6 research outputs found
Relato de una experiencia: La Maranya, una escuela de democracia ciudadana con jóvenes
El siguiente artículo busca difundir una experiencia asociativa
enmarcada por la autogestión juvenil en el municipio de Benicàssim.
Contamos cómo nace el centro cívico La Maranya y cuál es la ideología
desde la que trabaja. La acción de esta asociación surge a partir del trabajo
en el tiempo libre y de ocio como herramienta educativa. El centro
parte de la participación cívica y democrática, el aprendizaje directo y
el interés por los problemas de la sociedad para generar una escuela ciudadana
de convivencia igualitaria. Este espacio trabaja con las jóvenes
y los jóvenes como ciudadanas y ciudadanos activos conectados intergeneracionalmente
con otros colectivos que lo conforman dentro de unos
valores de progreso y participación social.Aquest article pretén difondre una experiència associativa
emmarcada per l’autogestió juvenil al municipi de Benicàssim. Expliquem
el naixement del centre cívic La Maranya i quina és la ideologia
des de la qual treballa. L’acció d’aquesta associació sorgeix arran del
treball en el temps lliure i d’esplai com a eina educativa. El centre parteix
de la participació cívica i democràtica, de l’aprenentatge directe i
l’interès pels problemes de la societat per a generar una escola ciutadana
de convivència igualitària. L’espai treballa amb les persones joves com a ciutadanes i ciutadans actius connectats intergeneracionalment amb
altres col·lectius que el conformen dins de valors de progrés i de participació
social.The following article reports on an associational experience
within the framework of young people’s self-management in the
town of Benicàssim. We describe how La Maranya Civic Centre came
into being and the ideology it is grounded on. The association’s action
is based on using free time and leisure as an educational tool. The Civic
Centre operates on the basis of democratic participation, non-formal
learning and interest in society’s problems to generate a citizens’ school
for egalitarian coexistence. The centre treats young people as active citizens
who participate as equals with other age groups and associations,
thus providing a context that fosters and promotes values associated with
progress and democratic participation
Long-term and transgenerational phenotypic, transcriptional and metabolic effects in rabbit males born following vitrified embryo transfer
[EN] The advent of assisted reproductive technologies (ART) in mammals involved an extraordinary change in the environment where the beginning of a new organism takes place. Under in vitro conditions, in which ART is currently being performed, it likely fails to mimic optimal in vivo conditions. This suboptimal environment could mediate in the natural developmental trajectory of the embryo, inducing lasting effects until later life stages that may be inherited by subsequent generations (transgenerational effects). Therefore, we evaluated the potential transgenerational effects of embryo exposure to the cryopreservation-transfer procedure in a rabbit model on the offspring phenotype, molecular physiology of the liver (transcriptome and metabolome) and reproductive performance during three generations (F1, F2 and F3). The results showed that, compared to naturally-conceived animals (NC group), progeny generated after embryo exposure to the cryopreservation-transfer procedure (VT group) exhibited lower body growth, which incurred lower adult body weight in the F1 (direct effects), F2 (intergenerational effects) and F3 (transgenerational effects) generations. Furthermore, VT animals showed intergenerational effects on heart weight and transgenerational effects on liver weight. The RNA-seq data of liver tissue revealed 642 differentially expressed transcripts (DETs) in VT animals from the F1 generation. Of those, 133 were inherited from the F2 and 120 from the F3 generation. Accordingly, 151, 190 and 159 differentially accumulated metabolites (DAMs) were detected from the F1, F2 and F3, respectively. Moreover, targeted metabolomics analysis demonstrated that transgenerational effects were mostly presented in the non-polar fraction. Functional analysis of molecular data suggests weakened zinc and fatty acid metabolism across the generations, associated with