71 results on '"Søren Besenbacher"'
Search Results
2. Unsupervised detection of fragment length signatures of circulating tumor DNA using non-negative matrix factorization
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Gabriel Renaud, Maibritt Nørgaard, Johan Lindberg, Henrik Grönberg, Bram De Laere, Jørgen Bjerggaard Jensen, Michael Borre, Claus Lindbjerg Andersen, Karina Dalsgaard Sørensen, Lasse Maretty, and Søren Besenbacher
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cell-free DNA ,cancer genomics ,liquid biopsy ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Sequencing of cell-free DNA (cfDNA) is currently being used to detect cancer by searching both for mutational and non-mutational alterations. Recent work has shown that the length distribution of cfDNA fragments from a cancer patient can inform tumor load and type. Here, we propose non-negative matrix factorization (NMF) of fragment length distributions as a novel and completely unsupervised method for studying fragment length patterns in cfDNA. Using shallow whole-genome sequencing (sWGS) of cfDNA from a cohort of patients with metastatic castration-resistant prostate cancer (mCRPC), we demonstrate how NMF accurately infers the true tumor fragment length distribution as an NMF component - and that the sample weights of this component correlate with ctDNA levels (r=0.75). We further demonstrate how using several NMF components enables accurate cancer detection on data from various early stage cancers (AUC = 0.96). Finally, we show that NMF, when applied across genomic regions, can be used to discover fragment length signatures associated with open chromatin.
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- 2022
- Full Text
- View/download PDF
3. The Mutationathon highlights the importance of reaching standardization in estimates of pedigree-based germline mutation rates
- Author
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Lucie A Bergeron, Søren Besenbacher, Tychele Turner, Cyril J Versoza, Richard J Wang, Alivia Lee Price, Ellie Armstrong, Meritxell Riera, Jedidiah Carlson, Hwei-yen Chen, Matthew W Hahn, Kelley Harris, April Snøfrid Kleppe, Elora H López-Nandam, Priya Moorjani, Susanne P Pfeifer, George P Tiley, Anne D Yoder, Guojie Zhang, and Mikkel H Schierup
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mutation rate ,ngs analysis ,pedigree-based estimation ,computational pipeline ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
In the past decade, several studies have estimated the human per-generation germline mutation rate using large pedigrees. More recently, estimates for various nonhuman species have been published. However, methodological differences among studies in detecting germline mutations and estimating mutation rates make direct comparisons difficult. Here, we describe the many different steps involved in estimating pedigree-based mutation rates, including sampling, sequencing, mapping, variant calling, filtering, and appropriately accounting for false-positive and false-negative rates. For each step, we review the different methods and parameter choices that have been used in the recent literature. Additionally, we present the results from a ‘Mutationathon,’ a competition organized among five research labs to compare germline mutation rate estimates for a single pedigree of rhesus macaques. We report almost a twofold variation in the final estimated rate among groups using different post-alignment processing, calling, and filtering criteria, and provide details into the sources of variation across studies. Though the difference among estimates is not statistically significant, this discrepancy emphasizes the need for standardized methods in mutation rate estimations and the difficulty in comparing rates from different studies. Finally, this work aims to provide guidelines for computational and statistical benchmarks for future studies interested in identifying germline mutations from pedigrees.
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- 2022
- Full Text
- View/download PDF
4. A site specific model and analysis of the neutral somatic mutation rate in whole-genome cancer data
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Johanna Bertl, Qianyun Guo, Malene Juul, Søren Besenbacher, Morten Muhlig Nielsen, Henrik Hornshøj, Jakob Skou Pedersen, and Asger Hobolth
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Multinomial logistic regression ,Site-specific model ,Somatic cancer mutations ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Biology (General) ,QH301-705.5 - Abstract
Abstract Background Detailed modelling of the neutral mutational process in cancer cells is crucial for identifying driver mutations and understanding the mutational mechanisms that act during cancer development. The neutral mutational process is very complex: whole-genome analyses have revealed that the mutation rate differs between cancer types, between patients and along the genome depending on the genetic and epigenetic context. Therefore, methods that predict the number of different types of mutations in regions or specific genomic elements must consider local genomic explanatory variables. A major drawback of most methods is the need to average the explanatory variables across the entire region or genomic element. This procedure is particularly problematic if the explanatory variable varies dramatically in the element under consideration. Results To take into account the fine scale of the explanatory variables, we model the probabilities of different types of mutations for each position in the genome by multinomial logistic regression. We analyse 505 cancer genomes from 14 different cancer types and compare the performance in predicting mutation rate for both regional based models and site-specific models. We show that for 1000 randomly selected genomic positions, the site-specific model predicts the mutation rate much better than regional based models. We use a forward selection procedure to identify the most important explanatory variables. The procedure identifies site-specific conservation (phyloP), replication timing, and expression level as the best predictors for the mutation rate. Finally, our model confirms and quantifies certain well-known mutational signatures. Conclusion We find that our site-specific multinomial regression model outperforms the regional based models. The possibility of including genomic variables on different scales and patient specific variables makes it a versatile framework for studying different mutational mechanisms. Our model can serve as the neutral null model for the mutational process; regions that deviate from the null model are candidates for elements that drive cancer development.
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- 2018
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5. Hierarchical Classification of Cancers of Unknown Primary Using Multi-Omics Data
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Elham Bavafaye Haghighi, Michael Knudsen, Britt Elmedal Laursen, and Søren Besenbacher
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
A cancer of unknown primary (CUP) is a metastatic cancer for which standard diagnostic tests fail to locate the primary cancer. As standard treatments are based on the cancer type, such cases are hard to treat and have very poor prognosis. Using molecular data from the metastatic cancer to predict the primary site can make treatment choice easier and enable targeted therapy. In this article, we first examine the ability to predict cancer type using different types of omics data. Methylation data lead to slightly better prediction than gene expression and both these are superior to classification using somatic mutations. After using 3 data types independently, we notice some differences between the classes that tend to be misclassified, suggesting that integrating the data might improve accuracy. In light of the different levels of information provided by different omics types and to be able to handle missing data, we perform multi-omics classification by hierarchically combining the classifiers. The proposed hierarchical method first classifies based on the most informative type of omics data and then uses the other types of omics data to classify samples that did not get a high confidence classification in the first step. The resulting hierarchical classifier has higher accuracy than any of the single omics classifiers and thus proves that the combination of different data types is beneficial. Our results show that using multi-omics data can improve the classification of cancer types. We confirm this by testing our method on metastatic cancers from the MET500 dataset.
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- 2019
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6. Multi-nucleotide de novo Mutations in Humans.
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Søren Besenbacher, Patrick Sulem, Agnar Helgason, Hannes Helgason, Helgi Kristjansson, Aslaug Jonasdottir, Adalbjorg Jonasdottir, Olafur Th Magnusson, Unnur Thorsteinsdottir, Gisli Masson, Augustine Kong, Daniel F Gudbjartsson, and Kari Stefansson
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Genetics ,QH426-470 - Abstract
Mutation of the DNA molecule is one of the most fundamental processes in biology. In this study, we use 283 parent-offspring trios to estimate the rate of mutation for both single nucleotide variants (SNVs) and short length variants (indels) in humans and examine the mutation process. We found 17812 SNVs, corresponding to a mutation rate of 1.29 × 10-8 per position per generation (PPPG) and 1282 indels corresponding to a rate of 9.29 × 10-10 PPPG. We estimate that around 3% of human de novo SNVs are part of a multi-nucleotide mutation (MNM), with 558 (3.1%) of mutations positioned less than 20kb from another mutation in the same individual (median distance of 525bp). The rate of de novo mutations is greater in late replicating regions (p = 8.29 × 10-19) and nearer recombination events (p = 0.0038) than elsewhere in the genome.
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- 2016
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7. Pathway Analysis of Skin from Psoriasis Patients after Adalimumab Treatment Reveals New Early Events in the Anti-Inflammatory Mechanism of Anti-TNF-α.
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Ane Langkilde, Lene C Olsen, Pål Sætrom, Finn Drabløs, Søren Besenbacher, Line Raaby, Claus Johansen, and Lars Iversen
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Medicine ,Science - Abstract
Psoriasis is a chronic cutaneous inflammatory disease. The immunopathogenesis is a complex interplay between T cells, dendritic cells and the epidermis in which T cells and dendritic cells maintain skin inflammation. Anti-tumour necrosis factor (anti-TNF)-α agents have been approved for therapeutic use across a range of inflammatory disorders including psoriasis, but the anti-inflammatory mechanisms of anti-TNF-α in lesional psoriatic skin are not fully understood. We investigated early events in skin from psoriasis patients after treatment with anti-TNF-α antibodies by use of bioinformatics tools. We used the Human Gene 1.0 ST Array to analyse gene expression in punch biopsies taken from psoriatic patients before and also 4 and 14 days after initiation of treatment with the anti-TNF-α agent adalimumab. The gene expression was analysed by gene set enrichment analysis using the Functional Annotation Tool from DAVID Bioinformatics Resources. The most enriched pathway was visualised by the Pathview Package on Kyoto Encyclopedia of Genes and Genomes (KEGG) graphs. The analysis revealed new very early events in psoriasis after adalimumab treatment. Some of these events have been described after longer periods of anti-TNF-α treatment when clinical and histological changes appear, suggesting that effects of anti-TNF-α treatment on gene expression appear very early before clinical and histological changes. Combining microarray data on biopsies from psoriasis patients with pathway analysis allowed us to integrate in vitro findings into the identification of mechanisms that may be important in vivo. Furthermore, these results may reflect primary effect of anti-TNF-α treatment in contrast to studies of gene expression changes following clinical and histological changes, which may reflect secondary changes correlated to the healing of the skin.
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- 2016
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8. Modeling non-equilibrium population using variable-chromosome-length genetic algorithm.
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Muhammad Marwan Muhammad Fuad and Søren Besenbacher
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- 2017
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9. Benchmarking the HLA typing performance of Polysolver and Optitype in 50 Danish parental trios.
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Maria Luisa Matey-Hernandez, Lasse Maretty, Jacob Malte Jensen, Bent Petersen, Jonas Andreas Sibbesen, Siyang Liu, Palle Villesen, Laurits Skov, Kirstine Belling, Christian Theil Have, José M. G. Izarzugaza, Marie Grosjean, Jette Bork-Jensen, Jakob Grove, Thomas D. Als, Shujia Huang, Yuqi Chang, Ruiqi Xu, Weijian Ye, Junhua Rao, Xiaosen Guo, Jihua Sun, Hongzhi Cao, Chen Ye, John van Beusekom, Thomas Espeseth, Esben N. Flindt, Rune M. Friborg, Anders E. Halager, Stephanie Le Hellard, Christina M. Hultman, Francesco Lescai, Shengting Li, Ole Lund, Peter Løngreen, Thomas Mailund, Ole Mors, Christian N. S. Pedersen, Thomas Sicheritz-Pontén, Patrick F. Sullivan, Ali Syed, David Westergaard, Rachita Yadav, Ning Li, Xun Xu, Torben Hansen, Anders Krogh, Lars Bolund, Thorkild I. A. Sørensen, Oluf Pedersen, Ramneek Gupta, Simon Rasmussen, Søren Besenbacher, Anders D. Børglum, Jun Wang 0004, Hans Eiberg, Karsten Kristiansen, Mikkel Heide Schierup, and Søren Brunak
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- 2018
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10. Sequencing and de novo assembly of 150 genomes from Denmark as a population reference.
