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2. Reducing pervasive false positive identical-by-descent segments detected by large-scale pedigree analysis

Author

Durand, Eric Y., Eriksson, Nicholas, and McLean, Cory Y.

Subjects
Quantitative Biology - Populations and Evolution, Quantitative Biology - Genomics
Abstract

Analysis of genomic segments shared identical-by-descent (IBD) between individuals is fundamental to many genetic applications, from demographic inference to estimating the heritability of diseases, but IBD detection accuracy in non-simulated data is largely unknown. In principle, it can be evaluated using known pedigrees, as IBD segments are by definition inherited without recombination down a family tree. We extracted 25,432 genotyped European individuals containing 2,952 father-mother-child trios from the 23andMe, Inc. dataset. We then used GERMLINE, a widely used IBD detection method, to detect IBD segments within this cohort. Exploiting known familial relationships, we identified a false positive rate over 67% for 2-4 centiMorgan (cM) segments, in sharp contrast with accuracies reported in simulated data at these sizes. Nearly all false positives arose from the allowance of haplotype switch errors when detecting IBD, a necessity for retrieving long (> 6 cM) segments in the presence of imperfect phasing. We introduce HaploScore, a novel, computationally efficient metric that scores IBD segments proportional to the number of switch errors they contain. Applying HaploScore filtering to the IBD data at a precision of 0.8 produced a 13-fold increase in recall when compared to length-based filtering. We replicate the false IBD findings and demonstrate the generalizability of HaploScore to alternative data sources using an independent cohort of 555 European individuals from the 1000 Genomes project. HaploScore can improve the accuracy of segments reported by any IBD detection method, provided that estimates of the genotyping error rate and switch error rate are available., Comment: 35 pages, 16 figures

Published
2013

3. Higher Levels of Neanderthal Ancestry in East Asians than in Europeans

Author

Wall, Jeffrey D, Yang, Melinda A, Jay, Flora, Kim, Sung K, Durand, Eric Y, Stevison, Laurie S, Gignoux, Christopher, Woerner, August, Hammer, Michael F, and Slatkin, Montgomery

Subjects
Biological Sciences, Genetics, Human Genome, Biotechnology, Animals, Asian People, Asia, Eastern, Gene Pool, Genetics, Population, Genome, Human, Haplotypes, Humans, Models, Genetic, Neanderthals, Phylogeny, White People, Developmental Biology, Biochemistry and cell biology
Abstract

Neanderthals were a group of archaic hominins that occupied most of Europe and parts of Western Asia from ∼30,000 to 300,000 years ago (KYA). They coexisted with modern humans during part of this time. Previous genetic analyses that compared a draft sequence of the Neanderthal genome with genomes of several modern humans concluded that Neanderthals made a small (1-4%) contribution to the gene pools of all non-African populations. This observation was consistent with a single episode of admixture from Neanderthals into the ancestors of all non-Africans when the two groups coexisted in the Middle East 50-80 KYA. We examined the relationship between Neanderthals and modern humans in greater detail by applying two complementary methods to the published draft Neanderthal genome and an expanded set of high-coverage modern human genome sequences. We find that, consistent with the recent finding of Meyer et al. (2012), Neanderthals contributed more DNA to modern East Asians than to modern Europeans. Furthermore we find that the Maasai of East Africa have a small but significant fraction of Neanderthal DNA. Because our analysis is of several genomic samples from each modern human population considered, we are able to document the extent of variation in Neanderthal ancestry within and among populations. Our results combined with those previously published show that a more complex model of admixture between Neanderthals and modern humans is necessary to account for the different levels of Neanderthal ancestry among human populations. In particular, at least some Neanderthal-modern human admixture must postdate the separation of the ancestors of modern European and modern East Asian populations.

