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Discovering the drivers of clonal hematopoiesis [article]

Oriol Pich, Iker Reyes-Salazar, Abel Gonzalez-Perez, Nuria Lopez-Bigas
<span title="2020-10-23">2020</span> <i title="Cold Spring Harbor Laboratory"> bioRxiv </i> &nbsp; <span class="release-stage" >pre-print</span>
Mutations in genes that confer a selective advantage to hematopoietic stem cells (HSCs) in certain conditions drive clonal hematopoiesis (CH). While some CH drivers have been identified experimentally or through epidemiological studies, the compendium of all genes able to drive CH upon mutations in HSCs is far from complete. We propose that identifying signals of positive selection in blood somatic mutations may be an effective way to identify CH driver genes, similarly as done to identify
more &raquo; ... r genes. Using a reverse somatic variant calling approach, we repurposed whole-genome and whole-exome blood/tumor paired samples of more than 12,000 donors from two large cancer genomics cohorts to identify blood somatic mutations. The application of IntOGen, a robust driver discovery pipeline, to blood somatic mutations across both cohorts, and more than 24,000 targeted sequenced samples yielded a list of close to 70 genes with signals of positive selection in CH, available at http://www.intogen.org/ch. This approach recovers all known CH genes, and discovers novel candidates. Generating this compendium is an essential step to understand the molecular mechanisms of CH and to accurately detect individuals with CH to ascertain their risk to develop related diseases.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/2020.10.22.350140">doi:10.1101/2020.10.22.350140</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/h7lqpdpkkrg3vbccbjiwhxjqou">fatcat:h7lqpdpkkrg3vbccbjiwhxjqou</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20201210083701/https://www.biorxiv.org/content/biorxiv/early/2020/10/23/2020.10.22.350140.full.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/6a/bd/6abdc524e3ef9c203ed1ec671c26d1ea14a2a072.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/2020.10.22.350140"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="external alternate icon"></i> biorxiv.org </button> </a>

The mutational footprints of cancer therapies [article]

Oriol Pich, Ferran Muinos, Martijn P Lolkema, Neeltje Steeghs, Abel Gonzalez-Perez, Nuria Lopez-Bigas
<span title="2019-06-27">2019</span> <i title="Cold Spring Harbor Laboratory"> bioRxiv </i> &nbsp; <span class="release-stage" >pre-print</span>
Some cancer therapies damage DNA and cause mutations both in cancer and healthy cells of the patient. These therapy-induced mutations may underlie some of the long-term and late side effects of the treatment, such as mental disabilities, organ toxicities and secondary neoplasms. Currently we ignore the mutation pattern and burden caused by different cancer treatments. Here we identify mutational signatures, or footprints of six widely-used anti-cancer therapies with the study of whole-genomes
more &raquo; ... om more than 3500 metastatic tumors originated in different organs. These include previously known and new mutational signatures generated by platinum-based drugs, and a novel signature of treatment with nucleoside metabolic inhibitors. Exploiting these mutational footprints, we estimate the contribution of different treatments to the mutation burden of tumors and their risk of causing coding and likely driver mutations in the genome. In summary, the mutational footprints identified here open a window to precisely appraise the mutational risk of different cancer therapies to understand their late side effects.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/683268">doi:10.1101/683268</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/ksdeme64nnfjtlv7afitfcvl6q">fatcat:ksdeme64nnfjtlv7afitfcvl6q</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20200325025300/https://www.biorxiv.org/content/biorxiv/early/2019/06/27/683268.full.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/e4/40/e44044f6139ddaa38711ea4ed9fb265325b56a69.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/683268"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="external alternate icon"></i> biorxiv.org </button> </a>

In silico saturation mutagenesis of cancer genes [article]

Ferran Muinos, Francisco Martinez-Jimenez, Oriol Pich, Abel Gonzalez-Perez, Nuria Lopez-Bigas
<span title="2020-06-04">2020</span> <i title="Cold Spring Harbor Laboratory"> bioRxiv </i> &nbsp; <span class="release-stage" >pre-print</span>
A maximum likelihood approach (Pich et al., 2018) was used to assign the most likely etiology to each of the driver mutations.  ...  posted June 9, 2020. ; https://doi.org/10.1101/2020.06.03.130211 doi: bioRxiv preprint al., 2013, 2020; Frigola et al., 2017; Gonzalez-Perez et al., 2019; Lawrence et al., 2013; Nik-Zainal et al., 2012; Pich  ... 
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/2020.06.03.130211">doi:10.1101/2020.06.03.130211</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/y3wnbdks3vbhlahkdsrvtpizjy">fatcat:y3wnbdks3vbhlahkdsrvtpizjy</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20201108193423/https://www.biorxiv.org/content/biorxiv/early/2020/06/09/2020.06.03.130211.full.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/d3/d5/d3d58863092cc849b544ce38358a3af142ad63a8.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/2020.06.03.130211"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="external alternate icon"></i> biorxiv.org </button> </a>

