial alleles, and/or the severity of environmental change. Kokanee salmon, the non‐migratory ecotype of sockeye salmon (Oncorhynchus nerka), is culturally and economically important and has already been impacted by the effects of climate change. To assess its climate vulnerability moving forward, we integrated analyses of standing genetic variation, genotype‐environment associations, and climate modeling based on sequence and structural genomic variation from 224 whole genomes sampled from 22 lakes in British Columbia and Yukon (Canada). We found that variables for extreme temperatures, particularly warmer temperatures, had the most pervasive signature of selection in the genome and were the strongest predictors of levels of standing variation and of putatively adaptive genomic variation, both sequence and structural. Genomic offset estimates, a measure of climate vulnerability, were significantly correlated with higher increases in extreme warm temperatures, further highlighting the risk of summer heat waves that are predicted to increase in frequency in the future. Levels of standing genetic variation, an important metric for population viability and resilience, were not correlated with genomic offset. Nonetheless, our combined approach highlights the importance of integrating different sources of information and genomic data to formulate more comprehensive and accurate predictions on the vulnerability of populations and species to future climate change.
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Zhu, Xian‐Liang, Jing Wang, Hong‐Feng Chen, and Ming Kang. "Lineage Differentiation and Genomic Vulnerability in a Relict Tree From Subtropical Forests." Evolutionary Applications 17, no. 11 (November 2024). http://dx.doi.org/10.1111/eva.70033.
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ABSTRACTThe subtropical forests of East Asia are renowned for their high plant diversity, particularly the abundance of ancient relict species. However, both the evolutionary history of these relict species and their capacity for resilience in the face of impending climatic changes remain unclear. Using whole‐genome resequencing data, we investigated the lineage differentiation and demographic history of the relict and endangered tree, Bretschneidera sinensis (Akaniaceae). We employed a combination of population genomic and landscape genomic approaches to evaluate variation in mutation load and genomic offset, aiming to predict how different populations may respond to climate change. Our analysis revealed a profound genomic divergence between the East and West lineages, likely as the result of recurrent bottlenecks due to climatic fluctuations during the glacial period. Furthermore, we identified several genes potentially linked to growth characteristics and hypoxia response that had been subjected to positive selection during the lineage differentiation. Our assessment of genomic vulnerability uncovered a significantly higher mutation load and genomic offset in the edge populations of B. sinensis compared to their core counterparts. This implies that the edge populations are likely to experience the most significant impact from the predicted climate conditions. Overall, our research sheds light on the historical lineage differentiation and contemporary genomic vulnerability of B. sinensis. Broadening our understanding of the speciation history and future resilience of relict and endangered species such as B. sinensis, is crucial in developing effective conservation strategies in anticipation of future climatic changes.
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Jeon, Jong Yoon, Yucheol Shin, Andrew J. Mularo, Xiao Feng, and J. Andrew DeWoody. "The integration of whole‐genome resequencing and ecological niche modelling to conserve profiles of local adaptation." Diversity and Distributions, April 11, 2024. http://dx.doi.org/10.1111/ddi.13847.
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AbstractBackgroundEcological and genomic attributes of populations can provide two orthologous perspectives on the biological profiles associated with local adaptation. The ability of organisms to track suitable habitats (ecological adaptability) and of populations to shift allele frequencies (adaptive potential) are prerequisite for population sustainability.AimsMany contemporary populations are threatened by habitat loss (ecological vulnerability) and a lack of adaptive potential (evolutionary vulnerability). Technical advances provide new opportunities to address these challenges in biological conservation: Future habitat shifts can be predicted by ecological niche modelling and adaptive genetic diversity can be discerned using genome sequence data. Together, these two approaches illuminate the local adaptation profile and help identify the environmental and genomic conditions that should maximize evolutionary fitness.Materials and MethodsHere, we reviewed the primary literature to identify key studies that utilize both whole‐genome resequencing (WGR) and ecological niche modelling (ENM) in an effort to envisage future research directions that may benefit conservation efforts.ResultsWe identified ways to integrate different approaches, such as ENM‐informed adaptive genomics and adaptive genomics‐informed ENMs, that can be used to delineate and conserve local adaptation profiles.DiscussionIntegrative approaches can identify adaptive characteristics, vulnerable populations subject to environmental changes, and the patterns of local adaptation from geographic and genomic analyses. We discuss future research directions, limitations and their potential solutions with suggestions for collaborative workflows.ConclusionThe integration of WGR and ENM is promising with their continuous advancement. An integrative approach can be used to evaluate eco‐evolutionary attributes, at both organismal and molecular levels, that can be used to help conserve local adaptation profiles.