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Lasse Maretty, Jacob Malte Jensen, Bent Petersen, Jonas Andreas Sibbesen, Siyang Liu, Palle Villesen, Laurits Skov, Kirstine Belling, Christian Theil Have, José M. G. Izarzugaza, Marie Grosjean, Jette Bork-Jensen, Jakob Grove, Thomas D. Als, Shujia Huang, Yuqi Chang, Ruiqi Xu, Weijian Ye, Junhua Rao, Xiaosen Guo, Jihua Sun, Hongzhi Cao, Chen Ye, John van Beusekom, Thomas Espeseth, Esben N. Flindt, Rune M. Friborg, Anders E. Halager, Stephanie Le Hellard, Christina M. Hultman, Francesco Lescai, Shengting Li, Ole Lund, Peter Løngreen, Thomas Mailund, Maria Luisa Matey-Hernandez, Ole Mors, Christian N. S. Pedersen, Thomas Sicheritz-Pontén, Patrick F. Sullivan, Ali Syed, David Westergaard, Rachita Yadav, Ning Li, Xun Xu, Torben Hansen, Anders Krogh, Lars Bolund, Thorkild I. A. Sørensen, Oluf Pedersen, Ramneek Gupta, Simon Rasmussen, Søren Besenbacher, Anders D. Børglum, Jun Wang 0004, Hans Eiberg, Karsten Kristiansen, Søren Brunak, and Mikkel Heide Schierup
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- 2017
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11. Evolution of the germline mutation rate across vertebrates
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Lucie A. Bergeron, Søren Besenbacher, Jiao Zheng, Panyi Li, Mads Frost Bertelsen, Benoit Quintard, Joseph I. Hoffman, Zhipeng Li, Judy St. Leger, Changwei Shao, Josefin Stiller, M. Thomas P. Gilbert, Mikkel H. Schierup, and Guojie Zhang
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Multidisciplinary - Abstract
The germline mutation rate determines the pace of genome evolution and is an evolving parameter itself1. However, little is known about what determines its evolution, as most studies of mutation rates have focused on single species with different methodologies2. Here we quantify germline mutation rates across vertebrates by sequencing and comparing the high-coverage genomes of 151 parent–offspring trios from 68 species of mammals, fishes, birds and reptiles. We show that the per-generation mutation rate varies among species by a factor of 40, with mutation rates being higher for males than for females in mammals and birds, but not in reptiles and fishes. The generation time, age at maturity and species-level fecundity are the key life-history traits affecting this variation among species. Furthermore, species with higher long-term effective population sizes tend to have lower mutation rates per generation, providing support for the drift barrier hypothesis3. The exceptionally high yearly mutation rates of domesticated animals, which have been continually selected on fecundity traits including shorter generation times, further support the importance of generation time in the evolution of mutation rates. Overall, our comparative analysis of pedigree-based mutation rates provides ecological insights on the mutation rate evolution in vertebrates.
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- 2023
12. Indexing and Searching a Mass Spectrometry Database.
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Søren Besenbacher, Benno Schwikowski, and Jens Stoye
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- 2010
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13. Prediction of Primary Tumors in Cancers of Unknown Primary.
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Dan Søndergaard, Svend V. Nielsen, Christian N. S. Pedersen, and Søren Besenbacher
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- 2017
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14. Author response: The Mutationathon highlights the importance of reaching standardization in estimates of pedigree-based germline mutation rates
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Lucie A Bergeron, Søren Besenbacher, Tychele Turner, Cyril J Versoza, Richard J Wang, Alivia Lee Price, Ellie Armstrong, Meritxell Riera, Jedidiah Carlson, Hwei-yen Chen, Matthew W Hahn, Kelley Harris, April Snøfrid Kleppe, Elora H López-Nandam, Priya Moorjani, Susanne P Pfeifer, George P Tiley, Anne D Yoder, Guojie Zhang, and Mikkel H Schierup
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- 2022
15. Expression patterns and prognostic potential of circular RNAs in mantle cell lymphoma:a study of younger patients from the MCL2 and MCL3 clinical trials
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Riikka Räty, Kirsten Grønbæk, Mats Jerkeman, Simon Husby, Lasse Sommer Kristensen, Søren Besenbacher, Christian Winther Eskelund, Mette Dahl, Christophe Côme, Christian H. Geisler, Jørgen Kjems, Sara Ek, Arne Kolstad, and Søren Fjelstrup
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Oncology ,Cancer Research ,medicine.medical_specialty ,CARCINOMA ,BIOGENESIS ,PROGRESSION ,Disease ,Tp53 mutation ,Blastoid ,IMMUNOCHEMOTHERAPY ,CYTOLOGY ,Text mining ,Chemoimmunotherapy ,Internal medicine ,medicine ,15-YEAR FOLLOW-UP ,GENE-EXPRESSION ,biology ,business.industry ,SIGNATURE ,Hematology ,biology.organism_classification ,medicine.disease ,CIRC-ZNF609 ,Clinical trial ,SURVIVAL ,Mantle cell lymphoma ,Stem cell ,business - Abstract
Mantle cell lymphoma (MCL) is characterized by marked differences in outcome, emphasizing the need for strong prognostic biomarkers. Here, we explore expression patterns and prognostic relevance of circular RNAs (circRNAs), a group of endogenous non-coding RNA molecules, in MCL. We profiled the circRNA expression landscape using RNA-sequencing and explored the prognostic potential of 40 abundant circRNAs in samples from the Nordic MCL2 and MCL3 clinical trials, using NanoString nCounter Technology. We report a circRNA-based signature (circSCORE) developed in the training cohort MCL2 that is highly predictive of time to progression (TTP) and lymphoma-specific survival (LSS). The dismal outcome observed in the large proportion of patients assigned to the circSCORE high-risk group was confirmed in the independent validation cohort MCL3, both in terms of TTP (HR 3.0; P = 0.0004) and LSS (HR 3.6; P = 0.001). In Cox multiple regression analysis incorporating MIPI, Ki67 index, blastoid morphology and presence of TP53 mutations, circSCORE retained prognostic significance for TTP (HR 3.2; P = 0.01) and LSS (HR 4.6; P = 0.01). In conclusion, circRNAs are promising prognostic biomarkers in MCL and circSCORE improves identification of high-risk disease among younger patients treated with cytarabine-containing chemoimmunotherapy and autologous stem cell transplant.
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- 2022
16. A method to build extended sequence context models of point mutations and indels
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Søren Besenbacher, April Snøfrid Kleppe, and Jörn Bethune
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Multidisciplinary ,General Physics and Astronomy ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology - Abstract
The mutation rate of a specific position in the human genome depends on the sequence context surrounding it. Modeling the mutation rate by estimating a rate for each possible k-mer, however, only works for small values of k since the data becomes too sparse for larger values of k. Here we propose a new method that solves this problem by grouping similar k-mers using IUPAC patterns. We refer to the method as k-mer pattern partition and have implemented it in a software package called kmerPaPa. We use a large set of human de novo mutations to show that this new method leads to improved prediction of mutation rates and makes it possible to create models using wider sequence contexts than previous studies. Revealing that for some mutation types, the mutation rate of a position is significantly affected by nucleotides that are up to four base pairs away. As the first method of its kind, it does not only predict rates for point mutations but also indels. We have additionally created a software package called Genovo that, given a k-mer pattern partition model, predicts the expected number of synonymous, missense, and other functional mutation types for each gene. Using this software, we show that the created mutation rate models increase the statistical power to detect genes containing disease-causing variants and to identify genes under strong constraint, e.g. haploinsufficient genes.
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- 2021
17. Studying mutation rate evolution in primates—a need for systematic comparison of computational pipelines
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Mikkel H. Schierup, Søren Besenbacher, Lucie A. Bergeron, and Guojie Zhang
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Mutation rate ,Computer science ,AcademicSubjects/SCI02254 ,Health Informatics ,Macaca mulatta ,Data science ,Opinion piece ,Computer Science Applications ,computational pipeline ,NGS sequencing ,Germline mutation ,Mutation Rate ,Commentary ,AcademicSubjects/SCI00960 ,Animals ,germline mutation rate ,Germ-Line Mutation - Abstract
The lack of consensus methods to estimate germline mutation rates from pedigrees has led to substantial differences in computational pipelines in the published literature. Here, we answer Susanne Pfeifer's opinion piece discussing the pipeline choices of our recent article estimating the germline mutation rate of rhesus macaques (Macaca mulatta). We acknowledge the differences between the method that we applied and the one preferred by Pfeifer. Yet, we advocate for full transparency and justification of choices as long as rigorous comparison of pipelines remains absent because it is the only way to conclude on best practices for the field.
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- 2021
18. Mutationathon: towards standardization in estimates of pedigree-based germline mutation rates
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Alivia Lee Price, Kelley Harris, Ellie E. Armstrong, Elora H. López-Nandam, Meritxell Riera, Jedidiah Carlson, Richard J. Wang, Lucie A. Bergeron, April S. Kleppe, George P. Tiley, Mikkel H. Schierup, Cyril J. Versoza, Tychele N. Turner, Hwei-yen Chen, Søren Besenbacher, Matthew W. Hahn, Guojie Zhang, Priya Moorjani, Susanne P. Pfeifer, and Anne D. Yoder
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Mutation rate ,Germline mutation ,Future studies ,Standardization ,Statistics ,Pedigree chart ,Biology - Abstract
In the past decade, several studies have estimated the human per-generation germline mutation rate using large pedigrees. More recently, estimates for various non-human species have been published. However, methodological differences among studies in detecting germline mutations and estimating mutation rates make direct comparisons difficult. Here, we describe the many different steps involved in estimating pedigree-based mutation rates, including sampling, sequencing, mapping, variant calling, filtering, and how to appropriately account for false-positive and false-negative rates. For each step, we review the different methods and parameter choices that have been used in the recent literature. Additionally, we present the results from a “Mutationathon”, a competition organized among five research labs to compare germline mutation rate estimates for a single pedigree of rhesus macaques. We report almost a two-fold variation in the final estimated rate among groups using different post-alignment processing, calling, and filtering criteria and provide details into the sources of variation across studies. Though the difference among estimates is not statistically significant, this discrepancy emphasizes the need for standardized methods in mutation rate estimations and the difficulty in comparing rates from different studies. Finally, this work aims to provide guidelines for computational and statistical benchmarks for future studies interested in identifying germline mutations from pedigrees.
- Published
- 2021
19. Discovering fragment length signatures of circulating tumor DNA using Non-negative Matrix Factorization
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Claus L. Andersen, Johan Lindberg, Gabriel Renaud, Maibritt Nørgaard, Lasse Maretty, Søren Besenbacher, Jørgen Bjerggaard Jensen, Karina Dalsgaard Sørensen, Michael Borre, Bram De Laere, and Henrik Grönberg
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Prostate cancer ,Fragment (logic) ,Circulating tumor DNA ,medicine ,Cancer ,Computational biology ,Biology ,medicine.disease ,Tumor Load ,Matrix decomposition ,Non-negative matrix factorization ,Chromatin - Abstract
Sequencing of cell-free DNA (cfDNA) is currently being used to detect cancer by searching both for mutational and non-mutational alterations. Recent work has shown that the length distribution of cfDNA fragments from a cancer patient can inform tumor load and type. Here, we propose non-negative matrix factorization (NMF) of fragment length distributions as a novel method to study fragment lengths in cfDNA samples.Using shallow whole-genome sequencing (sWGS) of cfDNA from a cohort of patients with metastatic castration-resistant prostate cancer (mCRPC), we demonstrate how NMF accurately infers the true tumor fragment length distribution as an NMF component - and that the sample weights of this component correlate with ctDNA levels (r=0.75). We further demonstrate how using several NMF components enables accurate cancer detection on data from various early stage cancers (AUC=0.96). Finally, we show that NMF, when applied across genomic regions, can be used to discover fragment length signatures associated with open chromatin.
- Published
- 2021
20. The germline mutational process in rhesus macaque and its implications for phylogenetic dating
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George Pacheco, Guojie Zhang, Maria Kamilari, Søren Besenbacher, Mikkel H. Schierup, Mikkel-Holger S. Sinding, Lucie A. Bergeron, Jaco Bakker, Panyi Li, Jiao Zheng, and M. Thomas P. Gilbert
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0106 biological sciences ,Male ,Mutation rate ,Lineage (genetic) ,mutation rate ,Evolution ,AcademicSubjects/SCI02254 ,primates ,Health Informatics ,Biology ,phylogeny ,010603 evolutionary biology ,01 natural sciences ,Germline ,Divergence ,03 medical and health sciences ,Germline mutation ,Phylogenetics ,Animals ,Molecular clock ,Germ-Line Mutation ,030304 developmental biology ,Genetics ,0303 health sciences ,Phylogenetic tree ,Research ,AcademicSubjects/SCI00020 ,biology.organism_classification ,Macaca mulatta ,Computer Science Applications ,Rhesus macaque ,Germ Cells ,Evolutionary biology ,AcademicSubjects/SCI00960 - Abstract
Background Understanding the rate and pattern of germline mutations is of fundamental importance for understanding evolutionary processes. Results Here we analyzed 19 parent-offspring trios of rhesus macaques (Macaca mulatta) at high sequencing coverage of ∼76× per individual and estimated a mean rate of 0.77 × 10−8de novo mutations per site per generation (95% CI: 0.69 × 10−8 to 0.85 × 10−8). By phasing 50% of the mutations to parental origins, we found that the mutation rate is positively correlated with the paternal age. The paternal lineage contributed a mean of 81% of the de novo mutations, with a trend of an increasing male contribution for older fathers. Approximately 3.5% of de novo mutations were shared between siblings, with no parental bias, suggesting that they arose from early development (postzygotic) stages. Finally, the divergence times between closely related primates calculated on the basis of the yearly mutation rate of rhesus macaque generally reconcile with divergence estimated with molecular clock methods, except for the Cercopithecoidea/Hominoidea molecular divergence dated at 58 Mya using our new estimate of the yearly mutation rate. Conclusions When compared to the traditional molecular clock methods, new estimated rates from pedigree samples can provide insights into the evolution of well-studied groups such as primates.