The evolution of hematopoietic cells under cancer therapy [article]

Oriol Pich, Albert Cortes-Bullich, Ferran Muinos, Marta Pratcorona, Abel Gonzalez-Perez, Nuria Lopez-Bigas
<span title="2020-10-29">2020</span> <i title="Cold Spring Harbor Laboratory"> bioRxiv </i> &nbsp; <span class="release-stage" >pre-print</span>
Pich, O., Reyes-Salazar, I., Gonzalez-Perez, A. & Lopez-Bigas, N.  ...  The identification of the somatic mutations in the blood samples of this cohort is explained in Pich et al ., 2020 38 .  ... 
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/2020.10.29.360230">doi:10.1101/2020.10.29.360230</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/dg6f7ewobnf6xcsoer5mdgk57a">fatcat:dg6f7ewobnf6xcsoer5mdgk57a</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20201212193326/https://www.biorxiv.org/content/biorxiv/early/2020/10/29/2020.10.29.360230.full.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/58/1f/581f4afd62e908448cd2c0cdf21971fa60fd0924.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/2020.10.29.360230"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="external alternate icon"></i> biorxiv.org </button> </a>

Genomic analysis of human polymorphisms affecting drug-protein interactions [article]

Oriol Pich i Rosello, Anna V Vlasova, Polina A Shichkova, Yuri Markov, Peter K Vlasov, Fyodor A Kondrashov
<span title="2017-03-23">2017</span> <i title="Cold Spring Harbor Laboratory"> bioRxiv </i> &nbsp; <span class="release-stage" >pre-print</span>
Human genetic variability is thought to account for a substantial fraction of individual biochemical characteristics — in biomedical sense, of individual drug response. However, only a handful of human genetic variants have been linked to medication outcomes. Here, we combine data on drug-protein interactions and human genome sequences to assess the impact of human variation on their binding affinity. Using data from the complexes of FDA-drugs and drug-like compounds, we predict SNPs
more &raquo; ... ly affecting the protein-ligand binding affinities. We estimate that an average individual carries ~6 SNPs affecting ~5 different FDA-approved drugs from among all of the approved compounds. SNPs affecting drug-protein binding affinity have low frequency in the population indicating that the genetic component for many ADEs may be highly personalized with each individual carrying a unique set of relevant SNPs. The reduction of ADEs, therefore, may primarily rely on the application of computational genome analysis in the clinic rather than the experimental study of common SNPs.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/119933">doi:10.1101/119933</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/3s42g2urdvdajemuoigzkx5z6q">fatcat:3s42g2urdvdajemuoigzkx5z6q</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20190504140312/https://www.biorxiv.org/content/biorxiv/early/2017/03/23/119933.full.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/ed/43/ed4378bc1f2b4c4be1f94079de7733946027ab41.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/119933"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="external alternate icon"></i> biorxiv.org </button> </a>

Long-Term Asymmetrical Acceleration of Protein Evolution after Gene Duplication

Oriol Pich i Roselló, Fyodor A. Kondrashov
<span title="2014-07-28">2014</span> <i title="Oxford University Press (OUP)"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/c3tk2qca4vdq5htca2effydqim" style="color: black;">Genome Biology and Evolution</a> </i> &nbsp;
Rapid divergence of gene copies after duplication is thought to determine the fate of the copies and evolution of novel protein functions. However, data on how long the gene copies continue to experience an elevated rate of evolution remain scarce. Standard theory of gene duplications based on some level of genetic redundancy of gene copies predicts that the period of accelerated evolution must end relatively quickly. Using a maximum-likelihood approach we estimate preduplication, initial
more &raquo; ... plication, and recent postduplication rates of evolution that occurred in the mammalian lineage. We find that both gene copies experience a similar in magnitude acceleration in their rate of evolution. The copy located in the original genomic position typically returns to the preduplication rates of evolution in a short period of time. The burst of faster evolution of the copy that is located in a new genomic position typically lasts longer. Furthermore, the fast-evolving copies on average continue to evolve faster than the preduplication rates far longer than predicted by standard theory of gene duplications. We hypothesize that the prolonged elevated rates of evolution are determined by functional properties that were acquired during, or soon after, the gene duplication event.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1093/gbe/evu159">doi:10.1093/gbe/evu159</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/25070510">pmid:25070510</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC4159008/">pmcid:PMC4159008</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/il7mabiyjngqrltqn4po36iuwa">fatcat:il7mabiyjngqrltqn4po36iuwa</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20190224071149/http://pdfs.semanticscholar.org/5e40/895615410cfb34c2a1643a2646f26f5cd54d.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/5e/40/5e40895615410cfb34c2a1643a2646f26f5cd54d.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1093/gbe/evu159"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> oup.com </button> </a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159008" title="pubmed link"> <button class="ui compact blue labeled icon button serp-button"> <i class="file alternate outline icon"></i> pubmed.gov </button> </a>

