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46 results on '"Kashin, Seva"'

1. A concerted neuron–astrocyte program declines in ageing and schizophrenia

Author

Ling, Emi, Nemesh, James, Goldman, Melissa, Kamitaki, Nolan, Reed, Nora, Handsaker, Robert E., Genovese, Giulio, Vogelgsang, Jonathan S., Gerges, Sherif, Kashin, Seva, Ghosh, Sulagna, Esposito, John M., Morris, Kiely, Meyer, Daniel, Lutservitz, Alyssa, Mullally, Christopher D., Wysoker, Alec, Spina, Liv, Neumann, Anna, Hogan, Marina, Ichihara, Kiku, Berretta, Sabina, and McCarroll, Steven A.

Published
2024
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4. An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder

Author

Werling, Donna M, Brand, Harrison, An, Joon-Yong, Stone, Matthew R, Zhu, Lingxue, Glessner, Joseph T, Collins, Ryan L, Dong, Shan, Layer, Ryan M, Markenscoff-Papadimitriou, Eirene, Farrell, Andrew, Schwartz, Grace B, Wang, Harold Z, Currall, Benjamin B, Zhao, Xuefang, Dea, Jeanselle, Duhn, Clif, Erdman, Carolyn A, Gilson, Michael C, Yadav, Rachita, Handsaker, Robert E, Kashin, Seva, Klei, Lambertus, Mandell, Jeffrey D, Nowakowski, Tomasz J, Liu, Yuwen, Pochareddy, Sirisha, Smith, Louw, Walker, Michael F, Waterman, Matthew J, He, Xin, Kriegstein, Arnold R, Rubenstein, John L, Sestan, Nenad, McCarroll, Steven A, Neale, Benjamin M, Coon, Hilary, Willsey, A Jeremy, Buxbaum, Joseph D, Daly, Mark J, State, Matthew W, Quinlan, Aaron R, Marth, Gabor T, Roeder, Kathryn, Devlin, Bernie, Talkowski, Michael E, and Sanders, Stephan J

Subjects
Biological Sciences, Genetics, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Pediatric, Autism, Biotechnology, Mental Health, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Autism Spectrum Disorder, Female, Genetic Predisposition to Disease, Genome, Genome-Wide Association Study, Humans, INDEL Mutation, Male, Polymorphism, Single Nucleotide, Protein Isoforms, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Genomic association studies of common or rare protein-coding variation have established robust statistical approaches to account for multiple testing. Here we present a comparable framework to evaluate rare and de novo noncoding single-nucleotide variants, insertion/deletions, and all classes of structural variation from whole-genome sequencing (WGS). Integrating genomic annotations at the level of nucleotides, genes, and regulatory regions, we define 51,801 annotation categories. Analyses of 519 autism spectrum disorder families did not identify association with any categories after correction for 4,123 effective tests. Without appropriate correction, biologically plausible associations are observed in both cases and controls. Despite excluding previously identified gene-disrupting mutations, coding regions still exhibited the strongest associations. Thus, in autism, the contribution of de novo noncoding variation is probably modest in comparison to that of de novo coding variants. Robust results from future WGS studies will require large cohorts and comprehensive analytical strategies that consider the substantial multiple-testing burden.

Published
2018

5. Long somatic DNA-repeat expansion drives neurodegeneration in Huntington disease

Author

Handsaker, Robert E., primary, Kashin, Seva, additional, Reed, Nora M., additional, Tan, Steven, additional, Lee, Won-Seok, additional, McDonald, Tara M., additional, Morris, Kiely, additional, Kamitaki, Nolan, additional, Mullally, Christopher D., additional, Morakabati, Neda, additional, Goldman, Melissa, additional, Lind, Gabriel, additional, Kohli, Rhea, additional, Lawton, Elisabeth, additional, Hogan, Marina, additional, Ichihara, Kiku, additional, Berretta, Sabina, additional, and McCarroll, Steven A., additional

Published
2024
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6. Identifying cis-mediators for trans-eQTLs across many human tissues using genomic mediation analysis