- Published
- 2021
21. Expression patterns and prognostic potential of circular RNAs in mantle cell lymphoma: a study of younger patients from the MCL2 and MCL3 clinical trials
- Author
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Mette, Dahl, Simon, Husby, Christian W, Eskelund, Søren, Besenbacher, Søren, Fjelstrup, Christophe, Côme, Sara, Ek, Arne, Kolstad, Riikka, Räty, Mats, Jerkeman, Christian H, Geisler, Jørgen, Kjems, Lasse S, Kristensen, and Kirsten, Grønbæk
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Male ,Hematopoietic Stem Cell Transplantation ,Lymphoma, Mantle-Cell ,RNA, Circular ,Middle Aged ,Prognosis ,Combined Modality Therapy ,Transplantation, Autologous ,Survival Rate ,Case-Control Studies ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,Humans ,Female ,RNA-Seq ,Follow-Up Studies - Abstract
Mantle cell lymphoma (MCL) is characterized by marked differences in outcome, emphasizing the need for strong prognostic biomarkers. Here, we explore expression patterns and prognostic relevance of circular RNAs (circRNAs), a group of endogenous non-coding RNA molecules, in MCL. We profiled the circRNA expression landscape using RNA-sequencing and explored the prognostic potential of 40 abundant circRNAs in samples from the Nordic MCL2 and MCL3 clinical trials, using NanoString nCounter Technology. We report a circRNA-based signature (circSCORE) developed in the training cohort MCL2 that is highly predictive of time to progression (TTP) and lymphoma-specific survival (LSS). The dismal outcome observed in the large proportion of patients assigned to the circSCORE high-risk group was confirmed in the independent validation cohort MCL3, both in terms of TTP (HR 3.0; P = 0.0004) and LSS (HR 3.6; P = 0.001). In Cox multiple regression analysis incorporating MIPI, Ki67 index, blastoid morphology and presence of TP53 mutations, circSCORE retained prognostic significance for TTP (HR 3.2; P = 0.01) and LSS (HR 4.6; P = 0.01). In conclusion, circRNAs are promising prognostic biomarkers in MCL and circSCORE improves identification of high-risk disease among younger patients treated with cytarabine-containing chemoimmunotherapy and autologous stem cell transplant.
- Published
- 2020
22. A fast algorithm for genome-wide haplotype pattern mining.
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Søren Besenbacher, Christian N. S. Pedersen, and Thomas Mailund
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- 2009
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23. Proteomic profiling identifies outcome-predictive markers in patients with peripheral T-cell lymphoma, not otherwise specified
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Knud Bendix, Tim Svenstrup Poulsen, Bent Honoré, Søren Besenbacher, Martin Bjerregård Pedersen, Stephen Hamilton-Dutoit, Francesco d'Amore, Kristina Lystlund Lauridsen, Michael Boe Møller, Maja Ludvigsen, and Peter Nørgaard
- Subjects
Male ,Proteomics ,0301 basic medicine ,Proteome ,Lymphoid Tissue ,Peripheral T-cell lymphoma not otherwise specified ,Biology ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Tandem Mass Spectrometry ,Biomarkers, Tumor ,medicine ,Humans ,Lymphoid Neoplasia ,Proteomic Profiling ,Aldehyde Dehydrogenase, Mitochondrial ,Tumor Suppressor Proteins ,Not Otherwise Specified ,Computational Biology ,Lymphoma, T-Cell, Peripheral ,Hematology ,Prognosis ,medicine.disease ,Lymphoma ,DNA-Binding Proteins ,030104 developmental biology ,Lymphatic system ,Phosphopyruvate Hydratase ,030220 oncology & carcinogenesis ,Cancer research ,Immunohistochemistry ,Female ,human activities ,Chromatography, Liquid - Abstract
Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) constitutes a heterogeneous category of lymphomas, which do not fit into any of the specifically defined T-cell lymphoma entities. Both the pathogenesis and tumor biology in PTCL-NOS are poorly understood. Protein expression in pretherapeutic PTCL-NOS tumors was analyzed by proteomics. Differentially expressed proteins were compared in 3 distinct scenarios: (A) PTCL-NOS tumor tissue (n = 18) vs benign lymphoid tissue (n = 8), (B) clusters defined by principal component analysis (PCA), and (C) tumors from patients with chemosensitive vs refractory PTCL-NOS. Selected differentially expressed proteins identified by proteomics were correlated with clinico-pathological features and outcome in a larger cohort of patients with PTCL-NOS (n = 87) by immunohistochemistry (IHC). Most proteins with altered expression were identified comparing PTCL-NOS vs benign lymphoid tissue. PCA of the protein profile defined 3 distinct clusters. All benign samples clustered together, whereas PTCL-NOS tumors separated into 2 clusters with different patient overall survival rates (P = .001). Differentially expressed proteins reflected large biological diversity among PTCL-NOS, particularly associated with alterations of “immunological” pathways. The 2 PTCL-NOS subclusters defined by PCA showed disturbance of “stress-related” and “protein metabolic” pathways. α-Enolase 1 (ENO1) was found differentially expressed in all 3 analyses, and high intratumoral ENO1 expression evaluated by IHC correlated with poor outcome (hazard ratio, 2.09; 95% confidence interval, 1.17-3.73; P = .013). High expression of triosephosphate isomerase (TPI1) also showed a tendency to correlate with poor survival (P = .057). In conclusion, proteomic profiling of PTCL-NOS provided evidence of markedly altered protein expression and identified ENO1 as a novel potential prognostic marker.
- Published
- 2018
24. Identifying disease associated genes by network propagation.
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Yu Qian, Søren Besenbacher, Thomas Mailund, and Mikkel Heide Schierup
- Published
- 2014
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25. Prediction of Primary Tumors in Cancers of Unknown Primary
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Søren Besenbacher, Dan Søndergaard, Svend V. Nielsen, and Christian N. S. Pedersen
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Biopsy ,precision medicine ,Metastasis ,03 medical and health sciences ,transcriptomics ,Internal medicine ,Journal Article ,medicine ,Humans ,Tumor biopsy ,Research Articles ,cancer of unknown origin ,Primary (chemistry) ,business.industry ,Gene Expression Profiling ,Diagnostic test ,Cancer ,General Medicine ,medicine.disease ,Primary tumor ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Cancer of unknown primary ,classification ,Unknown primary ,Neoplasms, Unknown Primary ,business ,TP248.13-248.65 ,Biotechnology - Abstract
A cancer of unknown primary (CUP) is a metastatic cancer for which standard diagnostic tests fail to identify the location of the primary tumor. CUPs account for 3–5% of cancer cases. Using molecular data to determine the location of the primary tumor in such cases can help doctors make the right treatment choice and thus improve the clinical outcome. In this paper, we present a new method for predicting the location of the primary tumor using gene expression data: locating cancers of unknown primary (LoCUP). The method models the data as a mixture of normal and tumor cells and thus allows correct classification even in impure samples, where the tumor biopsy is contaminated by a large fraction of normal cells. We find that our method provides a significant increase in classification accuracy (95.8% over 90.8%) on simulated low-purity metastatic samples and shows potential on a small dataset of real metastasis samples with known origin.
- Published
- 2017
26. Association Mapping and Disease: Evolutionary Perspectives
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Søren, Besenbacher, Thomas, Mailund, Bjarni J, Vilhjálmsson, and Mikkel H, Schierup
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Evolution, Molecular ,Models, Statistical ,Gene Frequency ,Models, Genetic ,Chromosome Mapping ,Computational Biology ,Genetic Variation ,Humans ,Confounding Factors, Epidemiologic ,Genetic Predisposition to Disease ,Alleles ,Genome-Wide Association Study - Abstract
In this chapter, we give a short introduction to the genetics of complex diseases emphasizing evolutionary models for disease genes and the effect of different models on the genetic architecture, and we give a survey of the state-of-the-art of genome-wide association studies (GWASs).
- Published
- 2019
27. A novel combined miRNA and methylation marker panel (miMe) for prediction of prostate cancer outcome after radical prostatectomy
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Søren Besenbacher, Karina Dalsgaard Sørensen, Torben F. Ørntoft, Anne K.I. Rasmussen, Michael Borre, Siri H. Strand, Helle Kristensen, Elham Bavafaye‐Haghighi, Søren Høyer, and Peter Mouritzen
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Oncology ,Male ,Cancer Research ,computer.internet_protocol ,PROMOTER ,medicine.medical_treatment ,Kaplan-Meier Estimate ,Cohort Studies ,Prostate cancer ,0302 clinical medicine ,Risk Factors ,Medicine ,BIOCHEMICAL RECURRENCE ,DNA methylation ,microRNA ,Prostatectomy ,Prostate ,Methylation ,Middle Aged ,prostate cancer ,Prognosis ,030220 oncology & carcinogenesis ,Cohort ,Disease Progression ,Biochemical recurrence ,Adult ,medicine.medical_specialty ,VALIDATION ,MIME ,03 medical and health sciences ,Internal medicine ,Biomarkers, Tumor ,Humans ,SIGNATURES ,Aged ,business.industry ,biomarkers ,Prostatic Neoplasms ,Nomogram ,Prostate-Specific Antigen ,medicine.disease ,HYPERMETHYLATION ,MicroRNAs ,Nomograms ,prognosis ,Neoplasm Recurrence, Local ,business ,computer - Abstract
Improved prognostic biomarkers are needed to guide personalized prostate cancer (PC) treatment decisions. Due to the prominent molecular heterogeneity of PC, multimarker panels may be more robust. Here, 25 selected top-candidate miRNA and methylation markers for PC were profiled by qPCR in malignant radical prostatectomy (RP) tissue specimens from 198 PC patients (Cohort 1, training). Using GLMnet, we trained a novel multimarker model (miMe) comprising nine miRNAs and three methylation markers that predicted postoperative biochemical recurrence (BCR) independently of the established clinicopathological CAPRA-S nomogram in Cox multivariate regression analysis in Cohort 1 (HR [95% CI]: 1.53 [1.26-1.84], p < 0.001). This result was successfully validated in two independent RP cohorts (Cohort 2, n = 159: HR [95% CI]: 1.35 [1.06-1.73], p = 0.015. TCGA, n = 350: HR [95% CI]: 1.34 [1.01-1.77], p = 0.04). Notably, in CAPRA-S low-risk patients, a high miMe score was associated with >6 times higher risk of BCR, suggesting that miMe may help identify PC patients at high risk of progression despite favorable clinicopathological factors postsurgery. Finally, miMe was a significant predictor of cancer-specific survival (p = 0.019, log-rank test) in a merged analysis of 357 RP patients. In conclusion, we trained, tested and validated a novel 12-marker panel (miMe) that showed significant independent prognostic value in three RP cohorts. In the future, combining miMe score with existing clinical nomograms may improve PC risk stratification and thus help guide treatment decisions.