Negative selection in tumor genome evolution acts on essential cellular functions and the immunopeptidome

Luis Zapata, Oriol Pich, Luis Serrano, Fyodor A. Kondrashov, Stephan Ossowski, Martin H. Schaefer
<span title="2018-05-31">2018</span> <i title="Springer Nature"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/6bzsiicmhvczjnsm7jbog7ysaa" style="color: black;">Genome Biology</a> </i> &nbsp;
Natural selection shapes cancer genomes. Previous studies used signatures of positive selection to identify genes driving malignant transformation. However, the contribution of negative selection against somatic mutations that affect essential tumor functions or specific domains remains a controversial topic. Results: Here, we analyze 7546 individual exomes from 26 tumor types from TCGA data to explore the portion of the cancer exome under negative selection. Although we find most of the genes
more &raquo; ... eutrally evolving in a pan-cancer framework, we identify essential cancer genes and immune-exposed protein regions under significant negative selection. Moreover, our simulations suggest that the amount of negative selection is underestimated. We therefore choose an empirical approach to identify genes, functions, and protein regions under negative selection. We find that expression and mutation status of negatively selected genes is indicative of patient survival. Processes that are most strongly conserved are those that play fundamental cellular roles such as protein synthesis, glucose metabolism, and molecular transport. Intriguingly, we observe strong signals of selection in the immunopeptidome and proteins controlling peptide exposition, highlighting the importance of immune surveillance evasion. Additionally, tumor typespecific immune activity correlates with the strength of negative selection on human epitopes. Conclusions: In summary, our results show that negative selection is a hallmark of cell essentiality and immune response in cancer. The functional domains identified could be exploited therapeutically, ultimately allowing for the development of novel cancer treatments.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1186/s13059-018-1434-0">doi:10.1186/s13059-018-1434-0</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/29855388">pmid:29855388</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC5984361/">pmcid:PMC5984361</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/6shgjmcsrrfttkd7ovpn7f6yge">fatcat:6shgjmcsrrfttkd7ovpn7f6yge</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20190427165958/https://genomebiology.biomedcentral.com/track/pdf/10.1186/s13059-018-1434-0" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/a9/38/a93831b2bbc47ebf9b1f7637bade0428f0ad4b91.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1186/s13059-018-1434-0"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> springer.com </button> </a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984361" title="pubmed link"> <button class="ui compact blue labeled icon button serp-button"> <i class="file alternate outline icon"></i> pubmed.gov </button> </a>

Somatic and Germline Mutation Periodicity Follow the Orientation of the DNA Minor Groove around Nucleosomes

Oriol Pich, Ferran Muiños, Radhakrishnan Sabarinathan, Iker Reyes-Salazar, Abel Gonzalez-Perez, Nuria Lopez-Bigas
<span title="2018-11-01">2018</span> <i title="Elsevier BV"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/iwommhyo5bdk7c3u37mhjzexfe" style="color: black;">Cell</a> </i> &nbsp;
Mutation rates along the genome are highly variable and influenced by several chromatin features. Here, we addressed how nucleosomes, the most pervasive chromatin structure in eukaryotes, affect the generation of mutations. We discovered that within nucleosomes, the somatic mutation rate across several tumor cohorts exhibits a strong 10 base pair (bp) periodicity. This periodic pattern tracks the alternation of the DNA minor groove facing toward and away from the histones. The strength and
more &raquo; ... of the mutation rate periodicity are determined by the mutational processes active in tumors. We uncovered similar periodic patterns in the genetic variation among human and Arabidopsis populations, also detectable in their divergence from close species, indicating that the same principles underlie germline and somatic mutation rates. We propose that differential DNA damage and repair processes dependent on the minor groove orientation in nucleosome-bound DNA contribute to the 10-bp periodicity in AT/CG content in eukaryotic genomes.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1016/j.cell.2018.10.004">doi:10.1016/j.cell.2018.10.004</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/30388444">pmid:30388444</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/ucrekzyrvveahju6ll6zuqecqi">fatcat:ucrekzyrvveahju6ll6zuqecqi</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20200319174121/http://diposit.ub.edu/dspace/bitstream/2445/141757/1/nucleosomes.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/96/dd/96dd21c904280dfb099003f82bd48bfd6a0ffe51.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1016/j.cell.2018.10.004"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="external alternate icon"></i> elsevier.com </button> </a>