Published
2013

4. Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf−/− mouse model

Author

Chapeau, Emilie A., Gembarska, Agnieszka, Durand, Eric Y., Mandon, Emeline, Estadieu, Claire, Romanet, Vincent, Wiesmann, Marion, Tiedt, Ralph, Lehar, Joseph, deWeck, Antoine, Rad, Roland, Barys, Louise, Jeay, Sebastien, Ferretti, Stephane, Kauffmann, Audrey, Sutter, Esther, Grevot, Armelle, Moulin, Pierre, Murakami, Masato, Sellers, William R., Hofmann, Francesco, and Jensen, Michael Rugaard

Published
2017

5. Data File S1 from Dose and Schedule Determine Distinct Molecular Mechanisms Underlying the Efficacy of the p53–MDM2 Inhibitor HDM201

Author

Jeay, Sébastien, primary, Ferretti, Stéphane, primary, Holzer, Philipp, primary, Fuchs, Jeanette, primary, Chapeau, Emilie A., primary, Wartmann, Markus, primary, Sterker, Dario, primary, Romanet, Vincent, primary, Murakami, Masato, primary, Kerr, Grainne, primary, Durand, Eric Y., primary, Gaulis, Swann, primary, Cortes-Cros, Marta, primary, Ruetz, Stephan, primary, Stachyra, Therese-Marie, primary, Kallen, Joerg, primary, Furet, Pascal, primary, Würthner, Jens, primary, Guerreiro, Nelson, primary, Halilovic, Ensar, primary, Jullion, Astrid, primary, Kauffmann, Audrey, primary, Kuriakose, Emil, primary, Wiesmann, Marion, primary, Jensen, Michael R., primary, Hofmann, Francesco, primary, and Sellers, William R., primary

Published
2023
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6. Data from Dose and Schedule Determine Distinct Molecular Mechanisms Underlying the Efficacy of the p53–MDM2 Inhibitor HDM201

Author

Jeay, Sébastien, primary, Ferretti, Stéphane, primary, Holzer, Philipp, primary, Fuchs, Jeanette, primary, Chapeau, Emilie A., primary, Wartmann, Markus, primary, Sterker, Dario, primary, Romanet, Vincent, primary, Murakami, Masato, primary, Kerr, Grainne, primary, Durand, Eric Y., primary, Gaulis, Swann, primary, Cortes-Cros, Marta, primary, Ruetz, Stephan, primary, Stachyra, Therese-Marie, primary, Kallen, Joerg, primary, Furet, Pascal, primary, Würthner, Jens, primary, Guerreiro, Nelson, primary, Halilovic, Ensar, primary, Jullion, Astrid, primary, Kauffmann, Audrey, primary, Kuriakose, Emil, primary, Wiesmann, Marion, primary, Jensen, Michael R., primary, Hofmann, Francesco, primary, and Sellers, William R., primary

Published
2023
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7. Supplementary material, methods and data from Dose and Schedule Determine Distinct Molecular Mechanisms Underlying the Efficacy of the p53–MDM2 Inhibitor HDM201

Author

Jeay, Sébastien, primary, Ferretti, Stéphane, primary, Holzer, Philipp, primary, Fuchs, Jeanette, primary, Chapeau, Emilie A., primary, Wartmann, Markus, primary, Sterker, Dario, primary, Romanet, Vincent, primary, Murakami, Masato, primary, Kerr, Grainne, primary, Durand, Eric Y., primary, Gaulis, Swann, primary, Cortes-Cros, Marta, primary, Ruetz, Stephan, primary, Stachyra, Therese-Marie, primary, Kallen, Joerg, primary, Furet, Pascal, primary, Würthner, Jens, primary, Guerreiro, Nelson, primary, Halilovic, Ensar, primary, Jullion, Astrid, primary, Kauffmann, Audrey, primary, Kuriakose, Emil, primary, Wiesmann, Marion, primary, Jensen, Michael R., primary, Hofmann, Francesco, primary, and Sellers, William R., primary

Published
2023
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9. A Draft Sequence of the Neandertal Genome

Author

Green, Richard E., Krause, Johannes, Briggs, Adrian W., Marcic, Tomislav, Stenzel, Udo, Kircher, Martin, Patterson, Nick, Li, Heng, Zhai, Weiwei, Fritz, Markus Hsi-Yang, Hansen, Nancy F., Durand, Eric Y., Malaspinas, Anna-Sapfo, Jensen, Jeffrey D., Marques-Bonet, Tomas, Alkan, Can, Prüfer, kay, Meyer, Matthias, Burbano, Hernán A., Good, Jeffrey M., Schultz, Rigo, Aximu-Petri, Ayinuer, Butthof, Anne, Höber, Barbara, Höffner, Barbara, Siegemund, Madlen, Weihmann, Antje, Nusbaum, Chad, Lander, Eric S., Russ, Carsten, Novod, Nathaniel, Affourtit, Jason, Egholm, Michael, Verna, Christine, Rudan, Pavao, Brajkovic, Dejana, Kucan, Zeljko, Gusic, Ivan, Doronichev, Vladimir B., Golovanova, Liubov V., Lalueza-Fox, Carles, de la Rasilla, Marco, Fortea, Javier, Rosas, Antonio, Schmitz, Ralf W., Johnson, Philip L F., Eichler, Evan E., Falush, Daniel, Birney, Ewan, Mullikin, James, Slatkin, Montgomery, Nielsen, Rasmus, Kelso, Janet, Lachmann, Michael, Reich, David, and Pääbo, Svante