alterations in a complex molecular network affecting global hepatic metabolism that could be associated with the phenotype of VT animals. However, these VT animals showed proper reproductive performance, which verified a functional health status. In conclusion, our results establish the long-term transgenerational effects following a vitrified embryo transfer procedure. We showed that the VT phenotype could be the result of the manifestation of embryonic developmental plasticity in response to the stressful conditions during ART procedures.Funding from the Ministry of Economy, Industry and Competitiveness (Research project: AGL2014-53405-C2-1-P) and Generalitat Valenciana (Research project: Prometeo II 2014/036) is acknowledged. X.G.D. was supported by a research grant from the Ministry of Economy, Industry and Competitiveness (BES-2015-072429). English text version was revised by N. Macowan English Language Service.Garcia-Dominguez, X.; Marco-Jiménez, F.; Peñaranda, D.; Diretto, G.; García-Carpintero, V.; Cañizares Sales, J.; Vicente Antón, JS. (2020). Long-term and transgenerational phenotypic, transcriptional and metabolic effects in rabbit males born following vitrified embryo transfer. Scientific Reports. 10(1):1-15. https://doi.org/10.1038/s41598-020-68195-9S115101Canovas, S., Ross, P. J., Kelsey, G. & Coy, P. DNA methylation in embryo development: epigenetic impact of ART (assisted reproductive technologies). BioEssays 39, 1 (2017).García-Martínez, S. et al. Mimicking physiological O2 tension in the female reproductive tract improves assisted reproduction outcomes in pig. Mol. Hum. Reprod. 24, 260–270 (2018).Ng, K. Y. B., Mingels, R., Morgan, H., Macklon, N. & Cheong, Y. In vivo oxygen, temperature and pH dynamics in the female reproductive tract and their importance in human conception: a systematic review. Hum. Reprod. Update 24, 15–34 (2018).Roseboom, T. J. Developmental plasticity and its relevance to assisted human reproduction. Hum. Reprod. 33, 546–552 (2018).Feuer, S. & Rinaudo, P. From embryos to adults: a DOHaD perspective on in vitro fertilization and other assisted reproductive technologies. Healthcare 4, E51 (2016).Zandstra, H. et al. Association of culture medium with growth, weight and cardiovascular development of IVF children at the age of 9 years. Hum. Reprod. 33, 1645–1656 (2018).Chen, M. & Heilbronn, L. K. The health outcomes of human offspring conceived by assisted reproductive technologies (ART). J. Dev. Orig. Health Dis. 8, 388–402 (2017).Chen, L. et al. Birth prevalence of congenital malformations in singleton pregnancies resulting from in vitro fertilization/intracytoplasmic sperm injection worldwide: a systematic review and meta-analysis. Arch. Gynecol. Obstet. 297, 1115–1130 (2018).Zhang, W. Y. et al. Vascular health of children conceived via in vitro fertilization. J. Pediatr. 214, 47–53 (2019).Guo, X. Y. et al. Cardiovascular and metabolic profiles of offspring conceived by assisted reproductive technologies: a systematic review and meta-analysis. Fertil. Steril. 107, 622–631 (2017).Vrooman, L. A. & Bartolomei, M. S. Can assisted reproductive technologies cause adult-onset disease? Evidence from human and mouse. Reprod. Toxicol. 68, 72–84 (2017).Duranthon, V. & Chavatte-Palmer, P. Long term effects of ART: What do animals tell us?. Mol. Reprod. Dev. 85, 348–368 (2018).Ramos-Ibeas, P. et al. Embryo responses to stress induced by assisted reproductive technologies. Mol. Reprod. Dev. 86, 1292–1306 (2019).Feuer, S. K. et al. Transcriptional signatures throughout development: the effects of mouse embryo manipulation in vitro. Reproduction 153, 107–122 (2017).Feuer, S. K. & Rinaudo, P. F. Physiological, metabolic and transcriptional postnatal phenotypes of in vitro fertilization (IVF) in the mouse. J. Dev. Orig. Health Dis. 8, 403–410 (2017).Sparks, A. E. T. Human embryo cryopreservation-methods, timing, and other considerations for optimizing an embryo cryopreservation program. Semin. Reprod. Med. 33, 128–144 (2015).Dulioust, E. et al. Long-term effects of embryo freezing in mice. Proc. Natl. Acad. Sci. USA. 92, 589–593 (1995).Auroux, M., Cerutti, I., Ducot, B. & Loeuillet, A. Is embryo-cryopreservation really neutral? A new long-term effect of embryo freezing in mice: protection of adults from induced cancer according to strain and sex. Reprod. Toxicol. 