Strand-resolved mutagenicity of DNA damage and repair [article]

Craig J. Anderson, Lana Talmane, Juliet Luft, Michael D. Nicholson, John Connelly, Oriol Pich, Susan Campbell, Vasavi Sundaram, Frances Connor, Paul A. Ginno, Núria López-Bigas, Paul Flicek (+5 others)
<span title="2022-06-10">2022</span> <i title="Cold Spring Harbor Laboratory"> bioRxiv </i> &nbsp; <span class="release-stage" >pre-print</span>
., Pich, O., Gonzalez-Perez, A. & Lopez-Bigas, N. In silico saturation mutagenesis of cancer genes. Nature 596, 428-432 (2021). 46. Bharati, B. K. et al.  ... 
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/2022.06.10.495644">doi:10.1101/2022.06.10.495644</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/l7plggyyifbsrm5q3vty5utjx4">fatcat:l7plggyyifbsrm5q3vty5utjx4</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20220615120253/https://www.biorxiv.org/content/biorxiv/early/2022/06/10/2022.06.10.495644.full.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/87/bc/87bcfd9ed86678363d9c702dbfe4a9817784e0ee.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/2022.06.10.495644"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="external alternate icon"></i> biorxiv.org </button> </a>

The whole-genome panorama of cancer drivers [article]

Radhakrishnan Sabarinathan, Oriol Pich, Inigo Martincorena, Carlota Rubio-Perez, Malene Juul, Jeremiah Wala, Steven Schumacher, Ofer Shapira, Nikos Sidiropoulos, Sebastian Waszak, David Tamborero, Loris Mularoni (+15 others)
<span title="2017-09-20">2017</span> <i title="Cold Spring Harbor Laboratory"> bioRxiv </i> &nbsp; <span class="release-stage" >pre-print</span>
The advance of personalized cancer medicine requires the accurate identification of the mutations driving each patient's tumor. However, to date, we have only been able to obtain partial insights into the contribution of genomic events to tumor development. Here, we design a comprehensive approach to identify the driver mutations in each patient's tumor and obtain a whole-genome panorama of driver events across more than 2,500 tumors from 37 types of cancer. This panorama includes coding and
more &raquo; ... -coding point mutations, copy number alterations and other genomic rearrangements of somatic origin, and potentially predisposing germline variants. We demonstrate that genomic events are at the root of virtually all tumors, with each carrying on average 4.6 driver events. Most individual tumors harbor a unique combination of drivers, and we uncover the most frequent co-occurring driver events. Half of all cancer genes are affected by several types of driver mutations. In summary, the panorama described here provides answers to fundamental questions in cancer genomics and bridges the gap between cancer genomics and personalized cancer medicine.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/190330">doi:10.1101/190330</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/ioafttojhfbf5oa5zv3nwhpvdu">fatcat:ioafttojhfbf5oa5zv3nwhpvdu</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20190502183813/https://www.biorxiv.org/content/biorxiv/early/2017/12/23/190330.full.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/64/c3/64c3b7ff54acff0d52a61318a740d9929e972fc0.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/190330"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="external alternate icon"></i> biorxiv.org </button> </a>

Pervasive lesion segregation shapes cancer genome evolution [article]