Author

Yang, Fan, Wang, Jiebiao, Consortium, The GTEx, Pierce, Brandon L, Chen, Lin S, Aguet, François, Ardlie, Kristin G, Cummings, Beryl B, Gelfand, Ellen T, Getz, Gad, Hadley, Kane, Handsaker, Robert E, Huang, Katherine H, Kashin, Seva, Karczewski, Konrad J, Lek, Monkol, Li, Xiao, MacArthur, Daniel G, Nedzel, Jared L, Nguyen, Duyen T, Noble, Michael S, Segrè, Ayellet V, Trowbridge, Casandra A, Tukiainen, Taru, Abell, Nathan S, Balliu, Brunilda, Barshir, Ruth, Basha, Omer, Battle, Alexis, Bogu, Gireesh K, Brown, Andrew, Brown, Christopher D, Castel, Stephane E, Chiang, Colby, Conrad, Donald F, Cox, Nancy J, Damani, Farhan N, Davis, Joe R, Delaneau, Olivier, Dermitzakis, Emmanouil T, Engelhardt, Barbara E, Eskin, Eleazar, Ferreira, Pedro G, Frésard, Laure, Gamazon, Eric R, Garrido-Martín, Diego, Gewirtz, Ariel DH, Gliner, Genna, Gloudemans, Michael J, Guigo, Roderic, Hall, Ira M, Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Im, Hae Kyung, Jo, Brian, Kang, Eun Yong, Kim, Yungil, Kim-Hellmuth, Sarah, Lappalainen, Tuuli, Li, Li, Xin, Liu, Boxiang, Mangul, Serghei, McCarthy, Mark I, McDowell, Ian C, Mohammadi, Pejman, Monlong, Jean, Montgomery, Stephen B, Muñoz-Aguirre, Manuel, Ndungu, Anne W, Nicolae, Dan L, Nobel, Andrew B, Oliva, Meritxell, Ongen, Halit, Palowitch, John J, Panousis, Nikolaos, Papasaikas, Panagiotis, Park, YoSon, Parsana, Princy, Payne, Anthony J, Peterson, Christine B, Quan, Jie, Reverter, Ferran, Sabatti, Chiara, Saha, Ashis, Sammeth, Michael, Scott, Alexandra J, Shabalin, Andrey A, Sodaei, Reza, Stephens, Matthew, Stranger, Barbara E, Strober, Benjamin J, Sul, Jae Hoon, Tsang, Emily K, Urbut, Sarah, van de Bunt, Martijn, and Wang, Gao

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Biotechnology, Human Genome, 2.1 Biological and endogenous factors, Underpinning research, Aetiology, 1.1 Normal biological development and functioning, Generic health relevance, Good Health and Well Being, Databases, Genetic, Gene Expression Profiling, Gene Expression Regulation, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Selection, Genetic, Tissue Distribution, GTEx Consortium, Medical and Health Sciences, Bioinformatics
Abstract

The impact of inherited genetic variation on gene expression in humans is well-established. The majority of known expression quantitative trait loci (eQTLs) impact expression of local genes (cis-eQTLs). More research is needed to identify effects of genetic variation on distant genes (trans-eQTLs) and understand their biological mechanisms. One common trans-eQTLs mechanism is "mediation" by a local (cis) transcript. Thus, mediation analysis can be applied to genome-wide SNP and expression data in order to identify transcripts that are "cis-mediators" of trans-eQTLs, including those "cis-hubs" involved in regulation of many trans-genes. Identifying such mediators helps us understand regulatory networks and suggests biological mechanisms underlying trans-eQTLs, both of which are relevant for understanding susceptibility to complex diseases. The multitissue expression data from the Genotype-Tissue Expression (GTEx) program provides a unique opportunity to study cis-mediation across human tissue types. However, the presence of complex hidden confounding effects in biological systems can make mediation analyses challenging and prone to confounding bias, particularly when conducted among diverse samples. To address this problem, we propose a new method: Genomic Mediation analysis with Adaptive Confounding adjustment (GMAC). It enables the search of a very large pool of variables, and adaptively selects potential confounding variables for each mediation test. Analyses of simulated data and GTEx data demonstrate that the adaptive selection of confounders by GMAC improves the power and precision of mediation analysis. Application of GMAC to GTEx data provides new insights into the observed patterns of cis-hubs and trans-eQTL regulation across tissue types.