18, 813–818 (2004).Vicente, J. S. et al. Rabbit morula vitrification reduces early foetal growth and increases losses throughout gestation. Cryobiology 67, 321–326 (2013).Saenz-De-Juano, M. D. et al. Vitrification alters rabbit foetal placenta at transcriptomic and proteomic level. Reproduction https://doi.org/10.1530/REP-14-0019 (2014).Saenz-de-Juano, M. D., Vicente, J. S., Hollung, K. & Marco-Jiménez, F. Effect of embryo vitrification on rabbit foetal placenta proteome during pregnancy. PLoS ONE 147, 789–801 (2015).Berntsen, S. & Pinborg, A. Large for gestational age and macrosomia in singletons born after frozen/thawed embryo transfer (FET) in assisted reproductive technology (ART). Birth Defects Res. 110, 630–643 (2018).Maheshwari, A. et al. Is frozen embryo transfer better for mothers and babies? Can cumulative meta-analysis provide a definitive answer?. Hum. Reprod. Update 24, 35–58 (2018).Garcia-Dominguez, X., Vicente, J. S. & Marco-Jiménez, F. Developmental plasticity in response to embryo cryopreservation: the importance of the vitrification device in rabbits. Animals 10, 804 (2020).Garcia-Dominguez, X., Marco-Jimenez, F., Viudes-de-Castro, M. P. & Vicente, J. S. Minimally invasive embryo transfer and embryo vitrification at the optimal embryo stage in rabbit model. J. Vis. Exp. 147, e58055 (2019).Garcia-Dominguez, X. et al. Long-term phenotypic effects following vitrified-thawed embryo transfer in a rabbit model. bioRxiv https://doi.org/10.1101/410514 (2018).Ventura-Juncá, P. et al. In vitro fertilization (IVF) in mammals: epigenetic and developmental alterations: scientific and bioethical implications for IVF in humans. Biol. Res. 48, 68 (2015).Calle, A. et al. Long-term and transgenerational effects of in vitro culture on mouse embryos. Theriogenology 77, 785–793 (2012).Calle, A. et al. Male mice produced by in vitro culture have reduced fertility and transmit organomegaly and glucose intolerance to their male Offspring1. Biol. Reprod. 87, 1–9 (2012).Mahsoudi, B., Li, A. & O’Neill, C. Assessment of the long-term and transgenerational consequences of perturbing preimplantation embryo development in Mice1. Biol. Reprod. 77, 889–896 (2007).Servick, K. Unsettled questions trail IVF’s success. Science (80-) 345, 744–746 (2014).Cifre, J., Baselga, M., Gómez, E. A. & De La Luz, G. M. Effect of embryo cryopreservation techniques on reproductive and growth traits in rabbits. Anim. Res. 48, 15–24 (1999).Lavara, R., Baselga, M., Marco-Jiménez, F. & Vicente, J. S. Embryo vitrification in rabbits: consequences for progeny growth. Theriogenology 84, 674–680 (2015).Nusbaumer, D., Da Cunha, L. M. & Wedekind, C. Sperm cryopreservation reduces offspring growth. Proc. R. Soc. B Biol. Sci. 286, 20191644 (2019).Feuer, S. K. et al. Sexually dimorphic effect of In Vitro Fertilization (IVF) on adult mouse fat and liver metabolomes. Endocrinology 155, 4554–4567 (2014).Feuer, S. K. et al. Use of a mouse in vitro fertilization model to understand the developmental origins of health and disease hypothesis. Endocrinology 155, 1956–1969 (2014).Velazquez, M. A. et al. Insulin and branched-chain amino acid depletion during mouse preimplantation embryo culture programmes body weight gain and raised blood pressure during early postnatal life. Biochim. Biophys. Acta Mol. Basis Dis. 1864, 590–600 (2018).Fernández-Gonzalez, R. et al. Long-term effect of in vitro culture of mouse embryos with serum on mRNA expression of imprinting genes, development, and behavior. Proc. Natl. Acad. Sci. U. S. A. 101, 5880–5885 (2004).Horsthemke, B. A critical view on transgenerational epigenetic inheritance in humans. Nat. Commun. 9, 2973 (2018).Perez, M. F. & Lehner, B. Intergenerational and transgenerational epigenetic inheritance in animals. Nat. Cell Biol. 21, 143–151 (2019).Lavara, R., Baselga, M., Marco-Jiménez, F. & Vicente, J. S. Long-term and transgenerational effects of cryopreservation on rabbit embryos. Theriogenology 81, 988–992 (2014).Rexhaj, E. et al. Mice generated by in vitro fertilization exhibit vascular dysfunction and shortened life span. J. Clin. Invest. 123, 5052–5060 (2013).Møller, S. & Bernardi, M. Interactions of the heart and the liver. Eur. Heart J. 34, 2804–2811 (2013).Hyatt, M. A., Budge, H. & Symonds, M. E. Early developmental influences on hepatic organogenesis. Organogenesis 4, 170–175 (2008).Skinner, M. K. What is an epigenetic transgenerational phenotype? F3 or F2. Reprod. Toxicol. 