- Published
- 2019
28. Hierarchical classification of cancers of unknown primary using multi-omics data
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Britt Elmedal Laursen, Elham Bavafaye Haghighi, Michael Knudsen, and Søren Besenbacher
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0301 basic medicine ,Cancer Research ,somatic variation ,Computer science ,multi-omics data ,medicine.medical_treatment ,Machine learning ,computer.software_genre ,Data type ,lcsh:RC254-282 ,Hierarchical classifier ,Targeted therapy ,Cancer of unknown primary ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Original Research ,business.industry ,Cancer ,Omics ,Missing data ,medicine.disease ,targeted therapy ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,hierarchical classification ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,gene expression ,Multi omics ,Artificial intelligence ,methylation ,business ,computer - Abstract
A cancer of unknown primary (CUP) is a metastatic cancer for which standard diagnostic tests fail to locate the primary cancer. As standard treatments are based on the cancer type, such cases are hard to treat and have very poor prognosis. Using molecular data from the metastatic cancer to predict the primary site can make treatment choice easier and enable targeted therapy. In this article, we first examine the ability to predict cancer type using different types of omics data. Methylation data lead to slightly better prediction than gene expression and both these are superior to classification using somatic mutations. After using 3 data types independently, we notice some differences between the classes that tend to be misclassified, suggesting that integrating the data might improve accuracy. In light of the different levels of information provided by different omics types and to be able to handle missing data, we perform multi-omics classification by hierarchically combining the classifiers. The proposed hierarchical method first classifies based on the most informative type of omics data and then uses the other types of omics data to classify samples that did not get a high confidence classification in the first step. The resulting hierarchical classifier has higher accuracy than any of the single omics classifiers and thus proves that the combination of different data types is beneficial. Our results show that using multi-omics data can improve the classification of cancer types. We confirm this by testing our method on metastatic cancers from the MET500 dataset.
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- 2019
29. Association mapping and disease:Evolutionary perspectives
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Mikkel H. Schierup, Thomas Mailund, Søren Besenbacher, and Anisimova, Maria
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Disease gene ,Association mapping ,Genome-wide association study ,Common disease/common variant ,Disease ,Computational biology ,Biology ,Complex diseases ,Genome-wide association studies ,Genetic architecture ,Genetic association ,Common disease-common variant - Abstract
In this chapter, we give a short introduction to the genetics of complex diseases emphasizing evolutionary models for disease genes and the effect of different models on the genetic architecture, and we give a survey of the state-of-the-art of genome-wide association studies (GWASs).
- Published
- 2019
30. Direct estimation of mutations in great apes reconciles phylogenetic dating
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Mikkel H. Schierup, Christina Hvilsom, Søren Besenbacher, Thomas Mailund, Tomas Marques-Bonet, and Danish Council for Independent Research
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0106 biological sciences ,Mutation rate ,Lineage (genetic) ,Population genetics ,Speciation ,Gorilla ,Biology ,010603 evolutionary biology ,01 natural sciences ,Evolutionary genetics ,Evolution, Molecular ,03 medical and health sciences ,biology.animal ,Animals ,Molecular clock ,Ecology, Evolution, Behavior and Systematics ,Phylogeny ,030304 developmental biology ,0303 health sciences ,Ecology ,Phylogenetic tree ,Human evolutionary genetics ,Fossils ,MOLECULAR CLOCK ,Genetic Variation ,Hominidae ,Biological Evolution ,EVOLUTION ,GENOME ,Phylogenetics ,Evolutionary biology ,Mutation (genetic algorithm) ,Mutation ,Molecular evolution - Abstract
The human mutation rate per generation estimated from trio sequencing has revealed an almost linear relationship with the age of the father and the age of the mother, with fathers contributing about three times as many mutations per year as mothers. The yearly trio-based mutation rate estimate of around 0.43 × 10 is markedly lower than previous indirect estimates of about 1 × 10 per year from phylogenetic comparisons of the great apes calibrated by fossil evidence. This suggests either a slowdown in the accumulation of mutations per year in the human lineage over the past 10 million years or an inaccurate interpretation of the fossil record. Here we inferred de novo mutations in chimpanzee, gorilla, and orangutan parent-offspring trios. Extrapolating the relationship between the mutation rate and the age of parents from humans to these other great apes, we estimated that each species has higher mutation rates per year by factors of 1.50 ± 0.10, 1.51 ± 0.23, and 1.42 ± 0.22 for chimpanzee, gorilla, and orangutan, respectively, and by a factor of 1.48 ± 0.08 for the three species combined. These estimates suggest an appreciable slowdown in the yearly mutation rate in the human lineage that is likely to be recent as genome comparisons almost adhere to a molecular clock. If the nonhuman rates rather than the human rate are extrapolated over the phylogeny of the great apes, we estimate divergence and speciation times that are much more in line with the fossil record and the biogeography., The study was supported by grant number 6108-00385A from the Danish Council for Independent Research | Natural Sciences (to M.H.S.).
- Published
- 2019
31. RBT - a tool for building refined Buneman trees.
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Søren Besenbacher, Thomas Mailund, Lasse Westh-Nielsen, and Christian N. S. Pedersen
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- 2005
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32. Direct estimation of mutations in great apes reveals significant recent human slowdown in the yearly mutation rate
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Christina Hvilsom, Mikkel H. Schierup, Tomas Marques-Bonet, Søren Besenbacher, and Thomas Mailund
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Estimation ,0303 health sciences ,Mutation rate ,Fossil Record ,Phylogenetic tree ,Slowdown ,Gorilla ,Biology ,Divergence ,03 medical and health sciences ,0302 clinical medicine ,Linear relationship ,Evolutionary biology ,biology.animal ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
The human mutation rate per generation estimated from trio sequencing has revealed an almost linear relationship with the age of the father and the age of the mother. The yearly trio-based mutation rate estimate of ~0.43×10−9 is markedly lower than prior indirect estimates of ~1×10−9 per year from phylogenetic comparisons of the great apes. This suggests either a slowdown over the past 10 million years or an inaccurate interpretation of the fossil record. Here we use sequencing of chimpanzee, gorilla and orangutan trios and find that each species has higher estimated mutation rates per year by factors of 1.67+/− 0.22, 1.54+/− 0.2 and 1.84+/− 0.19, respectively. These estimates suggest a very recent and appreciable slowdown in human mutation rate, and, if extrapolated over the great apes phylogeny, yields divergence estimates much more in line with the fossil record and the biogeography.
- Published
- 2018
33. Whole genome association mapping by incompatibilities and local perfect phylogenies.
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Thomas Mailund, Søren Besenbacher, and Mikkel H. Schierup
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- 2006
- Full Text
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34. Whole genome characterization of sequence diversity of 15,220 Icelanders
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Sigurjon A. Gudjonsson, Marteinn T. Hardarson, Michael L. Frigge, Kari Stefansson, Aslaug Jonasdottir, Snaedis Kristmundsdottir, Gisli Masson, Kristjan E. Hjorleifsson, Arnaldur Gylfason, Hannes P. Eggertsson, Thorunn Rafnar, Simon N. Stacey, Florian Zink, Daniel F. Gudbjartsson, Eirikur Hjartarson, Hannes Helgason, Birte Kehr, Olafur Th Magnusson, Agnar Helgason, Patrick Sulem, Einar A. Helgason, Augustine Kong, Søren Besenbacher, Adalbjorg Jonasdottir, Unnur Thorsteinsdottir, Hakon Jonsson, Lucas D. Ward, Gudny A. Arnadottir, Bjarni V. Halldorsson, Læknadeild (HÍ), Faculty of Medicine (UI), Félags- og mannvísindadeild (HÍ), Faculty of Social and Human Sciences (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Félagsvísindasvið (HÍ), School of Social Sciences (UI), Tækni- og verkfræðideild (HR), School of Science and Engineering (RU), Háskóli Íslands, University of Iceland, Háskólinn í Reykjavík, and Reykjavik University
- Subjects
0301 basic medicine ,Statistics and Probability ,Mutation rate ,Data Descriptor ,Erfðabreytileiki ,Iceland ,Population genetics ,Computational biology ,Biology ,Library and Information Sciences ,Genome ,Polymorphism, Single Nucleotide ,DNA sequencing ,Education ,03 medical and health sciences ,INDEL Mutation ,Genetic variation ,Humans ,Erfðafræði ,Indel ,Genetics ,Genome, Human ,Haplotype ,Rare variants ,DNA-rannsóknir ,Computer Science Applications ,030104 developmental biology ,Haplotypes ,False positive rate ,Statistics, Probability and Uncertainty ,Information Systems - Abstract
Understanding of sequence diversity is the cornerstone of analysis of genetic disorders, population genetics, and evolutionary biology. Here, we present an update of our sequencing set to 15,220 Icelanders who we sequenced to an average genome-wide coverage of 34X. We identified 39,020,168 autosomal variants passing GATK filters: 31,079,378 SNPs and 7,940,790 indels. Calling de novo mutations (DNMs) is a formidable challenge given the high false positive rate in sequencing datasets relative to the mutation rate. Here we addressed this issue by using segregation of alleles in three-generation families. Using this transmission assay, we controlled the false positive rate and identified 108,778 high quality DNMs. Furthermore, we used our extended family structure and read pair tracing of DNMs to a panel of phased SNPs, to determine the parent of origin of 42,961 DNMs.
- Published
- 2017
35. A site specific model and analysis of the neutral somatic mutation rate in whole-genome cancer data
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Johanna Bertl, Qianyun Guo, Jakob Skou Pedersen, Morten Muhlig Nielsen, Søren Besenbacher, Henrik Hornshøj, Malene Juul, and Asger Hobolth
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0301 basic medicine ,Epigenomics ,Mutation rate ,Context (language use) ,Computational biology ,Biology ,lcsh:Computer applications to medicine. Medical informatics ,Biochemistry ,Polymorphism, Single Nucleotide ,Genome ,03 medical and health sciences ,Germline mutation ,Mutation Rate ,Structural Biology ,Neoplasms ,Somatic cancer mutations ,Databases, Genetic ,medicine ,Humans ,lcsh:QH301-705.5 ,Molecular Biology ,Multinomial logistic regression ,Genetics ,Replication timing ,Models, Genetic ,Site-specific model ,Genome, Human ,Null model ,Applied Mathematics ,Cancer ,Regression analysis ,medicine.disease ,Expression (mathematics) ,Computer Science Applications ,030104 developmental biology ,lcsh:Biology (General) ,Mutation ,lcsh:R858-859.7 ,Regression Analysis ,Research Article - Abstract
BackgroundDetailed modelling of the neutral mutational process in cancer cells is crucial for identifying driver mutations and understanding the mutational mechanisms that act during cancer development. The neutral mutational process is very complex: whole-genome analyses have revealed that the mutation rate differs between cancer types, between patients and along the genome depending on the genetic and epigenetic context. Therefore, methods that predict the number of different types of mutations in regions or specific genomic elements must consider local genomic explanatory variables. A major drawback of most methods is the need to average the explanatory variables across the entire region or genomic element. This procedure is particularly problematic if the explanatory variable varies dramatically in the element under consideration.ResultsTo take into account the fine scale of the explanatory variables, we model the probabilities of different types of mutations for each position in the genome by multinomial logistic regression. We analyse 505 cancer genomes from 14 different cancer types and compare the performance in predicting mutation rate for both regional based models and site-specific models. We show that for 1000 randomly selected genomic positions, the site-specific model predicts the mutation rate much better than regional based models. We use a forward selection procedure to identify the most important explanatory variables. The procedure identifies site-specific conservation (phyloP), replication timing, and expression level as the best predictors for the mutation rate. Finally, our model confirms and quantifies certain well-known mutational signatures.ConclusionWe find that our site-specific multinomial regression model outperforms the regional based models. The possibility of including genomic variables on different scales and patient specific variables makes it a versatile framework for studying different mutational mechanisms. Our model can serve as the neutral null model for the mutational process; regions that deviate from the null model are candidates for elements that drive cancer development.
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- 2017
36. Variation and association to diabetes in 2000 full mtDNA sequences mined from an exome study in a Danish population
- Author
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Niels Grarup, Rasmus Nielsen, Mikkel H. Schierup, Søren Besenbacher, Oluf Pedersen, Anders Albrechtsen, Jun Wang, Lars Bolund, Karsten Kristiansen, Torben Hansen, Yingrui Li, Thomas Sparsø, Shengting Li, and Thorfinn Sand Korneliussen
- Subjects
medicine.medical_specialty ,Diabetes risk ,Genotype ,Denmark ,Population ,Population genetics ,Biology ,DNA, Mitochondrial ,White People ,Article ,Diabetes mellitus genetics ,Quantitative Trait, Heritable ,Gene Frequency ,Genetic variation ,Diabetes Mellitus ,Genetics ,medicine ,Humans ,Exome ,education ,Allele frequency ,Genetic Association Studies ,Phylogeny ,Genetics (clinical) ,education.field_of_study ,Polymorphism, Genetic ,diabetes ,mtDNA ,Genetic Variation ,Genetics, Population ,Case-Control Studies ,Medical genetics ,population history - Abstract
In this paper, we mine full mtDNA sequences from an exome capture data set of 2000 Danes, showing that it is possible to get high-quality full-genome sequences of the mitochondrion from this resource. The sample includes 1000 individuals with type 2 diabetes and 1000 controls. We characterise the variation found in the mtDNA sequence in Danes and relate the variation to diabetes risk as well as to several blood phenotypes of the controls but find no significant associations. We report 2025 polymorphisms, of which 393 have not been reported previously. These 393 mutations are both very rare and estimated to be caused by very recent mutations but individuals with type 2 diabetes do not possess more of these variants. Population genetics analysis using Bayesian skyline plot shows a recent history of rapid population growth in the Danish population in accordance with the fact that >40% of variable sites are observed as singletons.European Journal of Human Genetics advance online publication, 22 January 2014; doi:10.1038/ejhg.2013.282.
