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The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair1. In microorganisms, transcription has been demonstrated to be mutagenic2,3; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes4. Here we show that ID4—a cancer insertion–deletion (indel) mutation signature of unknown aetiology5 characterized by short (2 to 5 base pair) deletions —is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activity at sites of genome-embedded ribonucleotides as a mechanistic basis. Such TOP1-mediated deletions occur somatically in cancer, and the ID-TOP1 signature is also found in physiological settings, contributing to genic de novo indel mutations in the germline. Thus, although topoisomerases protect against genome instability by relieving topological stress6, their activity may also be an important source of mutations in the human genome. We thank S. Jinks-Robertson for suggesting the traffic light reporter approach; H. Klein for guidance on fluctuation assays; R. van Boxtel for sharing sequencing data for MLH1-KO organoids; A. Bretherick, O. B. Reina and G. Kudla for advice on HygroR re-coding; staff at the IGC core services (L. Murphy, C. Nicol, C. Warnock, E. Freyer, S. Brown and J. Joseph), C. Logan, A. Fluteau, A. Robertson and the staff at Edinburgh Genomics for technical assistance; staff at Liverpool CLL Biobank (funded by Blood Cancer UK) for samples used to generate GEL WGS data; A. Ewing, C.-A. Martin, N. Hastie and W. Bickmore for discussions. Funding for this work: UK Medical Research Council Human Genetics Unit core grants (MC_UU_00007/5 to A.P.J., MC_UU_00007/11 to M.S.T.); Edinburgh Clinical Academic Track PhD programme (Wellcome Trust 204802/Z/16/Z) to T.C.W.; 2021 AACR-Amgen Fellowship in Clinical/Translational Cancer Research (grant number 21-40-11-NADE) to F.N.; a CRUK Brain Tumour Centre of Excellence Award (C157/A27589) to M.D.N.; EKFS research grant (2019_A09), Wilhelm Sander-Stiftung (2019.046.1) to K.A., CRUK programme grant (C20807/A2864) to T.S.; La Caixa Foundation (CLLEvolution-LCF/PR/HR17/52150017, Health Research 2017 Program HR17-00221) to E.C.; E.C. is an Academia Researcher of the Institució Catalana de Recerca i Estudis Avançats of the Generalitat de Catalunya. Edinburgh Genomics is partly supported by NERC (R8/H10/56), MRC (MR/K001744/1) and BBSRC (BB/J004243/1). This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. Peer Reviewed "Article signat per 22 autors/es: Martin A. M. Reijns, David A. Parry, Thomas C. Williams, Ferran Nadeu, Rebecca L. Hindshaw, Diana O. Rios Szwed, Michael D. Nicholson, Paula Carroll, Shelagh Boyle, Romina Royo, Alex J. Cornish, Hang Xiang, Kate Ridout, The Genomics England Research Consortium, Colorectal Cancer Domain UK 100,000 Genomes Project, Anna Schuh, Konrad Aden, Claire Palles, Elias Campo, Tatjana Stankovic, Martin S. Taylor & Andrew P. Jackson "

Quinoa stands out as an excellent crop in the Cerrado region for cultivation in the offseason or irrigated winter season. Here, we tested the effects of different water regimes on the agronomic characteristics, physiology, and grain quality of different elite quinoa genotypes under field conditions. The experiment was conducted under field conditions at Embrapa Cerrados (Planaltina, DF, Brazil). The experimental design was in randomized blocks, in a split-plot scheme, with four replications. The plots were composed of 18 quinoa genotypes and modified BRS Piabiru (the currently used genotype), and the split-plots were divided into 4 different water regimes. The following variables were evaluated: productivity and productivity per unit of applied water (PUAA), plant height, flavonoids, anthocyanins, gas exchange, chlorophyll, leaf proline, and relative water content. Our results showed that water regimes between 309 and 389 mm can be recommended for quinoa in the Cerrado region. CPAC6 and CPAC13 presented the highest yield and PUAA under high and intermediate WRs, and hence were the most suitable for winter growth under irrigation. CPAC17 is most suitable for off-season growth under rainfed conditions, as it presented the highest PUAA under the low WRs (247 and 150). CPAC9 stood out in terms of accumulation of flavonoids and anthocyanins in all WRs. Physiological analyses revealed different responses of the genotypes to water restriction, together with symptoms of stress under lower water regimes. Our study reinforces the importance of detailed analyses of the relationship between productivity, physiology, and water use when choosing genotypes for planting and harvest in different seasons. Made available in DSpace on 2021-10-15T15:01:10Z (GMT). No. of bitstreams: 1 Quinoa-for-the-Brazilian-Cerrado-Walter.pdf: 922634 bytes, checksum: d2a808f11d2312455e6231c398583d95 (MD5) Previous issue date: 2021

Made available in DSpace on 2019-12-20T18:10:10Z (GMT). No. of bitstreams: 1 LETICIA19302440main.pdf: 1096270 bytes, checksum: a8aa0eeaa906a2ac2615a6ba20c2afe9 (MD5) Previous issue date: 2019

We here present reults of a crystal-chemical study of a suite of pyrochlore-group minerals from the holocrystalline syenitic ejecta scattered within the Plio-Pleistocene pyroclastic deposits of Latium, in central Italy. Despite their high actinide content, the samples studied are non-metamict owing to their young age of formation, as suggested by the well-defined and sharp peaks in the X-ray powder-diffraction patterns. The measured a unit-cell dimension is correlated with the (Ti + Fe3+) content at the B site of the structure. Following the IMA classification scheme for pyrochlore-group minerals modified according to the “50% rule” adopted in 1992, the samples are classified as betafite, pyrochlore and uranpyrochlore. In comparison with known data for pyrochlore-group minerals, the samples have extremely high Ti contents (up to 81.3 atom % Ti relative to the Ti + Nb + Ta sum) and significant and variable contents of Zr (up to 8.44 wt.% ZrO2) and W (up to 12.14 wt.% WO3). Some crystals display strong compositional zoning, consistent with the substitution 3Nb5+ + Na+ ⇌ 3Ti4+ + U4+. The accommodation of extremely high amounts of W6+ can be related to the coupled substitution 2(Nb + Ta)5+ ⇌ Ti4+ + W6+ at the B site. Pyrochlore-group minerals from Latium have significantly high REE contents (up to 7.75 wt.% oxide). Chondrite-normalized patterns follow the general trend typical of unaltered pyrochlore, i.e., with an extreme Ce-enrichment and a decrease toward the heavy REE.