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Carrero, Dido, Maria Pascual-Torner, Diana Álvarez-Puente, Víctor Quesada, Claudia García-Gómez, and Carlos López-Otín. "Insights into aging mechanisms from comparative genomics in orange and silver roughies." Scientific Reports 14, no. 1 (August 26, 2024). http://dx.doi.org/10.1038/s41598-024-70642-w.
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AbstractThe demersal fish orange roughy (Hoplostethus atlanticus) can live for up to 250 years, twenty times more than its congener silver roughy (Hoplostethus mediterraneus). Studies of Hoplostethus have focused mainly on its ecology and conservation due to its vulnerability to commercial fishing. In this work, we present the de novo genomes of orange and silver roughies and explore the genomic mechanisms that could contribute to such differential longevities. Using comparative genomics on a list of more than 400 genes, we identified gene candidates with differential residue changes in Hoplostethus that are related to genomic instability, disabled macroautophagy and intercellular communication. We hypothesized that these mechanisms could have been selected as adaptations to the deep environment and, as an epiphenomenon of these mechanisms, may have contributed to an extension of the lifespan of H. atlanticus.
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Miller, Courtney A., Geraud C. Tasse Taboue, Eric B. Fokam, Katy Morgan, Ying Zhen, Ryan J. Harrigan, Vinh Le Underwood, et al. "Environmental variation predicts patterns of genomic variation in an African tropical forest frog." Frontiers in Conservation Science 5 (June 5, 2024). http://dx.doi.org/10.3389/fcosc.2024.1366248.
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Central African rainforests are predicted to be disproportionately affected by future climate change. How species will cope with these changes is unclear, but rapid environmental changes will likely impose strong selection pressures. Here we examined environmental drivers of genomic variation in the central African puddle frog (Phrynobatrachus auritus) to identify areas of elevated environmentally-associated turnover. We also compared current and future climate models to pinpoint areas of high genomic vulnerability where allele frequencies will have to shift the most in order to keep pace with future climate change. Neither physical landscape barriers nor the effects of past Pleistocene refugia influenced genomic differentiation. Alternatively, geographic distance and seasonal aspects of precipitation are the most important drivers of SNP allele frequency variation. Patterns of genomic differentiation coincided with key ecological gradients across the forest-savanna ecotone, montane areas, and a coastal to interior rainfall gradient. Areas of greatest vulnerability were found in the lower Sanaga basin, the southeastern region of Cameroon, and southwest Gabon. In contrast with past conservation efforts that have focused on hotspots of species richness or endemism, our findings highlight the importance of maintaining environmentally heterogeneous landscapes to preserve genomic variation and ongoing evolutionary processes in the face of climate change.
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VARGHESE, SNEHA S., ALESSANDRO G. HERNANDEZ-DE LA PENA, SUPRIYO BHATTACHARYA, and SANGEETA DHAWAN. "1724-P: DNA Damage Vulnerability of Immature Beta Cells." Diabetes 73, Supplement_1 (June 14, 2024). http://dx.doi.org/10.2337/db24-1724-p.
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Introduction & Objective: A healthy reserve of functional β-cells is crucial for maintaining glucose homeostasis and is disrupted in diabetes. Most of this reserve is established in early neonatal life via replication, following which β-cells exit cell-cycle and undergo functional maturation. Although the process of replication is extremely vulnerable to DNA damage and consequent genomic instability, the extent and impact of such vulnerabilities on β-cell maturation and subsequent viability is not clear. Here, we sought to determine the DNA damage vulnerability of replicating β-cells in the neonatal growth phase. Methods: We quantified β-cell replication (Ki67, pHH3) and DNA damage (ɣH2AX) in early (p7) and late (p21) neonatal B6 mice (N=8 animals/ group). We acquired super-resolution 3D images of DNA damage foci and cohesins (modulators of genomic stability) in replicating β-cells using the Zeiss Elyra 7 Lattice SIM^2 and LSM880 with Airyscan, and analyzed using the Imaris software. Results: Our data revealed that while the overall number of β-cells with DNA damage decreased as replication declined from p7 to p21, ~20% of replicating β-cells at each stage harbored DNA damage. Notably, the G2 phase had the highest density of DNA damage foci, which were resolved by the M phase. Single-cell RNA-seq of murine neonatal islets showed the enrichment of DNA damage repair pathways in replicating β-cells. Conclusion: Collectively, our data establish the high DNA damage vulnerability of neonatal β-cells and suggest the existence of robust mechanisms that assist the resolution of DNA damage with cell cycle progression to maintain genomic stability. Disclosure S.S. Varghese: None. A.G. Hernandez-De La Pena: None. S. Bhattacharya: None. S. Dhawan: None. Funding Postdoctoral Fellowship from California Institute of Regenerative Medicine (EDU4-12772); NIH-National Institute of Diabetes and Digestive and Kidney Diseases (R01DK120523)