- Published
- 2014
37. Multi-nucleotide de novo Mutations in Humans
- Author
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Daniel F. Gudbjartsson, Unnur Thorsteinsdottir, Gisli Masson, Hannes Helgason, Helgi Kristjansson, Adalbjorg Jonasdottir, Augustine Kong, Olafur Th Magnusson, Agnar Helgason, Aslaug Jonasdottir, Kari Stefansson, Patrick Sulem, and Søren Besenbacher
- Subjects
0301 basic medicine ,Cancer Research ,Mutation rate ,DNA Mutational Analysis ,Genome ,Biochemistry ,Polymerases ,chemistry.chemical_compound ,0302 clinical medicine ,INDEL Mutation ,Mutation Rate ,Genetics (clinical) ,Genetics ,Recombination, Genetic ,Insertion Mutation ,Nucleotides ,Organic Compounds ,High-Throughput Nucleotide Sequencing ,Nucleic acids ,Chemistry ,Mutation (genetic algorithm) ,Physical Sciences ,Cytosine ,Statistics (Mathematics) ,Research Article ,lcsh:QH426-470 ,DNA recombination ,Permutation ,Biology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,DNA-binding proteins ,Confidence Intervals ,Humans ,Insertion ,Allele ,Indel ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Alleles ,Discrete Mathematics ,Genome, Human ,Organic Chemistry ,Chemical Compounds ,Biology and Life Sciences ,Proteins ,DNA ,lcsh:Genetics ,030104 developmental biology ,Pyrimidines ,chemistry ,Combinatorics ,Genetic Loci ,Mutation ,030217 neurology & neurosurgery ,Mathematics - Abstract
Mutation of the DNA molecule is one of the most fundamental processes in biology. In this study, we use 283 parent-offspring trios to estimate the rate of mutation for both single nucleotide variants (SNVs) and short length variants (indels) in humans and examine the mutation process. We found 17812 SNVs, corresponding to a mutation rate of 1.29 × 10−8 per position per generation (PPPG) and 1282 indels corresponding to a rate of 9.29 × 10−10 PPPG. We estimate that around 3% of human de novo SNVs are part of a multi-nucleotide mutation (MNM), with 558 (3.1%) of mutations positioned less than 20kb from another mutation in the same individual (median distance of 525bp). The rate of de novo mutations is greater in late replicating regions (p = 8.29 × 10−19) and nearer recombination events (p = 0.0038) than elsewhere in the genome., Author Summary In each generation new genetic variants are introduced by mutations. In this study we use whole genome sequence data from Icelandic families to directly observe such new mutations. Our estimate of the mutation rate implies that a newborn with 30-year-old parents will on average carry 75 new SNV mutations and 6 new short indel mutations. We observe that some of the found mutations occur much closer together than would be expected by chance. Our analysis shows that mutational hotspots cannot explain this clustering, instead the clustering mutations are likely created by a single mutational event. We observe a different composition for mutations that cluster very close together compared to more distant clustering mutations. This suggests that there is likely more than one type of underlying mutational mechanism creating the multi nucleotide mutation events. We furthermore observe a higher mutation rate near recombination events but find that this effect cannot explain the large number of clustering mutations that we observe.
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- 2016
38. Author Correction: Direct estimation of mutations in great apes reconciles phylogenetic dating
- Author
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Søren Besenbacher, Christina Hvilsom, Thomas Mailund, Tomas Marques-Bonet, and Mikkel H. Schierup
- Subjects
Estimation ,History ,Ecology ,Phylogenetic tree ,language ,Library science ,Catalan ,Ecology, Evolution, Behavior and Systematics ,language.human_language - Abstract
In the version of this article initially published, Tomas Marques-Bonet was missing the following affiliations: Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain; CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain; and Institut Catala de Paleontologia Miquel Crusafont, Universitat Autonoma de Barcelona, Barcelona, Spain. The affiliations have been added in the PDF and HTML versions of the article.
- Published
- 2019
39. Corrigendum: Common variants at 19p13 are associated with susceptibility to ovarian cancer
- Author
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Falk Thiel, Simon A. Gayther, Susan Kruger-Kjaer, Matthias Dürst, Robert M Brown, Thilo Doerk, Martin Gore, James M. Flanagan, Ian Tomlinson, Stephen J. Chanock, Thorunn Rafnar, Susan J. Ramus, Brooke L. Fridley, Jonathan Beesley, Jennifer A. Doherty, Tanya Sher, Jan Lubinski, Ya Yu Tsai, Wendy Brewster, Edwin S. Iversen, Evelyn Despierre, Mary Anne Rossing, Jenny Gross, Stanley B. Kaye, Galina Lurie, Natalia Bogdanova, Douglas A. Levine, Peter A. Fasching, Honglin Song, Patrick Sulem, Anna H. Wu, Angela Brooks-Wilson, Ingo B. Runnebaum, Estrid Høgdall, Natalia Antonenkova, Robert P. Edwards, Kara L. Cushing-Haugen, Francesmary Modugno, Ignace Vergote, Søren Besenbacher, Matthias W. Beckmann, Michael J. Birrer, Anna Jakubowska, Paul D.P. Pharoah, Kirsten B. Moyisch, David Van Den Berg, Steven A. Narod, Anne M. van Altena, Lambertus A. Kiemeney, Andrew Berchuck, Daniel W. Cramer, Arto Leminen, Peter Hillemanns, Alice S. Whittemore, Kunle Odunsi, Beth Y. Karlan, Douglas F. Easton, Diether Lambrechts, T A Sellers, Joellen M. Schildkraut, Heli Nevanlinna, Jolanta Lissowska, Kathryn L. Terry, Robert A. Vierkant, Ralf Bützow, Tuomas Heikkinenen, Jan Blaeker, Katja K.H. Aben, Krzysztof Mędrek, Georgia Chenevix-Trench, Weiva Sieh, Leon F.A.G. Massuger, Maria Notaridou, Linda S. Cook, Montserrat Garcia-Closas, Julie A. Baker, Kari Stefansson, Frédéric Amant, Michael E. Carney, Rachel T. Palmieri, Jacek Gronwald, Catherine M. Phelan, Chu Chen, Claus Høgdall, Pamela J. Thompson, Arif B. Ekici, Xiaoqing Chen, Eva Wozniak, Argyrios Ziogas, Aleksandra Gentry-Maharaj, Daniel Paik, Valerie McGuire, Marc T. Goodman, Ian G. Campbell, Hoda Anton-Culver, Shan Wang-Gohrke, Linda E. Kelemen, Jonathan Tyrer, Julie M. Cunningham, Celeste Leigh Pearce, Penelope M. Webb, Rebecca Hein, Dena G. Hernandez, Kelly L. Bolton, Chris Jones, Patricia G. Moorman, Joanne B. Weidhaas, Nhu D. Le, Daniel O. Stram, Roberta B. Ness, James Paul, Hanna P. Yang, Richard S. Houlston, Ellen L. Goode, Sharon E. Johnatty, and Jenny Chang-Claude
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Genotype ,MEDLINE ,Biology ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,Internal medicine ,Genetics ,medicine ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Humans ,Genetic Predisposition to Disease ,Adaptor Proteins, Signal Transducing ,Oligonucleotide Array Sequence Analysis ,Ovarian Neoplasms ,Genome, Human ,Published Erratum ,Gene Expression Profiling ,Ovary ,Middle Aged ,medicine.disease ,Adenocarcinoma, Mucinous ,Cystadenocarcinoma, Serous ,Endometrial Neoplasms ,030104 developmental biology ,Case-Control Studies ,Female ,Ovarian cancer ,Chromosomes, Human, Pair 19 ,Adenocarcinoma, Clear Cell ,Genome-Wide Association Study - Abstract
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5 × 10⁻⁴ and P = 6 × 10⁻⁴, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3 × 10⁻⁹ and P = 4 × 10⁻¹¹, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.
- Published
- 2016
40. Rate of de novo mutations and the importance of father’s age to disease risk
- Author
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Gudmar Thorleifsson, Patrick Sulem, Asgeir Sigurdsson, Michael L. Frigge, Gunnar Th. Sigurdsson, Daniel F. Gudbjartsson, Kari Stefansson, Adalbjorg Jonasdottir, G. Bragi Walters, Gisli Masson, Sigurjon A. Gudjonsson, Augustine Kong, Olafur T. Magnusson, Unnur Thorsteinsdottir, Stacy Steinberg, Gisli Magnusson, Hannes Helgason, Wendy S.W. Wong, Aslaug Jonasdottir, Søren Besenbacher, Agnar Helgason, and deCODE Genetics, Sturlugata 8, 101 Reykjavik, Iceland.
- Subjects
Adult ,Male ,Mutation rate ,medicine.risk_factor ,Iceland ,Mothers ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,Paternal Age ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Mutation Rate ,Risk Factors ,Polymorphism (computer science) ,medicine ,Chromosomes, Human ,Humans ,Genetic Predisposition to Disease ,Autistic Disorder ,Selection, Genetic ,Young adult ,Paternal age effect ,De novo mutations ,Ovum ,030304 developmental biology ,Genetics ,0303 health sciences ,Multidisciplinary ,Genome, Human ,Sequence Analysis, DNA ,Middle Aged ,medicine.disease ,Spermatozoa ,Human genetics ,Pedigree ,Schizophrenia ,Autism ,Female ,030217 neurology & neurosurgery - Abstract
To access publisher full text version of this article. Please click on the hyperlink in Additional Links field. Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. Here we conduct a study of genome-wide mutation rates by sequencing the entire genomes of 78 Icelandic parent-offspring trios at high coverage. We show that in our samples, with an average father's age of 29.7, the average de novo mutation rate is 1.20 × 10(-8) per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5 years. After accounting for random Poisson variation, father's age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father's age on the risk of diseases such as schizophrenia and autism. National Institutes of Health MH071425 info:eu-repo/grantAgreement/EC/FP7/223423 IAPP-MC-251592 European Community IMI grant EU-AIMS 115300
- Published
- 2012
41. Identification of low-frequency variants associated with gout and serum uric acid levels
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Ole A. Andreassen, Ingileif Jonsdottir, Olafur T. Magnusson, Patrick Sulem, Hafdis T. Helgadottir, Gisli Masson, Jesper Holst Pedersen, Helgi Jonsson, Lambertus A. Kiemeney, Agnar Helgason, G. Bragi Walters, Marieke de Visser, Jona Saemundsdottir, Ari Karason, Sigurjon A. Gudjonsson, Gisli Magnusson, Gudmundur I. Eyjolfsson, Thorunn Rafnar, Isleifur Olafsson, Unnur Thorsteinsdottir, Augustine Kong, Daniel F. Gudbjartsson, Gyda Bjornsdottir, Arni Jon Geirsson, Allan I. Pack, Kari Stefansson, Carlo Zanon, Arnaldur Gylfason, Eirikur Hjartarson, Adalbjorg Jonasdottir, Søren Besenbacher, Hreinn Stefansson, and Hilma Holm
- Subjects
Genetics and epigenetic pathways of disease [NCMLS 6] ,Gout ,Population ,Iceland ,Mutation, Missense ,Biology ,Polymorphism, Single Nucleotide ,Molecular epidemiology [NCEBP 1] ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Humans ,education ,Molecular epidemiology Aetiology, screening and detection [NCEBP 1] ,030304 developmental biology ,030203 arthritis & rheumatology ,0303 health sciences ,education.field_of_study ,Hormonal regulation [IGMD 6] ,Serum uric acid ,nutritional and metabolic diseases ,medicine.disease ,humanities ,Uric Acid ,Immunology ,Disease risk ,Identification (biology) - Abstract
Contains fulltext : 97981.pdf (Publisher’s version ) (Closed access) We tested 16 million SNPs, identified through whole-genome sequencing of 457 Icelanders, for association with gout and serum uric acid levels. Genotypes were imputed into 41,675 chip-genotyped Icelanders and their relatives, for effective sample sizes of 968 individuals with gout and 15,506 individuals for whom serum uric acid measurements were available. We identified a low-frequency missense variant (c.1580C>G) in ALDH16A1 associated with gout (OR = 3.12, P = 1.5 x 10(-16), at-risk allele frequency = 0.019) and serum uric acid levels (effect = 0.36 s.d., P = 4.5 x 10(-21)). We confirmed the association with gout by performing Sanger sequencing on 6,017 Icelanders. The association with gout was stronger in males relative to females. We also found a second variant on chromosome 1 associated with gout (OR = 1.92, P = 0.046, at-risk allele frequency = 0.986) and serum uric acid levels (effect = 0.48 s.d., P = 4.5 x 10(-16)). This variant is close to a common variant previously associated with serum uric acid levels. This work illustrates how whole-genome sequencing data allow the detection of associations between low-frequency variants and complex traits.