Sarah J Aitken, Craig J Anderson, Frances Connor, Oriol Pich, Vasavi Sundaram, Christine Feig, Tim F Rayner, Margus Lukk, Stuart Aitken, Juliet Luft, Elissavet Kentepozidou, Claudia Arnedo-Pac (+17 others)
<span title="2019-12-08">2019</span> <i title="Cold Spring Harbor Laboratory"> biorxiv/medrxiv </i> &nbsp; <span class="release-stage" >pre-print</span>
Cancers arise through the acquisition of oncogenic mutations and grow through clonal expansion 1,2. Here we reveal that most mutagenic DNA lesions are not resolved as mutations within a single cell-cycle. Instead, DNA lesions segregate unrepaired into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterise this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can
more &raquo; ... e multiple alternative alleles in successive cell divisions, thereby increasing both multi-allelic and combinatorial genetic diversity. The phasing of lesions enables the accurate measurement of strand biased repair processes, the quantification of oncogenic selection, and the fine mapping of sister chromatid exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/868679">doi:10.1101/868679</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/43cdxjkqnfcjjpwnenqwws5mk4">fatcat:43cdxjkqnfcjjpwnenqwws5mk4</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20210428212450/https://www.pure.ed.ac.uk/ws/portalfiles/portal/142849071/Pervasive_lesion_segregation_shapes_cancer_genome_evolution.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/75/15/7515cb53bb53ede1c2c6c24bc1087ffe568cfc77.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/868679"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="external alternate icon"></i> biorxiv.org </button> </a>

Mutational dynamics and transmission properties of SARS-CoV-2 superspreading events in Austria [article]

Alexandra Popa, Jakob-Wendelin Genger, Michael Nicholson, Thomas Penz, Daniela Schmid, Stephan W Aberle, Benedikt Agerer, Alexander Lercher, Lukas Endler, Henrique Colaco, Mark Smyth, Michael Schuster (+26 others)
<span title="2020-07-17">2020</span> <i title="Cold Spring Harbor Laboratory"> bioRxiv </i> &nbsp; <span class="release-stage" >pre-print</span>
Superspreading events shape the COVID-19 pandemic. Here we provide a national-scale analysis of SARS-CoV-2 outbreaks in Austria, a country that played a major role for virus transmission across Europe and beyond. Capitalizing on a national epidemiological surveillance system, we performed deep whole-genome sequencing of virus isolates from 576 samples to cover major Austrian SARS-CoV-2 clusters. Our data chart a map of early viral spreading in Europe, including the path from low-frequency
more &raquo; ... ons to fixation. Detailed epidemiological surveys enabled us to calculate the effective SARS-CoV-2 population bottlenecks during transmission and unveil time-resolved intra-patient viral quasispecies dynamics. This study demonstrates the power of integrating deep viral genome sequencing and epidemiological data to better understand how SARS-CoV-2 spreads through populations.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/2020.07.15.204339">doi:10.1101/2020.07.15.204339</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/kiivophcb5b4vfuybt7f7ktzcu">fatcat:kiivophcb5b4vfuybt7f7ktzcu</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20201108173945/https://www.biorxiv.org/content/biorxiv/early/2020/07/17/2020.07.15.204339.full.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/77/27/772794505d1525dc148827fec41c96b9a37c11bf.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/2020.07.15.204339"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="external alternate icon"></i> biorxiv.org </button> </a>

Genomic epidemiology of superspreading events in Austria reveals mutational dynamics and transmission properties of SARS-CoV-2

Alexandra Popa, Jakob-Wendelin Genger, Michael D. Nicholson, Thomas Penz, Daniela Schmid, Stephan W. Aberle, Benedikt Agerer, Alexander Lercher, Lukas Endler, Henrique Colaço, Mark Smyth, Michael Schuster (+26 others)
<span title="2020-11-23">2020</span> <i title="American Association for the Advancement of Science (AAAS)"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/yfp7fpewebcjxcnf3x5jsya7hi" style="color: black;">Science Translational Medicine</a> </i> &nbsp;
Superspreading events shaped the Coronavirus Disease 2019 (COVID-19) pandemic, and their rapid identification and containment are essential for disease control. Here we provide a national-scale analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) superspreading during the first wave of infections in Austria, a country that played a major role in initial virus transmissions in Europe. Capitalizing on Austria's well-developed epidemiological surveillance system, we identified
more &raquo; ... ajor SARS-CoV-2 clusters during the first wave of infections and performed deep whole-genome sequencing of more than 500 virus samples. Phylogenetic-epidemiological analysis enabled the reconstruction of superspreading events and charts a map of tourism-related viral spread originating from Austria in spring 2020. Moreover, we exploited epidemiologically well-defined clusters to quantify SARS-CoV-2 mutational dynamics, including the observation of a low-frequency mutation that progressed to fixation within the infection chain. Time-resolved virus sequencing unveiled viral mutation dynamics within individuals with COVID-19, and epidemiologically validated infector-infectee pairs enabled us to determine an average transmission bottleneck size of 103 SARS-CoV-2 particles. In conclusion, this study illustrates the power of combining epidemiological analysis with deep viral genome sequencing to unravel the spread of SARS-CoV-2, and to gain fundamental insights into mutational dynamics and transmission properties.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1126/scitranslmed.abe2555">doi:10.1126/scitranslmed.abe2555</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/33229462">pmid:33229462</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/rjt32e3l25ha3ora2dfpi4ybg4">fatcat:rjt32e3l25ha3ora2dfpi4ybg4</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20201126111014/https://stm.sciencemag.org/content/scitransmed/early/2020/11/20/scitranslmed.abe2555.full.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/14/d2/14d23d8ee3cbe323f324b37b71ffe2df1e542deb.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1126/scitranslmed.abe2555"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> sciencemag.org </button> </a>