25, 2–6 (2008).Hajkova, P. Epigenetic reprogramming in the germline: towards the ground state of the epigenome. Philos. Trans. R. Soc. B Biol. Sci. 366, 2266–2273 (2011).Lacal, I. & Ventura, R. Epigenetic inheritance: concepts, mechanisms and perspectives. Front. Mol. Neurosci. 11, 292 (2018).Fraser, R. & Lin, C. J. Epigenetic reprogramming of the zygote in mice and men: on your marks, get set, go!. Reproduction 152, R211–R222 (2016).Adamek, A. & Kasprzak, A. Insulin-like growth factor (IGF) system in liver diseases. Int. J. Mol. Sci. 19, E1308 (2018).Kineman, R. D., del Rio-Moreno, M. & Sarmento-Cabral, A. 40 years of IGF1: understanding the tissue-specific roles of IGF1/IGF1R in regulating metabolism using the Cre/loxP system. J. Mol. Endocrinol. 61, T187–T198 (2018).Davis, S. R. & Cousins, R. J. Metallothionein expression in animals: a physiological perspective on function. J. Nutr. 130, 1085–1088 (2000).Günes, Ć et al. Embryonic lethality and liver degeneration in mice lacking the metal-responsive transcriptional activator MTF-1. EMBO J. 17, 2846–2854 (1998).Kambe, T., Tsuji, T., Hashimoto, A. & Itsumura, N. The physiological, biochemical, and molecular roles of zinc transporters in zinc homeostasis and metabolism. Physiol. Rev. 95, 749–784 (2015).Xia, X. et al. Serum levels of trace elements in children born after assisted reproductive technology. Clin. Chim. Acta 495, 664–669 (2019).Bird, A. J. Cellular sensing and transport of metal ions: Implications in micronutrient homeostasis. J. Nutr. Biochem. 26, 1103–1115 (2015).Meesapyodsuk, D. & Qiu, X. The front-end desaturase: Structure, function, evolution and biotechnological use. Lipids 47, 227–237 (2012).Chimhashu, T. et al. Sensitivity of fatty acid desaturation and elongation to plasma zinc concentration: a randomised controlled trial in Beninese children. Br. J. Nutr. https://doi.org/10.1017/S000711451700366X (2018).Wang, L. Y. et al. Alteration of fatty acid metabolism in the liver, adipose tissue, and testis of male mice conceived through assisted reproductive technologies: fatty acid metabolism in ART mice. Lipids Health Dis. 12, 5 (2013).Li, J., Yin, H., Bibus, D. M. & Byelashov, O. A. The role of Omega-3 docosapentaenoic acid in pregnancy and early development. Eur. J. Lipid Sci. Technol. 118, 1692–1701 (2016).Hadley, K. B., Ryan, A. S., Forsyth, S., Gautier, S. & Salem, N. The essentiality of arachidonic acid in infant development. Nutrients 8, 216 (2016).Makowski, L. & Hotamisligil, G. S. The role of fatty acid binding proteins in metabolic syndrome and atherosclerosis. Curr. Opin. Lipidol. 16, 543–548 (2005).Waynforth, D. Effects of conception using assisted reproductive technologies on infant health and development: An evolutionary perspective and analysis using UK millennium cohort data. Yale J. Biol. Med. 91, 225–235 (2018).Sullivan, E. M. et al. Mechanisms bywhich dietary fatty acids regulate mitochondrial structure-function in health and disease. Adv. Nutr. 9, 247–262 (2018).Richardson, U. I. & Wurtman, R. J. Polyunsaturated fatty acids stimulate phosphatidylcholine synthesis in PC12 cells. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1771, 558–563 (2007).Singh, A. et al. Human glutathione S-transferase enzyme gene polymorphisms and their association with neurocysticercosis. Mol. Neurobiol. 54, 2843–2851 (2017).Yu, H. F. et al. Malic enzyme 1 is important for uterine decidualization in response to progesterone/cAMP/PKA/HB-EGF pathway. FASEB J. 34, 3820–3837 (2020).Chen, M. et al. Altered glucose metabolism in mouse and humans conceived by IVF. Diabetes 63, 3189–3198 (2014).Auroux, M. Long-term effects in progeny of paternal environment and of gamete/embryo cryopreservation. Hum. Reprod. Update 6, 550–563 (2000).Belva, F. et al. Semen quality of young adult ICSI offspring: The first results. Hum. Reprod. 