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- 2011
42. European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene
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Paolo Vineis, Søren Besenbacher, Giuseppe Matullo, Jennifer H. Barrett, Klaus Golka, Daniel Ovsiannikov, Manuel Sanchez, Vigdis Petursdottir, Kari Stefansson, Maria D. Garcia-Prats, Margaret A. Knowles, Cecilia Arici, Abdolaziz Khezri, Carlo Zanon, Roel A. Ophoff, Lambertus A. Kiemeney, Daniel F. Gudbjartsson, Holger Gerullis, Gudmar Thorleifsson, Peter Rudnai, Jon G. Jonasson, Kvetoslava Koppova, Eirikur Jonsson, Unnur Thorsteinsdottir, Maurice P. Zeegers, D. Timothy Bishop, Hrefna Johannsdottir, Simon N. Stacey, Frank Buntinx, Mahyar Malekzadeh, Leonard H. van den Berg, Petra J. de Verdier, Gerald W. Verhaegh, Eugene Gurzau, Sita H. Vermeulen, Laufey Tryggvadottir, Anne J. Grotenhuis, Carlotta Sacerdote, Angeles Panadero, Gabriel Valdivia, Alireza Aminsharifi, Jacopo Fostinelli, Rajesh Kumar, Stefano Porru, Thorunn Rafnar, Ananya Choudhury, Charlotta Ryk, Daniele Andreoli, Annika Lindblom, Julius Gudmundsson, Katja K.H. Aben, Jan G. Hengstler, Sei Chung-Sak, Gunnar Steineck, Eliane Kellen, Augustine Kong, Faye Elliott, Abbas Ghaderi, José I Sanz-Velez, Christina A. Hulsbergen-van de Kaa, Patrick Sulem, J. Alfred Witjes, Jose I. Mayordomo, Anne E. Kiltie, Silvia Polidoro, Jan H. Veldink, Gudmundur Geirsson, Silvia Selinski, Simonetta Guarrera, Sigfus Nikulasson, Hjordis Bjarnason, Hafdis T. Helgadottir, deCODE Genetics, Sturlugata 8, 101 Reykjavik, Iceland., Complexe Genetica, RS: CAPHRI School for Public Health and Primary Care, and RS: NUTRIM - R4 - Gene-environment interaction
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Male ,LOCI ,Genome-wide association study ,Aetiology, screening and detection [ONCOL 5] ,Cancer risk ,0302 clinical medicine ,Risk Factors ,DNA-REPAIR GENES ,SEQUENCE VARIANTS ,TRANSITIONAL-CELL CARCINOMA ,CONFERS SUSCEPTIBILITY ,Genetics (clinical) ,RISK ,Aged, 80 and over ,Genetics ,0303 health sciences ,Bladder cancer ,Association Studies Articles ,FLUID INTAKE ,genome-wide association ,General Medicine ,Middle Aged ,3. Good health ,Transitional cell carcinoma ,030220 oncology & carcinogenesis ,Disease Progression ,Urinary bladder cancer ,Female ,SMOKING ,Human ,Adult ,Genotype ,European Continental Ancestry Group ,Single-nucleotide polymorphism ,Locus (genetics) ,Biology ,Polymorphism, Single Nucleotide ,White People ,Molecular epidemiology [NCEBP 1] ,Young Adult ,03 medical and health sciences ,Translational research [ONCOL 3] ,medicine ,Humans ,SNP ,Genetic Predisposition to Disease ,1000 Genomes Project ,Molecular Biology ,POLYMORPHISMS ,Molecular epidemiology Aetiology, screening and detection [NCEBP 1] ,Aged ,030304 developmental biology ,Genetic association ,CHINESE POPULATION ,Membrane Transport Proteins ,Reproducibility of Results ,Odds ratio ,medicine.disease ,Urinary Bladder Neoplasms ,Susceptibility ,Genetic Loci ,Chromosomes, Human, Pair 18 ,Genome-Wide Association Study - Abstract
To access publisher full text version of this article. Please click on the hyperlink in Additional Links field. Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC. info:eu-repo/grantAgreement/EC/FP7/018827 info:eu-repo/grantAgreement/EC/FP7/218071 Radboud University Nijmegen Medical Centre (RUNMC) Prinses Beatrix Fonds VSB Fonds National Institute of Mental Health (NIH/NIMH) MH078075 Cancer Research UK Yorkshire Cancer Research European Union 513943 Compagnia di San Paolo-Human Genetics Foundation (HuGeF) Italian Association for Cancer Research, Italy Piedmont Region Progetti di Ricerca Sanitaria Finalizzata Flemish government Belgian province of Limburg Swedish Cancer Society Swedish Research Council Shiraz Institute for Cancer Research Shiraz, Iran ICR-87-502 Red Tematica de Investigacion Cooperativa en Cancer RD06/0020/1054
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- 2011
43. Prognostic miRNA classifier in early-stage mycosis fungoides: Development and validation in a Danish nationwide study
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Claus Johansen, Lars Iversen, Thorbjørn Krejsgaard, Lise M. Lindahl, Anne Hald Rittig, Anders Woetmann, Søren Besenbacher, Pamela Celis, Andreas Willerslev-Olsen, Niels Ødum, Lise Mette Rahbek Gjerdrum, and Thomas Litman
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Skin Neoplasms ,Denmark ,Immunology ,Disease ,Malignancy ,Biochemistry ,03 medical and health sciences ,Mycosis Fungoides ,0302 clinical medicine ,Internal medicine ,microRNA ,Biomarkers, Tumor ,Journal Article ,medicine ,Humans ,Progression-free survival ,Neoplasm Staging ,Mycosis fungoides ,Proportional hazards model ,business.industry ,Cell Biology ,Hematology ,Prognosis ,medicine.disease ,Progression-Free Survival ,Lymphoma ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cohort ,Disease Progression ,Transcriptome ,business ,Classifier (UML) - Abstract
Mycosis fungoides (MF) is the most frequent form of cutaneous T-cell lymphoma. The disease often takes an indolent course, but in approximately one-third of the patients, the disease progresses to an aggressive malignancy with a poor prognosis. At the time of diagnosis, it is impossible to predict which patients develop severe disease and are in need of aggressive treatment. Accordingly, we investigated the prognostic potential of microRNAs (miRNAs) at the time of diagnosis in MF. Using a quantitative reverse transcription polymerase chain reaction platform, we analyzed miRNA expression in diagnostic skin biopsies from 154 Danish patients with early-stage MF. The patients were subdivided into a discovery cohort (n = 82) and an independent validation cohort (n = 72). The miRNA classifier was built using a LASSO (least absolute shrinkage and selection operator) Cox regression to predict progression-free survival (PFS). We developed a 3-miRNA classifier, based on miR-106b-5p, miR-148a-3p, and miR-338-3p, which successfully separated patients into high-risk and low-risk groups of disease progression. PFS was significantly different between these groups in both the discovery cohort and the validation cohort. The classifier was stronger than existing clinical prognostic factors and remained a strong independent prognostic tool after stratification and adjustment for these factors. Importantly, patients in the high-risk group had a significantly reduced overall survival. The 3-miRNA classifier is an effective tool to predict disease progression of early-stage MF at the time of diagnosis. The classifier adds significant prognostic value to existing clinical prognostic factors and may facilitate more individualized treatment of these patients.
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- 2018
44. 531 Prognostic miRNA classifier in early-stage mycosis fungoides: Development and validation in a Danish nationwide study
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Søren Besenbacher, Lise M. Lindahl, Anne Hald Rittig, Claus Johansen, Lars Iversen, and Niels Ødum
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Oncology ,Mycosis fungoides ,medicine.medical_specialty ,business.industry ,Cell Biology ,Dermatology ,medicine.disease ,Biochemistry ,language.human_language ,Danish ,Internal medicine ,medicine ,language ,business ,Molecular Biology ,Classifier (UML) - Published
- 2018
45. A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer
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Gunnar Steineck, Michael A. van Es, Eliane Kellen, Augustine Kong, Faye Elliott, Giuseppe Matullo, Carolyn D. Hurst, Margaret A. Knowles, Maurice P. Zeegers, Gerald W. Verhaegh, Simonetta Guarrera, Kristleifur Kristjansson, Rajesh Kumar, Sei C. Sak, Jennifer H. Barrett, N. Aydin Mungan, Charlotta Ryk, Berta Saez Gutierrez, Thorunn Rafnar, Annika Lindblom, Maria D. Garcia-Prats, Cecilia Arici, Stefan T Palsson, Patrick Sulem, Oskar B Skarphedinsson, Lambertus A. Kiemeney, Julius Gudmundsson, Gudmundur Geirsson, Unnur Thorsteinsdottir, Jan G. Hengstler, Petra J. de Verdier, Sigfus Nikulasson, Sita H. Vermeulen, Marcello Campagna, Carlotta Sacerdote, Gabriel Valdivia, D. Timothy Bishop, Silvia Polidoro, Anne E. Kiltie, Sigurjon A. Gudjonsson, Katja K H Aben, Asgeir Sigurdsson, Anne J. Grotenhuis, Peter Rudnai, Leonard H. van den Berg, Thorgeir E. Thorgeirsson, Roel A. Ophoff, Daniel F. Gudbjartsson, Eirikur Jonsson, J. Alfred Witjes, José I Sanz-Velez, Klaus Golka, Søren Besenbacher, Paolo Vineis, Kari Stefansson, Gisli Masson, Stefano Porru, Carlo Zanon, Ananya Choudhury, Holger Dietrich, Vigdis Petursdottir, Jelena Kostic, Frank Buntinx, Donatella Placidi, Jose I. Mayordomo, Meinolf Blaszkewicz, Kristin Alexiusdottir, Manuel Sanchez-Zalabardo, Gudmar Thorleifsson, Kvetoslava Koppova, Simon N. Stacey, Eugene Gurzau, Hjordis Bjarnason, Complexe Genetica, Family Medicine, RS: CAPHRI School for Public Health and Primary Care, RS: NUTRIM - R4 - Gene-environment interaction, Genetica & Celbiologie, Zonguldak Bülent Ecevit Üniversitesi, and Department of Epidemiology, Biostatistics and Health Technology Assessment, Nijmegen, The Netherlands. b.kiemeney@ebh.umcn.nl
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Male ,Somatic cell ,Genome-wide association study ,Aetiology, screening and detection [ONCOL 5] ,medicine.disease_cause ,Germline ,DISEASE ,0302 clinical medicine ,Recurrence ,Genotype ,Genetics ,RISK ,0303 health sciences ,Mutation ,Manchester Cancer Research Centre ,Smoking ,Urinary Bladder Neoplasms/genetics ,3. Good health ,Receptor, Fibroblast Growth Factor, Type 3/genetics ,Europe ,030220 oncology & carcinogenesis ,bladder cancer ,Female ,Chromosomes, Human, Pair 4 ,Risk ,EXPRESSION ,medicine.medical_specialty ,genome-wide association study ,FGFR3 ,Urology ,Biology ,Article ,Disease-Free Survival ,Molecular epidemiology [NCEBP 1] ,03 medical and health sciences ,Text mining ,Translational research [ONCOL 3] ,medicine ,UROTHELIAL CELL-CARCINOMA ,Humans ,Receptor, Fibroblast Growth Factor, Type 3 ,Genetic Predisposition to Disease ,Allele ,Alleles ,Sequence (medicine) ,030304 developmental biology ,Bladder cancer ,Models, Genetic ,Urinary Bladder Cancer ,business.industry ,ResearchInstitutes_Networks_Beacons/mcrc ,fungi ,Genetic Variation ,Cancer ,medicine.disease ,Neck of urinary bladder ,Urinary Bladder Neoplasms ,Evaluation of complex medical interventions [NCEBP 2] ,FGFR3 MUTATIONS ,business - Abstract
Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 × 10 12). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC. © 2010 Nature America, Inc. All rights reserved., Vlaamse regering 513943 Compagnia di San Paolo Yorkshire Cancer Research Adessium Foundation European Commission: LSHC-CT-2005 218071 Associazione Italiana per la Ricerca sul Cancro Prinses Beatrix Spierfonds, We thank the individuals who participated in the study and whose contribution made this work possible. We also thank the nurses at deCODE’s recruitment center and the personnel at the deCODE core facilities. We acknowledge the Icelandic Cancer Registry for assistance in the ascertainment of the Icelandic UBC cases. C.Z. and S.B. are funded by a FP7-MC-IAPP Grant agreement no. 218071 (CancerGene). Collection of samples and data in Iceland and The Netherlands was funded in part by the European Commission (POLYGENE: LSHC-CT-2005) and a research investment grant of the Radboud University Nijmegen Medical Centre. Control samples for the Dutch follow-up group were genotyped with generous support from the ‘Prinses Beatrix Fonds’, VSB Fonds, H. Kersten and M. Kersten (Kersten Foundation), The Netherlands ALS Foundation, J.R. van Dijk and the Adessium foundation. The controls from the Dutch Schizophrenia GWA study were genotyped with the support of the US National Institute of Mental Health (R.A.O.). The Leeds Bladder Cancer Study was funded by Cancer Research UK and Yorkshire Cancer Research. The Torino Bladder Cancer Case Control Study was supported by a grant to ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating within the European Union Sixth Framework Program, Priority 5:‘Food Quality and Safety’ (Contract No. 513943), and by grants of the Compagnia di San Paolo, of the Italian Association for Cancer Research and of the Piedmont Region Progetti de Ricerca Sanitaria Finalizzata, Italy. The Belgian case-control study on bladder cancer risk was supported by a grant of the Flemish government, the government of the Belgian province of Limburg and the Limburg Cancer Fund., 1Department of Epidemiology, Biostatistics and Health Technology Assessment and 2Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 3Comprehensive Cancer Center East, Nijmegen, The Netherlands. 4deCODE Genetics, Reykjavik, Iceland. 5Section of Epidemiology and Biostatistics and 6Section of Experimental Oncology, Leeds Institute of Molecular Medicine, St. James’s University Hospital, Leeds, UK. 7Christie Hospital National Health Service Foundation Trust, Manchester, UK. 8Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. 9National Institute of Environmental Health, Budapest, Hungary. 10Environmental Health Centre, Cluj-Napoca, Romania. 11State Health Institute, Banska Bystrica, Slovakia. 12Institute for Scientific Interchange (ISI) Foundation, Torino, Italy. 13Department of Epidemiology and Public Health, Imperial College, London, UK. 14Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy. 15Unit of Cancer Epidemiology, University of Torino, Torino, Italy. 16Centre for Cancer Epidemiology and Prevention (CPO Piemonte), Torino, Italy. 17Department of Experimental and Applied Medicine, Section of Occupational Medicine and Industrial Hygiene, University of Brescia, Brescia, Italy. 18Unit of Genetic Epidemiology, Department of Public Health and Epidemiology, University of Birmingham, Birmingham, UK. 19Department of Complex Genetics, Cluster of Genetics and Cell Biology, Nutrition and Toxicology Research Institute, Maastricht University, Maastricht, The Netherlands. 20Leuven University Centre for Cancer Prevention (LUCK), Leuven, Belgium. 21Department of Medicine, University of Zaragoza, Zaragoza, Spain. 22Division of Urology, San Jorge Hospital, Huesca, Spain. 23Division of Urology, Hospital Clinico, Zaragoza, Spain. 24Department of Urology, University of Zaragoza School of Medicine, Zaragoza, Spain. 25Division of Surgical Pathology, San Jorge Hospital, Huesca, Spain. 26Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany. 27Department of Urology, Paul Gerhardt Foundation, Lutherstadt Wittenberg, Germany. 28Department of Medical Genetics, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands. 29University of California Los Angeles Center for Neurobehavioral Genetics, Los Angeles, USA. 30Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands. 31Department of Medical Oncology, 32Department of Urology and 33Department of Pathology, Landspitali–University Hospital, Reykjavik, Iceland. 34Department of Urology, Zonguldak Karaelmas University, Zonguldak, Turkey. 35Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. 36Department of General Practice, Catholic University of Leuven, Leuven, Belgium. 37Department of General Practice, Maastricht University, Maastricht, The Netherlands. 38Division of Medical Oncology, University of Zaragoza, Zaragoza, Spain. 39Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany. 40Section of Clinical Cancer Epidemiology, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. 41Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, Gothenburg, Sweden. 42Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK. 43Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 44These authors contributed equally to this work. Correspondence should be addressed to L.A.K. (b.kiemeney@ebh.umcn.nl) or K.S. (kstefans@decode.is).
- Published
- 2010
46. Local Phylogeny Mapping of Quantitative Traits: Higher Accuracy and Better Ranking Than Single-Marker Association in Genomewide Scans
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Søren Besenbacher, Mikkel H. Schierup, and Thomas Mailund
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Genetic Markers ,Genetics ,Linkage disequilibrium ,Models, Genetic ,Quantitative Trait Loci ,Chromosome Mapping ,Genome-wide association study ,Investigations ,Quantitative trait locus ,Biology ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,Data set ,Set (abstract data type) ,Ranking ,Databases, Genetic ,Computer Simulation ,Spurious relationship ,Cluster analysis ,Phylogeny ,Software ,Genome-Wide Association Study - Abstract
We present a new method, termed QBlossoc, for linkage disequilibrium (LD) mapping of genetic variants underlying a quantitative trait. The method uses principles similar to a previously published method, Blossoc, for LD mapping of case/control studies. The method builds local genealogies along the genome and looks for a significant clustering of quantitative trait values in these trees. We analyze its efficiency in terms of localization and ranking of true positives among a large number of negatives and compare the results with single-marker approaches. Simulation results of markers at densities comparable to contemporary genotype chips show that QBlossoc is more accurate in localization of true positives as expected since it uses the additional information of LD between markers simultaneously. More importantly, however, for genomewide surveys, QBlossoc places regions with true positives higher on a ranked list than single-marker approaches, again suggesting that a true signal displays itself more strongly in a set of adjacent markers than a spurious (false) signal. The method is both memory and central processing unit (CPU) efficient. It has been tested on a real data set of height data for 5000 individuals measured at ∼317,000 markers and completed analysis within 5 CPU days.
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- 2009
47. The Proteome of Seed Development in the Model Legume Lotus japonicus
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Søren Besenbacher, Jens Stougaard, Ida B. Thøgersen, Svend Dam, Brian Søgaard Laursen, Bjarne Jochimsen, Nicolas Goffard, Jan J. Enghild, Jane H. Ørnfelt, Lene Krusell, Hans Henrik Stærfeldt, Carsten Friis, Satoshi Tabata, Shusei Sato, and Kasper Nielsen
- Subjects
Medicago ,biology ,Physiology ,fungi ,Lotus ,Lotus japonicus ,food and beverages ,Plant Science ,biology.organism_classification ,Pisum ,Endosperm ,Proteome ,Botany ,Genetics ,Lotus corniculatus ,Legume - Abstract
We have characterized the development of seeds in the model legume Lotus japonicus. Like soybean (Glycine max) and pea (Pisum sativum), Lotus develops straight seed pods and each pod contains approximately 20 seeds that reach maturity within 40 days. Histological sections show the characteristic three developmental phases of legume seeds and the presence of embryo, endosperm, and seed coat in desiccated seeds. Furthermore, protein, oil, starch, phytic acid, and ash contents were determined, and this indicates that the composition of mature Lotus seed is more similar to soybean than to pea. In a first attempt to determine the seed proteome, both a two-dimensional polyacrylamide gel electrophoresis approach and a gel-based liquid chromatography-mass spectrometry approach were used. Globulins were analyzed by two-dimensional polyacrylamide gel electrophoresis, and five legumins, LLP1 to LLP5, and two convicilins, LCP1 and LCP2, were identified by matrix-assisted laser desorption ionization quadrupole/time-of-flight mass spectrometry. For two distinct developmental phases, seed filling and desiccation, a gel-based liquid chromatography-mass spectrometry approach was used, and 665 and 181 unique proteins corresponding to gene accession numbers were identified for the two phases, respectively. All of the proteome data, including the experimental data and mass spectrometry spectra peaks, were collected in a database that is available to the scientific community via a Web interface (http://www.cbs.dtu.dk/cgi-bin/lotus/db.cgi). This database establishes the basis for relating physiology, biochemistry, and regulation of seed development in Lotus. Together with a new Web interface (http://bioinfoserver.rsbs.anu.edu.au/utils/PathExpress4legumes/) collecting all protein identifications for Lotus, Medicago, and soybean seed proteomes, this database is a valuable resource for comparative seed proteomics and pathway analysis within and beyond the legume family.
- Published
- 2009
48. Large-scale whole-genome sequencing of the Icelandic population
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Gisli Masson, Einar Björnsson, Hrefna Johannsdottir, Hilma Holm, Bjarni Thjodleifsson, Arnaldur Gylfason, Olafur Th Magnusson, Agnar Helgason, Asmundur Oddson, Gudmundur I. Eyjolfsson, Thora Steingrimsdottir, Thora S. Gudmundsdottir, Thorunn Rafnar, Augustine Kong, Asgeir Sigurdsson, Unnur Thorsteinsdottir, Hafdis T. Helgadottir, Sigurjon A. Gudjonsson, Olof Sigurdardottir, Søren Besenbacher, Eirikur Hjartarson, Simon N. Stacey, Daniel F. Gudbjartsson, Jon G. Jonasson, Florian Zink, David O. Arnar, Jon Th. Sverrisson, Gunnlaugur Sigfússon, Kari Stefansson, Gunnar Th. Sigurdsson, Petur Ludvigsson, G. Bragi Walters, Hildur Thorarinsdottir, Isleifur Olafsson, Ásgeir Theodórs, Hakon Gudbjartsson, Sigurdur Olafsson, Gyda Bjornsdottir, Patrick Sulem, Michael L. Frigge, Solveig Gretarsdottir, Hannes Helgason, Gisli Magnusson, Jon J. Jonsson, Bjarni V. Halldorsson, Ólafur Thorarensen, Jona Saemundsdottir, and Gudmundur Thorgeirsson
- Subjects
Male ,Risk ,ATP Binding Cassette Transporter, Subfamily B ,Myosin Light Chains ,Hearing Loss, Sensorineural ,Population ,Bulbar Palsy, Progressive ,Iceland ,Thyrotropin ,Genome-wide association study ,Single-nucleotide polymorphism ,Biology ,Genome ,Polymorphism, Single Nucleotide ,Frameshift mutation ,Receptors, G-Protein-Coupled ,Gene Frequency ,INDEL Mutation ,Atrial Fibrillation ,Genetics ,Chromogranins ,GTP-Binding Protein alpha Subunits, Gs ,Humans ,Genetic Predisposition to Disease ,education ,Frameshift Mutation ,P-Glycoproteins ,Allele frequency ,Aged ,Whole genome sequencing ,Aged, 80 and over ,education.field_of_study ,Genome, Human ,Liver Diseases ,Molecular Sequence Annotation ,Sequence Analysis, DNA ,Middle Aged ,Minor allele frequency ,Phylogeography ,Female ,Genome-Wide Association Study - Abstract
Here we describe the insights gained from sequencing the whole genomes of 2,636 Icelanders to a median depth of 20×. We found 20 million SNPs and 1.5 million insertions-deletions (indels). We describe the density and frequency spectra of sequence variants in relation to their functional annotation, gene position, pathway and conservation score. We demonstrate an excess of homozygosity and rare protein-coding variants in Iceland. We imputed these variants into 104,220 individuals down to a minor allele frequency of 0.1% and found a recessive frameshift mutation in MYL4 that causes early-onset atrial fibrillation, several mutations in ABCB4 that increase risk of liver diseases and an intronic variant in GNAS associating with increased thyroid-stimulating hormone levels when maternally inherited. These data provide a study design that can be used to determine how variation in the sequence of the human genome gives rise to human diversity.