Published
2017

7. Co-expression networks reveal the tissue-specific regulation of transcription and splicing

Author

Saha, Ashis, Kim, Yungil, Gewirtz, Ariel DH, Jo, Brian, Gao, Chuan, McDowell, Ian C, Consortium, The GTEx, Engelhardt, Barbara E, Battle, Alexis, Aguet, François, Ardlie, Kristin G, Cummings, Beryl B, Gelfand, Ellen T, Getz, Gad, Hadley, Kane, Handsaker, Robert E, Huang, Katherine H, Kashin, Seva, Karczewski, Konrad J, Lek, Monkol, Li, Xiao, MacArthur, Daniel G, Nedzel, Jared L, Nguyen, Duyen T, Noble, Michael S, Segrè, Ayellet V, Trowbridge, Casandra A, Tukiainen, Taru, Abell, Nathan S, Balliu, Brunilda, Barshir, Ruth, Basha, Omer, Bogu, Gireesh K, Brown, Andrew, Brown, Christopher D, Castel, Stephane E, Chen, Lin S, Chiang, Colby, Conrad, Donald F, Cox, Nancy J, Damani, Farhan N, Davis, Joe R, Delaneau, Olivier, Dermitzakis, Emmanouil T, Eskin, Eleazar, Ferreira, Pedro G, Frésard, Laure, Gamazon, Eric R, Garrido-Martín, Diego, Gliner, Genna, Gloudemans, Michael J, Guigo, Roderic, Hall, Ira M, Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Im, Hae Kyung, Kang, Eun Yong, Kim-Hellmuth, Sarah, Lappalainen, Tuuli, Li, Li, Xin, Liu, Boxiang, Mangul, Serghei, McCarthy, Mark I, Mohammadi, Pejman, Monlong, Jean, Montgomery, Stephen B, Muñoz-Aguirre, Manuel, Ndungu, Anne W, Nicolae, Dan L, Nobel, Andrew B, Oliva, Meritxell, Ongen, Halit, Palowitch, John J, Panousis, Nikolaos, Papasaikas, Panagiotis, Park, YoSon, Parsana, Princy, Payne, Anthony J, Peterson, Christine B, Quan, Jie, Reverter, Ferran, Sabatti, Chiara, Sammeth, Michael, Scott, Alexandra J, Shabalin, Andrey A, Sodaei, Reza, Stephens, Matthew, Stranger, Barbara E, Strober, Benjamin J, and Sul, Jae Hoon

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Biotechnology, Human Genome, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Generic health relevance, Bayes Theorem, Databases, Genetic, Gene Expression Profiling, Gene Expression Regulation, Gene Regulatory Networks, Genotyping Techniques, Humans, Organ Specificity, Polymorphism, Single Nucleotide, RNA Splicing, Sequence Analysis, RNA, GTEx Consortium, Medical and Health Sciences, Bioinformatics
Abstract

Gene co-expression networks capture biologically important patterns in gene expression data, enabling functional analyses of genes, discovery of biomarkers, and interpretation of genetic variants. Most network analyses to date have been limited to assessing correlation between total gene expression levels in a single tissue or small sets of tissues. Here, we built networks that additionally capture the regulation of relative isoform abundance and splicing, along with tissue-specific connections unique to each of a diverse set of tissues. We used the Genotype-Tissue Expression (GTEx) project v6 RNA sequencing data across 50 tissues and 449 individuals. First, we developed a framework called Transcriptome-Wide Networks (TWNs) for combining total expression and relative isoform levels into a single sparse network, capturing the interplay between the regulation of splicing and transcription. We built TWNs for 16 tissues and found that hubs in these networks were strongly enriched for splicing and RNA binding genes, demonstrating their utility in unraveling regulation of splicing in the human transcriptome. Next, we used a Bayesian biclustering model that identifies network edges unique to a single tissue to reconstruct Tissue-Specific Networks (TSNs) for 26 distinct tissues and 10 groups of related tissues. Finally, we found genetic variants associated with pairs of adjacent nodes in our networks, supporting the estimated network structures and identifying 20 genetic variants with distant regulatory impact on transcription and splicing. Our networks provide an improved understanding of the complex relationships of the human transcriptome across tissues.