31, 2811–2820 (2016).Marco-Jiménez, F. & Vicente, J. S. Overweight in young males reduce fertility in rabbit model. PLoS ONE 12, e0180679 (2017).Laubach, Z. M. et al. Epigenetics and the maintenance of developmental plasticity: extending the signalling theory framework. Biol. Rev. 93, 1323–1338 (2018).Estany, J., Camacho, J., Baselga, M. & Blasco, A. Selection response of growth rate in rabbits for meat production. Genet. Sel. Evol. 24, 527–537 (1992).Vicente, J. S., Viudes-de-Castro, M. P., de la García, M. L. & Baselga, M. Effect of rabbit line on a program of cryopreserved embryos by vitrification. Reprod. Nutr. Dev. 43, 137–143 (2003).Zucker, I. & Beery, A. K. Males still dominate animal studies. Nature 465, 690 (2010).Vicente, J. S., Viudes-De-Castro, M. P. & García, M. L. In vivo survival rate of rabbit morulae after vitrification in a medium without serum protein. Reprod. Nutr. Dev. 39, 657–662 (1999).Besenfelder, U. & Brem, G. Laparoscopic embryo transfer in rabbits. J. Reprod. Fertil. 99, 53–56 (1993).Blasco, A. The use of Bayesian statistics in meat quality analyses: a review. Meat Sci. 69, 115–122 (2005).Andrews, S. FASTQC a quality control tool for high throughput sequence data. Babraham Institute (2015). Available at: https://www.bioinformatics.babraham.ac.uk/projects/fastqc.Kim, D., Langmead, B. & Salzberg, S. L. HISAT: A fast spliced aligner with low memory requirements. Nat. Methods 12, 357–360 (2015).Pertea, M. et al. StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat. Biotechnol. 33, 290–295 (2015).Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2009).Wang, Y. E., Kutnetsov, L., Partensky, A., Farid, J. & Quackenbush, J. WebMeV: a cloud platform for analyzing and visualizing cancer genomic data. Cancer Res. 77, e11–e14 (2017).Metsalu, T. & Vilo, J. ClustVis: a web tool for visualizing clustering of multivariate data using principal component analysis and heatmap. Nucleic Acids Res. 44, 566–570 (2015).Heberle, H., Meirelles, V. G., da Silva, F. R., Telles, G. P. & Minghim, R. InteractiVenn: a web-based tool for the analysis of sets through Venn diagrams. BMC Bioinformatics 16, 169 (2015).Huang, D. W., Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57 (2009).Diretto, G. et al. Tissue-specific accumulation of sulfur compounds and saponins in different parts of garlic cloves from purple and white ecotypes. Molecules 22, E1359 (2017).Cappelli, G. et al. A Corylus avellana L. extract enhances human macrophage bactericidal response against Staphylococcus aureus by increasing the expression of anti-inflammatory and iron metabolism genes. J. Funct. Foods 45, 499–511 (2018).Di Meo, F. et al. Anti-cancer activity of grape seed semi-polar extracts in human mesothelioma cell lines. J. Funct. Foods 61, 103515 (2019).Fiore, A. et al. A quadruple mutant of Arabidopsis reveals a β-carotene hydroxylation activity for LUT1/CYP97C1 and a regulatory role of xanthophylls on determination of the PSI/PSII ratio. BMC Plant Biol. 12, 50 (2012).Rambla, J. L. et al. Gene-metabolite networks of volatile metabolism in Airen and Tempranillo grape cultivars revealed a distinct mechanism of aroma bouquet production. Front. Plant Sci. 7, 1619 (2016).Sulli, M. et al. Molecular and biochemical characterization of a potato collection with contrasting tuber carotenoid content. PLoS ONE 12, e0184143 (2017)
Exploiting the diversity of tomato: the development of a phenotypically and genetically detailed germplasm collection
A collection of 163 accessions, including Solanum pimpinellifolium, Solanum lycopersicum var. cerasiforme and Solanum lycopersicum var. lycopersicum, was selected to represent the genetic and morphological variability of tomato at its centers of origin and domestication: Andean regions of Peru and Ecuador and Mesoamerica. The collection is enriched with S. lycopersicum var. cerasiforme from the Amazonian region that has not been analyzed previously nor used extensively. The collection has been morphologically characterized showing diversity for fruit, flower and vegetative traits. Their genomes were sequenced in the Varitome project and are publicly available (solgenomics.net/projects/varitome). The identified SNPs have been annotated with respect to their impact and a total number of 37,974 out of 19,364,146 SNPs have been described as high impact by the SnpEeff analysis. GWAS has shown associations for different traits, demonstrating the potential of this collection for this kind of analysis. We have not only identified known QTLs and genes, but also new regions associated with traits such as fruit color, number of flowers per inflorescence or inflorescence architecture. To speed up and facilitate the use of this information, F2 populations were constructed by crossing the whole collection with three different parents. This F2 collection is useful for testing SNPs identified by GWAs, selection sweeps or any other candidate gene. All data is available on Solanaceae Genomics Network and the accession and F2 seeds are freely available at COMAV and at TGRC genebanks. All these resources together make this collection a good candidate for genetic studies