Published
2010

17. Genetic history of an archaic hominin group from Denisova Cave in Siberia

Author

Reich, David, Green, Richard E., Kircher, Martin, Krause, Johannes, Patterson, Nick, Durand, Eric Y., Viola, Bence, Briggs, Adrian W., Stenzel, Udo, Johnson, Philip L. F., Maricic, Tomislav, Good, Jeffrey M., Marques-Bonet, Tomas, Alkan, Can, Fu, Qiaomei, Mallick, Swapan, Li, Heng, Meyer, Matthias, Eichler, Evan E., Stoneking, Mark, Richards, Michael, Talamo, Sahra, Shunkov, Michael V., Derevianko, Anatoli P., Hublin, Jean-Jacques, Kelso, Janet, Slatkin, Montgomery, and Pääbo, Svante

Published
2010
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18. Dose and Schedule Determine Distinct Molecular Mechanisms Underlying the Efficacy of the p53–MDM2 Inhibitor HDM201

Author

Jeay, Sébastien, primary, Ferretti, Stéphane, additional, Holzer, Philipp, additional, Fuchs, Jeanette, additional, Chapeau, Emilie A., additional, Wartmann, Markus, additional, Sterker, Dario, additional, Romanet, Vincent, additional, Murakami, Masato, additional, Kerr, Grainne, additional, Durand, Eric Y., additional, Gaulis, Swann, additional, Cortes-Cros, Marta, additional, Ruetz, Stephan, additional, Stachyra, Therese-Marie, additional, Kallen, Joerg, additional, Furet, Pascal, additional, Würthner, Jens, additional, Guerreiro, Nelson, additional, Halilovic, Ensar, additional, Jullion, Astrid, additional, Kauffmann, Audrey, additional, Kuriakose, Emil, additional, Wiesmann, Marion, additional, Jensen, Michael R., additional, Hofmann, Francesco, additional, and Sellers, William R., additional

Published
2018
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19. Forecasting changes in population genetic structure of Alpine plants in response to global warming

Author

Jay, Flora, Manel, Stéphanie, Alvarez, Nadir, Durand, Eric Y, Thuiller, Wilfried, Holderegger, Rolf, Taberlet, Pierre, François, Olivier, Biologie Computationnelle et Mathématique (TIMC-IMAG-BCM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre d’Ecologie Fonctionnelle et Evolutive (CEFE), Université Paul-Valéry - Montpellier 3 (UM3)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-École pratique des hautes études (EPHE)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Laboratoire d'Entomologie Evolutive, Université de Neuchâtel (UNINE), Laboratoire d'Ecologie Alpine (LECA), Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Joseph Fourier - Grenoble 1 (UJF)-Université Grenoble Alpes (UGA), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Université Paul-Valéry - Montpellier 3 (UPVM)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut de Recherche pour le Développement (IRD [France-Sud]), and Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])

Subjects
MESH: Forecasting, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Genotype, Models, Genetic, Altitude, Population Dynamics, Temperature, MESH: Plants, MESH: Genetics, Population, MESH: Global Warming, Plants, MESH: Population Dynamics, MESH: Altitude, Adaptation, Physiological, Global Warming, MESH: Adaptation, Physiological, MESH: Temperature, MESH: Genotype, Genetics, Population, MESH: Models, Genetic, Forecasting
Abstract