Published
2017

8. Dynamic landscape and regulation of RNA editing in mammals

Author

Aguet, François, Ardlie, Kristin G, Cummings, Beryl B, Gelfand, Ellen T, Getz, Gad, Hadley, Kane, Handsaker, Robert E, Huang, Katherine H, Kashin, Seva, Karczewski, Konrad J, Lek, Monkol, Li, Xiao, MacArthur, Daniel G, Nedzel, Jared L, Nguyen, Duyen T, Noble, Michael S, Segrè, Ayellet V, Trowbridge, Casandra A, Tukiainen, Taru, Abell, Nathan S, Balliu, Brunilda, Barshir, Ruth, Basha, Omer, Battle, Alexis, Bogu, Gireesh K, Brown, Andrew, Brown, Christopher D, Castel, Stephane E, Chen, Lin S, Chiang, Colby, Conrad, Donald F, Cox, Nancy J, Damani, Farhan N, Davis, Joe R, Delaneau, Olivier, Dermitzakis, Emmanouil T, Engelhardt, Barbara E, Eskin, Eleazar, Ferreira, Pedro G, Frésard, Laure, Gamazon, Eric R, Garrido-Martín, Diego, Gewirtz, Ariel DH, Gliner, Genna, Gloudemans, Michael J, Guigo, Roderic, Hall, Ira M, Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Kyung Im, Hae, Jo, Brian, Yong Kang, Eun, Kim, Yungil, Kim-Hellmuth, Sarah, Lappalainen, Tuuli, Li, Gen, Li, Xin, Liu, Boxiang, Mangul, Serghei, McCarthy, Mark I, McDowell, Ian C, Mohammadi, Pejman, Monlong, Jean, Montgomery, Stephen B, Muñoz-Aguirre, Manuel, Ndungu, Anne W, Nicolae, Dan L, Nobel, Andrew B, Oliva, Meritxell, Ongen, Halit, Palowitch, John J, Panousis, Nikolaos, Papasaikas, Panagiotis, Park, YoSon, Parsana, Princy, Payne, Anthony J, Peterson, Christine B, Quan, Jie, Reverter, Ferran, Sabatti, Chiara, Saha, Ashis, Sammeth, Michael, Scott, Alexandra J, Shabalin, Andrey A, Sodaei, Reza, Stephens, Matthew, Stranger, Barbara E, Strober, Benjamin J, Sul, Jae Hoon, Tsang, Emily K, Urbut, Sarah, van de Bunt, Martijn, Wang, Gao, Wen, Xiaoquan, Wright, Fred A, Xi, Hualin S, Yeger-Lotem, Esti, and Zappala, Zachary

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Adenosine Deaminase, Animals, Female, Genotype, HEK293 Cells, Humans, Male, Mice, Muscles, Nuclear Proteins, Organ Specificity, Primates, Proteolysis, RNA Editing, RNA-Binding Proteins, Spatio-Temporal Analysis, Species Specificity, Transcriptome, GTEx Consortium, Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group, Statistical Methods groups—Analysis Working Group, Enhancing GTEx (eGTEx) groups, NIH Common Fund, NIH/NCI, NIH/NHGRI, NIH/NIMH, NIH/NIDA, Biospecimen Collection Source Site—NDRI, Biospecimen Collection Source Site—RPCI, Biospecimen Core Resource—VARI, Brain Bank Repository—University of Miami Brain Endowment Bank, Leidos Biomedical—Project Management, ELSI Study, Genome Browser Data Integration &Visualization—EBI, Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz, General Science & Technology
Abstract

Adenosine-to-inosine (A-to-I) RNA editing is a conserved post-transcriptional mechanism mediated by ADAR enzymes that diversifies the transcriptome by altering selected nucleotides in RNA molecules. Although many editing sites have recently been discovered, the extent to which most sites are edited and how the editing is regulated in different biological contexts are not fully understood. Here we report dynamic spatiotemporal patterns and new regulators of RNA editing, discovered through an extensive profiling of A-to-I RNA editing in 8,551 human samples (representing 53 body sites from 552 individuals) from the Genotype-Tissue Expression (GTEx) project and in hundreds of other primate and mouse samples. We show that editing levels in non-repetitive coding regions vary more between tissues than editing levels in repetitive regions. Globally, ADAR1 is the primary editor of repetitive sites and ADAR2 is the primary editor of non-repetitive coding sites, whereas the catalytically inactive ADAR3 predominantly acts as an inhibitor of editing. Cross-species analysis of RNA editing in several tissues revealed that species, rather than tissue type, is the primary determinant of editing levels, suggesting stronger cis-directed regulation of RNA editing for most sites, although the small set of conserved coding sites is under stronger trans-regulation. In addition, we curated an extensive set of ADAR1 and ADAR2 targets and showed that many editing sites display distinct tissue-specific regulation by the ADAR enzymes in vivo. Further analysis of the GTEx data revealed several potential regulators of editing, such as AIMP2, which reduces editing in muscles by enhancing the degradation of the ADAR proteins. Collectively, our work provides insights into the complex cis- and trans-regulation of A-to-I editing.