The GB4.0 Platform, an All-In-One Tool for CRISPR/Cas-Based Multiplex Genome Engineering in Plants
[EN] CRISPR/Cas ability to target several loci simultaneously (multiplexing) is a game-changer in plant breeding. Multiplexing not only accelerates trait pyramiding but also can unveil traits hidden by functional redundancy. Furthermore, multiplexing enhances dCas-based programmable gene expression and enables cascade-like gene regulation. However, the design and assembly of multiplex constructs comprising tandemly arrayed guide RNAs (gRNAs) requires scarless cloning and is still troublesome due to the presence of repetitive sequences, thus hampering a more widespread use. Here we present a comprehensive extension of the software-assisted cloning platform GoldenBraid (GB), in which, on top of its multigene cloning software, we integrate new tools for the Type IIS-based easy and rapid assembly of up to six tandemly-arrayed gRNAs with both Cas9 and Cas12a, using the gRNA-tRNA-spaced and the crRNA unspaced approaches, respectively. As stress tests for the new tools, we assembled and used for Agrobacterium-mediated stable transformation a 17 Cas9-gRNAs construct targeting a subset of the Squamosa-Promoter Binding Protein-Like (SPL) gene family in Nicotiana tabacum. The 14 selected genes are targets of miR156, thus potentially playing an important role in juvenile-to-adult and vegetative-to-reproductive phase transitions. With the 17 gRNAs construct we generated a collection of Cas9-free SPL edited T-1 plants harboring up to 9 biallelic mutations and showing leaf juvenility and more branching. The functionality of GB-assembled dCas9 and dCas12a-based CRISPR/Cas activators and repressors using single and multiplexing gRNAs was validated using a Luciferase reporter with the Solanum lycopersicum Mtb promoter or the Agrobacterium tumefaciens nopaline synthase promoter in transient expression in Nicotiana benthamiana. With the incorporation of the new web-based tools and the accompanying collection of DNA parts, the GB4.0 genome edition turns an all-in-one open platform for plant genome engineering.This work had been funded by EU Horizon 2020 Project Newcotiana Grant 760331 and PID2019-108203RB-100 Plan Nacional I+D, Spanish Ministry of Economy and Competitiveness. MV-V was recipient of aGeneralitat Valenciana and Fondo Social Europeo post-doctoral grant. JB-O and SS were recipients of FPI fellowships. CP was recipient of a Santiago Grisolia fellowship (Generalitat Valenciana).Vazquez-Vilar, M.; Garcia-Carpintero, V.; Selma, S.; Bernabé-Orts, JM.; Sánchez-Vicente, J.; Salazar-Sarasua, B.; Ressa, A.... (2021). The GB4.0 Platform, an All-In-One Tool for CRISPR/Cas-Based Multiplex Genome Engineering in Plants. Frontiers in Plant Science. 12:1-14. https://doi.org/10.3389/fpls.2021.6899371141
Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality
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GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19
Data availability: Downloadable summary data are available through the GenOMICC data site (https://genomicc.org/data). Summary statistics are available, but without the 23andMe summary statistics, except for the 10,000 most significant hits, for which full summary statistics are available. The full GWAS summary statistics for the 23andMe discovery dataset will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. For further information and to apply for access to the data, see the 23andMe website (https://research.23andMe.com/dataset-access/). All individual-level genotype and whole-genome sequencing data (for both academic and commercial uses) can be accessed through the UKRI/HDR UK Outbreak Data Analysis Platform (https://odap.ac.uk). A restricted dataset for a subset of GenOMICC participants is also available through the Genomics