International audience; Species range shifts in response to climate and land use change are commonly forecasted with species distribution models based on species occurrence or abundance data. Although appealing, these models ignore the genetic structure of species, and the fact that different populations might respond in different ways because of adaptation to their environment. Here, we introduced ancestry distribution models, that is, statistical models of the spatial distribution of ancestry proportions, for forecasting intra-specific changes based on genetic admixture instead of species occurrence data. Using multi-locus genotypes and extensive geographic coverage of distribution data across the European Alps, we applied this approach to 20 alpine plant species considering a global increase in temperature from 0.25 to 4 °C. We forecasted the magnitudes of displacement of contact zones between plant populations potentially adapted to warmer environments and other populations. While a global trend of movement in a north-east direction was predicted, the magnitude of displacement was species-specific. For a temperature increase of 2 °C, contact zones were predicted to move by 92 km on average (minimum of 5 km, maximum of 212 km) and by 188 km for an increase of 4 °C (minimum of 11 km, maximum of 393 km). Intra-specific turnover-measuring the extent of change in global population genetic structure-was generally found to be moderate for 2 °C of temperature warming. For 4 °C of warming, however, the models indicated substantial intra-specific turnover for ten species. These results illustrate that, in spite of unavoidable simplifications, ancestry distribution models open new perspectives to forecast population genetic changes within species and complement more traditional distribution-based approaches.

Published
2012
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20. POPS: A Software for Prediction of Population Genetic Structure Using Latent Regression Models Olivier François Eric Y. Durand

Author

Jay, Flora, François, Olivier, Durand, Eric Y, Blum, Michael Gb, Biologie Computationnelle et Mathématique (TIMC-IMAG-BCM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), and VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)

Subjects
[STAT]Statistics [stat], population genetic struc-ture, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], MCMC, environmental covariates, mixture models, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, latent class regression models
Abstract

International audience; The software POPS performs inference of population genetic structure using multi-locus genotypic data. Based on a hierarchical Bayesian framework for latent regression models, POPS implements algorithms that improve estimation of individual admixture proportions and cluster membership probabilities by using geographic and environmental information. In addition, POPS defines ancestry distribution models allowing its users to forecast admixture proportion and cluster membership geographic variation under changing environmental conditions. We illustrate a typical use of POPS using data for an alpine plant species, for which POPS predicts changes in spatial population structure assuming a particular scenario of climate change.

Published
2015

21. Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf −/− mouse model

Author

Chapeau, Emilie A., primary, Gembarska, Agnieszka, additional, Durand, Eric Y., additional, Mandon, Emeline, additional, Estadieu, Claire, additional, Romanet, Vincent, additional, Wiesmann, Marion, additional, Tiedt, Ralph, additional, Lehar, Joseph, additional, de Weck, Antoine, additional, Rad, Roland, additional, Barys, Louise, additional, Jeay, Sebastien, additional, Ferretti, Stephane, additional, Kauffmann, Audrey, additional, Sutter, Esther, additional, Grevot, Armelle, additional, Moulin, Pierre, additional, Murakami, Masato, additional, Sellers, William R., additional, Hofmann, Francesco, additional, and Jensen, Michael Rugaard, additional

Published
2017
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22. Antioxidative effect of lipophilized caffeic acid in fish oil enriched mayonnaise and milk

Author

Alemán, Mercedes, Bou, Ricard, Guardiola, F., Durand, Eric Y., Villeneuve, P., Jacobsen, Charlotte, Sørensen, A., Alemán, Mercedes, Bou, Ricard, Guardiola, F., Durand, Eric Y., Villeneuve, P., Jacobsen, Charlotte, and Sørensen, A.

Abstract

The antioxidative effect of lipophilized caffeic acid was assessed in two different fish oil enriched food products: mayonnaise and milk. In both emulsion systems, caffeic acid esterified with fatty alcohols of different chain lengths (C1-C20) were better antioxidants than the original phenolic compound. The optimal chain length with respect to protection against oxidation was, however, different for the two food systems. Fish oil enriched mayonnaise with caffeates of medium alkyl chain length (butyl, octyl and dodecyl) added resulted in a better oxidative stability than caffeates with shorter (methyl) or longer (octadecyl) alkyl chains. Whereas in fish oil enriched milk emulsions the most effective caffeates were those with shorter alkyl chains (methyl and butyl) rather than the ones with medium and long chains (octyl, dodecyl, hexadecyl and eicosyl). These results demonstrate that there might be an optimum alkyl chain length for each phenolipid in each type of emulsion systems. © 2014 Elsevier Ltd. All rights reserved.