Published
2017

9. Landscape of X chromosome inactivation across human tissues

Author

Aguet, François, Ardlie, Kristin G, Cummings, Beryl B, Gelfand, Ellen T, Getz, Gad, Hadley, Kane, Handsaker, Robert E, Huang, Katherine H, Kashin, Seva, Karczewski, Konrad J, Lek, Monkol, Li, Xiao, MacArthur, Daniel G, Nedzel, Jared L, Nguyen, Duyen T, Noble, Michael S, Segrè, Ayellet V, Trowbridge, Casandra A, Tukiainen, Taru, Abell, Nathan S, Balliu, Brunilda, Barshir, Ruth, Basha, Omer, Battle, Alexis, Bogu, Gireesh K, Brown, Andrew, Brown, Christopher D, Castel, Stephane E, Chen, Lin S, Chiang, Colby, Conrad, Donald F, Cox, Nancy J, Damani, Farhan N, Davis, Joe R, Delaneau, Olivier, Dermitzakis, Emmanouil T, Engelhardt, Barbara E, Eskin, Eleazar, Ferreira, Pedro G, Frésard, Laure, Gamazon, Eric R, Garrido-Martín, Diego, Gewirtz, Ariel DH, Gliner, Genna, Gloudemans, Michael J, Guigo, Roderic, Hall, Ira M, Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Kyung Im, Hae, Jo, Brian, Yong Kang, Eun, Kim, Yungil, Kim-Hellmuth, Sarah, Lappalainen, Tuuli, Li, Gen, Li, Xin, Liu, Boxiang, Mangul, Serghei, McCarthy, Mark I, McDowell, Ian C, Mohammadi, Pejman, Monlong, Jean, Montgomery, Stephen B, Muñoz-Aguirre, Manuel, Ndungu, Anne W, Nicolae, Dan L, Nobel, Andrew B, Oliva, Meritxell, Ongen, Halit, Palowitch, John J, Panousis, Nikolaos, Papasaikas, Panagiotis, Park, YoSon, Parsana, Princy, Payne, Anthony J, Peterson, Christine B, Quan, Jie, Reverter, Ferran, Sabatti, Chiara, Saha, Ashis, Sammeth, Michael, Scott, Alexandra J, Shabalin, Andrey A, Sodaei, Reza, Stephens, Matthew, Stranger, Barbara E, Strober, Benjamin J, Sul, Jae Hoon, Tsang, Emily K, Urbut, Sarah, van de Bunt, Martijn, Wang, Gao, Wen, Xiaoquan, Wright, Fred A, Xi, Hualin S, Yeger-Lotem, Esti, and Zappala, Zachary

Subjects
Genetics, Clinical Research, Human Genome, Generic health relevance, Good Health and Well Being, Chromosomes, Human, X, Female, Genes, X-Linked, Genome, Human, Genomics, Humans, Male, Organ Specificity, Phenotype, Sequence Analysis, RNA, Single-Cell Analysis, Transcriptome, X Chromosome Inactivation, GTEx Consortium, Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group, Statistical Methods groups—Analysis Working Group, Enhancing GTEx (eGTEx) groups, NIH Common Fund, NIH/NCI, NIH/NHGRI, NIH/NIMH, NIH/NIDA, Biospecimen Collection Source Site—NDRI, Biospecimen Collection Source Site—RPCI, Biospecimen Core Resource—VARI, Brain Bank Repository—University of Miami Brain Endowment Bank, Leidos Biomedical—Project Management, ELSI Study, Genome Browser Data Integration &Visualization—EBI, Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz, General Science & Technology
Abstract

X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of 'escape' from inactivation varying between genes and individuals. The extent to which XCI is shared between cells and tissues remains poorly characterized, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression and phenotypic traits. Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity. Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI.