Premio a las mejores Comunicaciones presentadas/ AEC

Equipo Editorial
<span title="">2019</span> <i title="Consejo Superior de Investigaciones Científicas"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/d52vspdpyjhdrbwio6zdlsapcu" style="color: black;">Informes de la Construccion</a> </i> &nbsp;
, Oriol París, Teresa Batlle Pages, Zuzana Procházkova University: Universidad Internacional de Cataluña Tittle: Climate Concrete-Prefabricated solution for Bioclimatic Façade Design. / aeC Premio /architecture  ...  University of Miami USA, ICEA, University of the Basque Country, University of Miami USA Tittle: Redefining susrainable concrete with fiber reinforced Polymer (FRP) Composite reinforcement Authors: Felipe Pich-Aguilera  ... 
<span class="external-identifiers"> <a target="_blank" rel="external noopener" href="https://doaj.org/article/a80a1af012aa498d954b8cb23488a4f1">doaj:a80a1af012aa498d954b8cb23488a4f1</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/iq4ehtaq3rhulif7zexicnjjqq">fatcat:iq4ehtaq3rhulif7zexicnjjqq</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20200120030520/http://informesdelaconstruccion.revistas.csic.es:80/index.php/informesdelaconstruccion/article/download/5947/7117" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/71/f4/71f49db46a9a95f5d3bd2f2810b47dc7be745f31.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a>

Discovery and characterization of coding and non-coding driver mutations in more than 2,500 whole cancer genomes [article]

Esther Rheinbay, Morten Muhlig Nielsen, Federico Abascal, Grace Tiao, Henrik Hornshøj, Julian M Hess, Randi Istrup Istrup Pedersen, Lars Feuerbach, Radhakrishnan Sabarinathan, Henrik Tobias Madsen, JAEGIL KIM, Loris Mularoni (+61 others)
<span title="2017-12-23">2017</span> <i title="Cold Spring Harbor Laboratory"> bioRxiv </i> &nbsp; <span class="release-stage" >pre-print</span>
Discovery of cancer drivers has traditionally focused on the identification of protein-coding genes. Here we present a comprehensive analysis of putative cancer driver mutations in both protein-coding and non-coding genomic regions across >2,500 whole cancer genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We developed a statistically rigorous strategy for combining significance levels from multiple driver discovery methods and demonstrate that the integrated results
more &raquo; ... rcome limitations of individual methods. We combined this strategy with careful filtering and applied it to protein-coding genes, promoters, untranslated regions (UTRs), distal enhancers and non-coding RNAs. These analyses redefine the landscape of non-coding driver mutations in cancer genomes, confirming a few previously reported elements and raising doubts about others, while identifying novel candidate elements across 27 cancer types. Novel recurrent events were found in the promoters or 5'UTRs of TP53, RFTN1, RNF34, and MTG2, in the 3'UTRs of NFKBIZ and TOB1, and in the non-coding RNA RMRP. We provide evidence that the previously reported non-coding RNAs NEAT1 and MALAT1 may be subject to a localized mutational process. Perhaps the most striking finding is the relative paucity of point mutations driving cancer in non-coding genes and regulatory elements. Though we have limited power to discover infrequent non-coding drivers in individual cohorts, combined analysis of promoters of known cancer genes show little excess of mutations beyond TERT.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/237313">doi:10.1101/237313</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/gt5imzwlure6vojs6hd3yxmb7a">fatcat:gt5imzwlure6vojs6hd3yxmb7a</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20190502050406/https://www.biorxiv.org/content/biorxiv/early/2017/12/23/237313.full.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/16/5e/165e8374bcab79a67152aaf5df877cff7218f085.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1101/237313"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="external alternate icon"></i> biorxiv.org </button> </a>
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