Published
2015

23. Genetic signature of population fragmentation varies with mobility in seven bird species of a fragmented Kenyan cloud forest

Author

Callens, Tom, Galbusera, Peter, Matthysen, Erik, Durand, Eric Y., Githiru, Mwangi, Huyghe, Jeroen R., and Lens, Luc

Subjects
Biology
Abstract

Habitat fragmentation can restrict geneflow, reduce neighbourhood effective population size, and increase genetic drift and inbreeding in small, isolated habitat remnants. The extent to which habitat fragmentation leads to population fragmentation, however, differs among landscapes and taxa. Commonly, researchers use information on the current status of a species to predict population effects of habitat fragmentation. Such methods, however, do not convey information on species-specific responses to fragmentation. Here, we compare levels of past population differentiation, estimated from microsatellite genotypes, with contemporary dispersal rates, estimated from multi-strata capturerecapture models, to infer changes in mobility over time in seven sympatric, forest-dependent bird species of a Kenyan cloud forest archipelago. Overall, populations of sedentary species were more strongly differentiated and clustered compared to those of vagile ones, while geographical patterning suggested an important role of landscape structure in shaping genetic variation. However, five of seven species with broadly similar levels of genetic differentiation nevertheless differed substantially in their current dispersal rates. We conclude that post-fragmentation levels of vagility, without reference to past population connectivity, may not be the best predictor of how forest fragmentation affects the life history of forest-dependent species. As effective conservation strategies often hinge on accurate prediction of shifts in ecological and genetic relationships among populations, conservation practices based solely upon current population abundances or movements may, in the long term, prove to be inadequate.

Published
2011

25. Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf-/- mouse model.

Author

Chapeau, Emilie A., Gembarska, Agnieszka, Durand, Eric Y., Mandon, Emeline, Estadieu, Claire, Romanet, Vincent, Wiesmann, Marion, Tiedt, Ralph, Lehar, Joseph, de Weck, Antoine, Rad, Roland, Barys, Louise, Jeay, Sebastien, Ferretti, Stephane, Kauffmann, Audrey, Sutter, Esther, Grevot, Armelle, Moulin, Pierre, Murakami, Masato, and Sellers, William R.

Subjects
MUTAGENESIS, LABORATORY mice, TRANSPOSONS, COHORT analysis, PHARMACOLOGY
Abstract

Inhibitors of double minute 2 protein (MDM2)-tumor protein 53 (TP53) interaction are predicted to be effective in tumors in which the TP53 gene is wild type, by preventing TP53 protein degradation. One such setting is represented by the frequent CDKN2A deletion in human cancer that, through inactivation of p14ARF, activates MDM2 protein, which in turn degrades TP53 tumor suppressor. Here we used piggyBac (PB) transposon insertional mutagenesis to anticipate resistance mechanisms occurring during treatment with the MDM2-TP53 inhibitor HDM201. Constitutive PB mutagenesis in Arf-/- mice provided a collection of spontaneous tumors with characterized insertional genetic landscapes. Tumors were allografted in large cohorts of mice to assess the pharmacologic effects of HDM201. Sixteen out of 21 allograft models were sensitive to HDM201 but ultimately relapsed under treatment. A comparison of tumors with acquired resistance to HDM201 and untreated tumors identified 87 genes that were differentially and significantly targeted by the PB transposon. Resistant tumors displayed a complex clonality pattern suggesting the emergence of several resistant subclones. Among the most frequent alterations conferring resistance, we observed somatic and insertional loss-of-function mutations in transformation-related protein 53 (Trp53) in 54% of tumors and transposonmediated gain-of-function alterations in B-cell lymphoma-extra large (Bcl-xL), Mdm4, and two TP53 family members, resulting in expression of the TP53 dominant negative truncations △NTrp63 and △NTrp73. Enhanced BCL-xL and MDM4 protein expression was confirmed in resistant tumors, as well as in HDM201-resistant patient-derived tumor xenografts. Interestingly, concomitant inhibition of MDM2 and BCL-xL demonstrated significant synergy in p53 wild-type cell lines in vitro. Collectively, our findings identify several potential mechanisms by which TP53 wild-type tumors may escape MDM2-targeted therapy. [ABSTRACT FROM AUTHOR]

Published
2017
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