- Published
- 2014
49. Pathway Analysis of Skin from Psoriasis Patients after Adalimumab Treatment Reveals New Early Events in the Anti-Inflammatory Mechanism of Anti-TNF-α
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Søren Besenbacher, Claus Johansen, Ane Langkilde, Lars Iversen, Line Raaby, Lene Christin Olsen, Pål Sætrom, and Finn Drabløs
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0301 basic medicine ,Chemokine ,Time Factors ,Cytokine Receptors ,Biopsy ,Anti-Inflammatory Agents ,Gene Expression ,lcsh:Medicine ,Immune Receptors ,Biochemistry ,White Blood Cells ,Animal Cells ,Medicine and Health Sciences ,lcsh:Science ,Oligonucleotide Array Sequence Analysis ,Skin ,Platelet-Derived Growth Factor ,Regulation of gene expression ,Principal Component Analysis ,Immune System Proteins ,Multidisciplinary ,biology ,medicine.diagnostic_test ,T Cells ,Chemotaxis ,Middle Aged ,Cell Motility ,Cytokines ,Anatomy ,Chemokines ,Cellular Types ,medicine.symptom ,Research Article ,Signal Transduction ,medicine.drug ,Adult ,medicine.medical_specialty ,Histology ,Immune Cells ,Immunology ,Surgical and Invasive Medical Procedures ,Inflammation ,Hematopoietic Cell Growth Factors ,Autoimmune Diseases ,03 medical and health sciences ,Psoriasis ,Genetics ,medicine ,Adalimumab ,Humans ,Gene Regulation ,Receptors, Cytokine ,KEGG ,Aged ,Blood Cells ,Tumor Necrosis Factor-alpha ,business.industry ,Microarray analysis techniques ,lcsh:R ,Biology and Life Sciences ,Proteins ,Cell Biology ,medicine.disease ,Dermatology ,030104 developmental biology ,biology.protein ,Clinical Immunology ,lcsh:Q ,Clinical Medicine ,business - Abstract
Psoriasis is a chronic cutaneous inflammatory disease. The immunopathogenesis is a complex interplay between T cells, dendritic cells and the epidermis in which T cells and dendritic cells maintain skin inflammation. Anti-tumour necrosis factor (anti-TNF)-α agents have been approved for therapeutic use across a range of inflammatory disorders including psoriasis, but the anti-inflammatory mechanisms of anti-TNF-α in lesional psoriatic skin are not fully understood. We investigated early events in skin from psoriasis patients after treatment with anti-TNF-α antibodies by use of bioinformatics tools. We used the Human Gene 1.0 ST Array to analyse gene expression in punch biopsies taken from psoriatic patients before and also 4 and 14 days after initiation of treatment with the anti-TNF-α agent adalimumab. The gene expression was analysed by gene set enrichment analysis using the Functional Annotation Tool from DAVID Bioinformatics Resources. The most enriched pathway was visualised by the Pathview Package on Kyoto Encyclopedia of Genes and Genomes (KEGG) graphs. The analysis revealed new very early events in psoriasis after adalimumab treatment. Some of these events have been described after longer periods of anti-TNF-α treatment when clinical and histological changes appear, suggesting that effects of anti-TNF-α treatment on gene expression appear very early before clinical and histological changes. Combining microarray data on biopsies from psoriasis patients with pathway analysis allowed us to integrate in vitro findings into the identification of mechanisms that may be important in vivo. Furthermore, these results may reflect primary effect of anti-TNF-α treatment in contrast to studies of gene expression changes following clinical and histological changes, which may reflect secondary changes correlated to the healing of the skin.
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- 2016
50. A common biological basis of obesity and nicotine addiction
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Peter Kovacs, Angela Döring, Frank Geller, Lenka Foretova, Dana Mates, Paul M. Ridker, Francesco Mauri, Mark J. Caulfield, Nora Franceschini, Neonilia Szeszenia-Dabrowska, Toshiko Tanaka, Pagona Lagiou, Jennifer E. Huffman, Paul Scheet, Gudmar Thorleifsson, Jacqueline M. Vink, Nicole Vogelzangs, Ida Surakka, Jeffrey R. Gulcher, Ulrich John, Veikko Salomaa, Eco J. C. de Geus, Hakon Hakonarson, Anne Barton, Luigi Barzan, H.-Erich Wichmann, Anneli Pouta, Peter Vollenweider, Kristina Kjærheim, Jed E. Rose, Ruth J. F. Loos, Susanne Lucae, Danielle Posthuma, Henning Tiemeier, Fangyi Gu, Mark I. McCarthy, Unnur Styrkarsdottir, James McKay, Talin Haritunians, Martin Preisig, Olle Melander, Xavier Castellsagué, William H. Matthai, Piera Angelica Merlini, Daniel I. Chasman, Michael Stumvoll, Ozren Polasek, Nilesh J. Samani, Søren Besenbacher, Jane Worthington, Daniel F. Gudbjartsson, Alistair S. Hall, Antonio Agudo, Keith Matthews, Gonçalo R. Abecasis, Jaana Laitinen, Norbert Dahmen, Robert W. Mahley, Mari Nelis, Inga Prokopenko, Anke Tönjes, Iris H Gudjonsdottir, Joshua W. Knowles, Jing Hua Zhao, Jouke-Jan Hottenga, Vincent Mooser, Jack Satsangi, Cristina Canova, Stephen P. Fortmann, Hreinn Stefansson, Manuela Uda, T. Brueckl, Mary Susan Burnett, Michael Boehnke, Veronique Vitart, Philip J. Barter, Ruth McPherson, Benjamin F. Voight, Patrick F. Sullivan, Pier Mannuccio Mannucci, Michael Wittig, Kari Stefansson, Lowell F. Satler, Eric Boerwinkle, Benjamin J. Wright, Ben A. Oostra, John Strauss, Stefania Bandinelli, S. Horstmann, Jonathan Marchini, Simone Benhamou, Stephen E. Epstein, Rajesh Rawal, Vladimir Janout, Miles Parkes, Liming Qu, Yuri Milaneschi, Peter Almgren, Kaisu Keskitalo, Matti Isohanni, Dan Rujescu, John P. A. Ioannidis, Peter Rudnai, Stefan Walter, Diego Ardissino, John B. Vincent, Leif Groop, Kent D. Taylor, Christopher J. O'Donnell, Christopher W. Knouff, David I. Conway, Thomas Quertermous, Joseph M. Lindsay, Stephen M. Schwartz, Tariq Ahmed, Jolanta Lissowska, Evan L. Thacker, Igor Rudan, Sreekumar G. Pillai, Janet Audrain-McGovern, Daniel Levy, S. Kathiresan, Timothy M. Frayling, Brenda W.J.H. Penninx, Shen Huei-Yi, Johannes H. Smit, Gonneke Willemsen, Henry Völzke, John R. B. Perry, Federica Tozzi, Roberto Elosua, Devin Absher, G B Walters, Augusto D. Pichard, Stephen J. Chanock, Katja K.H. Aben, Anna-Liisa Hartikainen, Maria Krestyaninova, Ivana Holcatova, Tim D. Spector, Ming D. Li, Xiangjun Xiao, Barbara McKnight, Hans J. Grabe, Martin den Heijer, Caroline Hayward, Unnur Thorsteinsdottir, Douglas F. Levinson, Claes Ladenvall, Robert L. Wilensky, Danyu Lin, Nicole Soranzo, Lefkos T. Middleton, Jason S. Liu, Wade H. Berrettini, Laura M. Thornton, Muredach P. Reilly, Jack M. Guralnik, Ron Waksman, Per Bakke, Alan F. Wright, Andre Franke, Thorgeir E. Thorgeirsson, Barbara Nitz, Anthony J. Balmforth, Jaspal S. Kooner, Gavin Lucas, Esther H. Lips, Helena Furberg, Albert Hofman, Patrick Sulem, Astrid Petersmann, Ivana Kolcic, Jaakko Tuomilehto, Lorenzo Richiardi, Pablo V. Gejman, Claire J. Steves, Thorarinn Tyrfingsson, Yurii S. Aulchenko, Brendan M. Everett, Ariana Znaor, Maxine Allen, Thorunn Rafnar, Mark Lathrop, Reedik Mägi, Kenneth M. Kent, M. Perola, Nicholas J. Wareham, Daniel J. Rader, John R. Thompson, Sarah R. Preis, Peter Kraft, Caryn Lerman, Hogni Oskarsson, Alan R. Sanders, Alexander Teumer, Xin Yuan, Cornelia M. van Duijn, Samuli Ripatti, André G. Uitterlinden, Carl A. Anderson, Martin Farrall, Kay-Tee Khaw, Joachim Heinrich, Heather M. Stringham, Bruce M. Psaty, Jaakko Kaprio, Valgerdur Steinthorsdottir, Steve Eyre, James F. Wilson, David J. Hunter, Johannes Kettunen, Wendy Thomson, Antero Kesäniemi, Karen L. Mohlke, Christian Gieger, Tatiana V. Macfarlane, Jubao Duan, Anne Farmer, Clyde Francks, Joshua C. Bis, Harry Campbell, Pierandrea Muglia, Andres Metspalu, Dawn M. Waterworth, Ramachandran S. Vasan, Hermine H. Maes, David Zaridze, Luisa Bernardinelli, Vladimir Bencko, Massimo Mangino, Lambertus A. Kiemeney, Solveig Gretarsdottir, Tõnu Esko, Anne U. Jackson, Claire M. Healy, Scott M. Grundy, David St Clair, Curt D. Furberg, Mingyao Li, Peter McGuffin, Christopher G. Mathew, David Altshuler, Dorret I. Boomsma, Susan Campbell, Jianxin Shi, Najaf Amin, James L. Kennedy, Ana M. Valdes, Anna F. Dominiczak, Themistocles L. Assimes, Susan E. Hankinson, Inês Barroso, Marjo-Riitta Järvelin, Guillaume Paré, Joe Devaney, Antonio Terracciano, David Schlessinger, Paul Brennan, Shih-Jen Hwang, Luigi Ferrucci, Ray Lowry, Jennifer Dackor, Eleonora Fabianova, Lina Zgaga, Emelia J. Benjamin, Fabio Busonero, Sarah H. Wild, Patricia B. Munroe, John C. Chambers, Carlos Iribarren, Marcus Ising, Yunjung Kim, Richard O. Day, Amund Gulsvik, Gérard Waeber, Claudia Lamina, Arne Schäfer, Functional Genomics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Hjelt Institute (-2014), Department of Public Health, Institute for Molecular Medicine Finland, Genetic Epidemiology, Human genetics, and NCA - Neurobiology of mental health
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obesity ,FOOD-INTAKE ,TAG Consortium ,medicine.medical_treatment ,Oxford-GSK Consortium ,LOCI ,Iceland ,Aetiology, screening and detection [ONCOL 5] ,VARIANTS ,3124 Neurology and psychiatry ,Nicotine ,0302 clinical medicine ,DEPENDENCE ,030212 general & internal medicine ,Age of Onset ,ENGAGE consortium ,POPULATION ,Addiction ,Body Mass Index ,Nicotine dependence ,Smoking ,media_common ,Psychiatry ,2. Zero hunger ,0303 health sciences ,education.field_of_study ,ASSOCIATION ,Tobacco Use Disorder ,DSM-V ,CANCER ,3142 Public health care science, environmental and occupational health ,3. Good health ,Psychiatry and Mental health ,Meta-analysis ,Original Article ,addiction ,Life Sciences & Biomedicine ,medicine.drug ,medicine.medical_specialty ,media_common.quotation_subject ,Population ,body mass index ,Polymorphism, Single Nucleotide ,smoking ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,SDG 3 - Good Health and Well-being ,Internal medicine ,medicine ,Humans ,SMOKING-BEHAVIOR ,nicotine dependence ,education ,Biological Psychiatry ,Molecular epidemiology Aetiology, screening and detection [NCEBP 1] ,030304 developmental biology ,Science & Technology ,business.industry ,Appetite ,medicine.disease ,Obesity ,BODY-MASS INDEX ,Behavior, Addictive ,Endocrinology ,Smoking cessation ,business ,Body mass index - Abstract
Contains fulltext : 128630.pdf (Publisher’s version ) (Open Access) Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34,216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 x 10(-7)). These findings replicate in a second large data set (N=127,274, thereof 76,242 smokers) for both SI (P=1.2 x 10(-5)) and CPD (P=9.3 x 10(-5)). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity.
- Published
- 2013
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