Published
2017

10. The impact of rare variation on gene expression across tissues

Author

Aguet, François, Ardlie, Kristin G, Cummings, Beryl B, Gelfand, Ellen T, Getz, Gad, Hadley, Kane, Handsaker, Robert E, Huang, Katherine H, Kashin, Seva, Karczewski, Konrad J, Lek, Monkol, Li, Xiao, MacArthur, Daniel G, Nedzel, Jared L, Nguyen, Duyen T, Noble, Michael S, Segrè, Ayellet V, Trowbridge, Casandra A, Tukiainen, Taru, Abell, Nathan S, Balliu, Brunilda, Barshir, Ruth, Basha, Omer, Battle, Alexis, Bogu, Gireesh K, Brown, Andrew, Brown, Christopher D, Castel, Stephane E, Chen, Lin S, Chiang, Colby, Conrad, Donald F, Cox, Nancy J, Damani, Farhan N, Davis, Joe R, Delaneau, Olivier, Dermitzakis, Emmanouil T, Engelhardt, Barbara E, Eskin, Eleazar, Ferreira, Pedro G, Frésard, Laure, Gamazon, Eric R, Garrido-Martín, Diego, Gewirtz, Ariel DH, Gliner, Genna, Gloudemans, Michael J, Guigo, Roderic, Hall, Ira M, Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Kyung Im, Hae, Jo, Brian, Yong Kang, Eun, Kim, Yungil, Kim-Hellmuth, Sarah, Lappalainen, Tuuli, Li, Gen, Li, Xin, Liu, Boxiang, Mangul, Serghei, McCarthy, Mark I, McDowell, Ian C, Mohammadi, Pejman, Monlong, Jean, Montgomery, Stephen B, Muñoz-Aguirre, Manuel, Ndungu, Anne W, Nicolae, Dan L, Nobel, Andrew B, Oliva, Meritxell, Ongen, Halit, Palowitch, John J, Panousis, Nikolaos, Papasaikas, Panagiotis, Park, YoSon, Parsana, Princy, Payne, Anthony J, Peterson, Christine B, Quan, Jie, Reverter, Ferran, Sabatti, Chiara, Saha, Ashis, Sammeth, Michael, Scott, Alexandra J, Shabalin, Andrey A, Sodaei, Reza, Stephens, Matthew, Stranger, Barbara E, Strober, Benjamin J, Sul, Jae Hoon, Tsang, Emily K, Urbut, Sarah, van de Bunt, Martijn, Wang, Gao, Wen, Xiaoquan, Wright, Fred A, Xi, Hualin S, Yeger-Lotem, Esti, and Zappala, Zachary

Subjects
Bayes Theorem, Female, Gene Expression Profiling, Genetic Variation, Genome, Human, Genomics, Genotype, Humans, Male, Models, Genetic, Organ Specificity, Sequence Analysis, RNA, GTEx Consortium, Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group, Statistical Methods groups—Analysis Working Group, Enhancing GTEx (eGTEx) groups, NIH Common Fund, NIH/NCI, NIH/NHGRI, NIH/NIMH, NIH/NIDA, Biospecimen Collection Source Site—NDRI, Biospecimen Collection Source Site—RPCI, Biospecimen Core Resource—VARI, Brain Bank Repository—University of Miami Brain Endowment Bank, Leidos Biomedical—Project Management, ELSI Study, Genome Browser Data Integration &Visualization—EBI, Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz, General Science & Technology
Abstract

Rare genetic variants are abundant in humans and are expected to contribute to individual disease risk. While genetic association studies have successfully identified common genetic variants associated with susceptibility, these studies are not practical for identifying rare variants. Efforts to distinguish pathogenic variants from benign rare variants have leveraged the genetic code to identify deleterious protein-coding alleles, but no analogous code exists for non-coding variants. Therefore, ascertaining which rare variants have phenotypic effects remains a major challenge. Rare non-coding variants have been associated with extreme gene expression in studies using single tissues, but their effects across tissues are unknown. Here we identify gene expression outliers, or individuals showing extreme expression levels for a particular gene, across 44 human tissues by using combined analyses of whole genomes and multi-tissue RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project v6p release. We find that 58% of underexpression and 28% of overexpression outliers have nearby conserved rare variants compared to 8% of non-outliers. Additionally, we developed RIVER (RNA-informed variant effect on regulation), a Bayesian statistical model that incorporates expression data to predict a regulatory effect for rare variants with higher accuracy than models using genomic annotations alone. Overall, we demonstrate that rare variants contribute to large gene expression changes across tissues and provide an integrative method for interpretation of rare variants in individual genomes.

Published
2017

11. Concerted neuron-astrocyte gene expression declines in aging and schizophrenia

Author

Ling, Emi, primary, Nemesh, James, additional, Goldman, Melissa, additional, Kamitaki, Nolan, additional, Reed, Nora, additional, Handsaker, Robert E., additional, Genovese, Giulio, additional, Vogelgsang, Jonathan S., additional, Gerges, Sherif, additional, Kashin, Seva, additional, Ghosh, Sulagna, additional, Esposito, John M., additional, French, Kiely, additional, Meyer, Daniel, additional, Lutservitz, Alyssa, additional, Mullally, Christopher D., additional, Wysoker, Alec, additional, Spina, Liv, additional, Neumann, Anna, additional, Hogan, Marina, additional, Ichihara, Kiku, additional, Berretta, Sabina, additional, and McCarroll, Steven A., additional

Published
2024
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12. An integrated map of structural variation in 2,504 human genomes.