England data service. Monocyte RNA-seq data are available under the title ‘Monocyte gene expression data’ within the Oxford University Research Archives (https://doi.org/10.5287/ora-ko7q2nq66). Sequencing data will be made freely available to organizations and researchers to conduct research in accordance with the UK Policy Framework for Health and Social Care Research through a data access agreement. Sequencing data have been deposited at the European Genome–Phenome Archive (EGA), which is hosted by the EBI and the CRG, under accession number EGAS00001007111.Extended data figures and tables are available online at https://www.nature.com/articles/s41586-023-06034-3#Sec21 .Supplementary information is available online at https://www.nature.com/articles/s41586-023-06034-3#Sec22 .Code availability:
Code to calculate the imputation of P values on the basis of SNPs in linkage disequilibrium is available at GitHub (https://github.com/baillielab/GenOMICC_GWAS).Acknowledgements: We thank the members of the Banco Nacional de ADN and the GRA@CE cohort group; and the research participants and employees of 23andMe for making this work possible. A full list of contributors who have provided data that were collated in the HGI project, including previous iterations, is available online (https://www.covid19hg.org/acknowledgements).Change history: 11 July 2023: A Correction to this paper has been published at: https://doi.org/10.1038/s41586-023-06383-z. -- In the version of this article initially published, the name of Ana Margarita Baldión-Elorza, of the SCOURGE Consortium, appeared incorrectly (as Ana María Baldion) and has now been amended in the HTML and PDF versions of the article.Copyright © The Author(s) 2023, Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).GenOMICC was funded by Sepsis Research (the Fiona Elizabeth Agnew Trust), the Intensive Care Society, a Wellcome Trust Senior Research Fellowship (to J.K.B., 223164/Z/21/Z), the Department of Health and Social Care (DHSC), Illumina, LifeArc, the Medical Research Council, UKRI, a BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070 and BBS/E/D/30002275) and UKRI grants MC_PC_20004, MC_PC_19025, MC_PC_1905 and MRNO2995X/1. A.D.B. acknowledges funding from the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z), the Edinburgh Clinical Academic Track (ECAT) programme. This research is supported in part by the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant MC_PC_20029). Laboratory work was funded by a Wellcome Intermediate Clinical Fellowship to B.F. (201488/Z/16/Z). We acknowledge the staff at NHS Digital, Public Health England and the Intensive Care National Audit and Research Centre who provided clinical data on the participants; and the National Institute for Healthcare Research Clinical Research Network (NIHR CRN) and the Chief Scientist’s Office (Scotland), who facilitate recruitment into research studies in NHS hospitals, and to the global ISARIC and InFACT consortia. GenOMICC genotype controls were obtained using UK Biobank Resource under project 788 funded by Roslin Institute Strategic Programme Grants from the BBSRC (BBS/E/D/10002070 and BBS/E/D/30002275) and Health Data Research UK (HDR-9004 and HDR-9003). UK Biobank data were used in the GSMR analyses presented here under project 66982. The UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government, British Heart Foundation and Diabetes UK. The work of L.K. was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). J.Y. is supported by the Westlake Education Foundation. SCOURGE is funded by the Instituto de Salud Carlos III (COV20_00622 to A.C., PI20/00876 to C.F.), European Union (ERDF) ‘A way of making Europe’, Fundación Amancio Ortega, Banco de Santander (to A.C.), Cabildo Insular de Tenerife (CGIEU0000219140 ‘Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19’ to C.F.) and Fundación Canaria Instituto de Investigación Sanitaria de Canarias (PIFIISC20/57 to C.F.). We also acknowledge the contribution of the Centro National de Genotipado (CEGEN) and Centro de Supercomputación de Galicia (CESGA) for funding this project by providing supercomputing infrastructures. A.D.L. is a recipient of fellowships from the National Council for Scientific and Technological Development (CNPq)-Brazil (309173/2019-1 and 201527/2020-0)