Author

Sudmant, Peter H, Rausch, Tobias, Gardner, Eugene J, Handsaker, Robert E, Abyzov, Alexej, Huddleston, John, Zhang, Yan, Ye, Kai, Jun, Goo, Fritz, Markus Hsi-Yang, Konkel, Miriam K, Malhotra, Ankit, Stütz, Adrian M, Shi, Xinghua, Casale, Francesco Paolo, Chen, Jieming, Hormozdiari, Fereydoun, Dayama, Gargi, Chen, Ken, Malig, Maika, Chaisson, Mark JP, Walter, Klaudia, Meiers, Sascha, Kashin, Seva, Garrison, Erik, Auton, Adam, Lam, Hugo YK, Mu, Xinmeng Jasmine, Alkan, Can, Antaki, Danny, Bae, Taejeong, Cerveira, Eliza, Chines, Peter, Chong, Zechen, Clarke, Laura, Dal, Elif, Ding, Li, Emery, Sarah, Fan, Xian, Gujral, Madhusudan, Kahveci, Fatma, Kidd, Jeffrey M, Kong, Yu, Lameijer, Eric-Wubbo, McCarthy, Shane, Flicek, Paul, Gibbs, Richard A, Marth, Gabor, Mason, Christopher E, Menelaou, Androniki, Muzny, Donna M, Nelson, Bradley J, Noor, Amina, Parrish, Nicholas F, Pendleton, Matthew, Quitadamo, Andrew, Raeder, Benjamin, Schadt, Eric E, Romanovitch, Mallory, Schlattl, Andreas, Sebra, Robert, Shabalin, Andrey A, Untergasser, Andreas, Walker, Jerilyn A, Wang, Min, Yu, Fuli, Zhang, Chengsheng, Zhang, Jing, Zheng-Bradley, Xiangqun, Zhou, Wanding, Zichner, Thomas, Sebat, Jonathan, Batzer, Mark A, McCarroll, Steven A, 1000 Genomes Project Consortium, Mills, Ryan E, Gerstein, Mark B, Bashir, Ali, Stegle, Oliver, Devine, Scott E, Lee, Charles, Eichler, Evan E, and Korbel, Jan O

Subjects
Genomes Project Consortium, Humans, Genetic Predisposition to Disease, Physical Chromosome Mapping, Sequence Analysis, DNA, Genetics, Medical, Genetics, Population, Genomics, Sequence Deletion, Amino Acid Sequence, Genotype, Haplotypes, Homozygote, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome, Human, Molecular Sequence Data, Genetic Variation, Genome-Wide Association Study, Mutation Rate, Sequence Analysis, DNA, Genetics, Medical, Population, Polymorphism, Single Nucleotide, Genome, Human, General Science & Technology
Abstract

Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association.

Published
2015

13. A marmoset brain cell census reveals regional specialization of cellular identities

Author

Krienen, Fenna M., primary, Levandowski, Kirsten M., additional, Zaniewski, Heather, additional, del Rosario, Ricardo C.H., additional, Schroeder, Margaret E., additional, Goldman, Melissa, additional, Wienisch, Martin, additional, Lutservitz, Alyssa, additional, Beja-Glasser, Victoria F., additional, Chen, Cindy, additional, Zhang, Qiangge, additional, Chan, Ken Y., additional, Li, Katelyn X., additional, Sharma, Jitendra, additional, McCormack, Dana, additional, Shin, Tay Won, additional, Harrahill, Andrew, additional, Nyase, Eric, additional, Mudhar, Gagandeep, additional, Mauermann, Abigail, additional, Wysoker, Alec, additional, Nemesh, James, additional, Kashin, Seva, additional, Vergara, Josselyn, additional, Chelini, Gabriele, additional, Dimidschstein, Jordane, additional, Berretta, Sabina, additional, Deverman, Benjamin E., additional, Boyden, Ed, additional, McCarroll, Steven A., additional, and Feng, Guoping, additional

Published
2023
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14. The impact of rare variation on gene expression across tissues

Author

Li, Xin, Kim, Yungil, Tsang, Emily K., Davis, Joe R., Damani, Farhan N., Chiang, Colby, Hess, Gaelen T., Zappala, Zachary, Strober, Benjamin J., Scott, Alexandra J., Li, Amy, Ganna, Andrea, Bassik, Michael C., Merker, Jason D., Aguet, Franois, Ardlie, Kristin G., Cummings, Beryl B., Gelfand, Ellen T., Getz, Gad, Hadley, Kane, Handsaker, Robert E., Huang, Katherine H., Kashin, Seva, Karczewski, Konrad J., Lek, Monkol, Li, Xiao, MacArthur, Daniel G., Nedzel, Jared L., Nguyen, Duyen T., Noble, Michael S., Segr, Ayellet V., Trowbridge, Casandra A., Tukiainen, Taru, Abell, Nathan S., Balliu, Brunilda, Barshir, Ruth, Basha, Omer, Battle, Alexis, Bogu, Gireesh K., Brown, Andrew, Brown, Christopher D., Castel, Stephane E., Chen, Lin S., Conrad, Donald F., Cox, Nancy J., Delaneau, Olivier, Dermitzakis, Emmanouil T., Engelhardt, Barbara E., Eskin, Eleazar, Ferreira, Pedro G., Frsard, Laure, Gamazon, Eric R., Garrido-Martn, Diego, Gewirtz, Ariel D.H., Gliner, Genna, Gloudemans, Michael J., Guigo, Roderic, Hall, Ira M., Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Kyung Im, Hae, Jo, Brian, Yong Kang, Eun, Kim-Hellmuth, Sarah, Lappalainen, Tuuli, Li, Gen, Liu, Boxiang, Mangul, Serghei, McCarthy, Mark I., McDowell, Ian C., Mohammadi, Pejman, Monlong, Jean, Montgomery, Stephen B., Muoz-Aguirre, Manuel, Ndungu, Anne W., Nicolae, Dan L., Nobel, Andrew B., Oliva, Meritxell, Ongen, Halit, Palowitch, John J., Panousis, Nikolaos, Papasaikas, Panagiotis, Park, YoSon, Parsana, Princy, Payne, Anthony J., Peterson, Christine B., Quan, Jie, Reverter, Ferran, Sabatti, Chiara, Saha, Ashis, Sammeth, Michael, Shabalin, Andrey A., Sodaei, Reza, Stephens, Matthew, Stranger, Barbara E., Sul, Jae Hoon, Urbut, Sarah, van de Bunt, Martijn, Wang, Gao, Wen, Xiaoquan, Wright, Fred A., Xi, Hualin S., Yeger-Lotem, Esti, Zaugg, Judith B., Zhou, Yi-Hui, Akey, Joshua M., Bates, Daniel, Chan, Joanne, Claussnitzer, Melina, Demanelis, Kathryn, Diegel, Morgan, Doherty, Jennifer A., Feinberg, Andrew P., Fernando, Marian S., Halow, Jessica, Hansen, Kasper D., Haugen, Eric, Hickey, Peter F., Hou, Lei, Jasmine, Farzana, Jian, Ruiqi, Jiang, Lihua, Johnson, Audra, Kaul, Rajinder, Kellis, Manolis, Kibriya, Muhammad G., Lee, Kristen, Billy Li, Jin, Li, Qin, Lin, Jessica, Lin, Shin, Linder, Sandra, Linke, Caroline, Liu, Yaping, Maurano, Matthew T., Molinie, Benoit, Nelson, Jemma, Neri, Fidencio J., Park, Yongjin, Pierce, Brandon L., Rinaldi, Nicola J., Rizzardi, Lindsay F., Sandstrom, Richard, Skol, Andrew, Smith, Kevin S., Snyder, Michael P., Stamatoyannopoulos, John, Tang, Hua, Wang, Li, Wang, Meng, Van Wittenberghe, Nicholas, Wu, Fan, Zhang, Rui, Nierras, Concepcion R., Branton, Philip A., Carithers, Latarsha J., Guan, Ping, Moore, Helen M., Rao, Abhi, Vaught, Jimmie B., Gould, Sarah E., Lockart, Nicole C., Martin, Casey, Struewing, Jeffery P., Volpi, Simona, Addington, Anjene M., Koester, Susan E., Little, A. Roger, Brigham, Lori E., Hasz, Richard, Hunter, Marcus, Johns, Christopher, Johnson, Mark, Kopen, Gene, Leinweber, William F., Lonsdale, John T., McDonald, Alisa, Mestichelli, Bernadette, Myer, Kevin, Roe, Brian, Salvatore, Michael, Shad, Saboor, Thomas, Jeffrey A., Walters, Gary, Washington, Michael, Wheeler, Joseph, Bridge, Jason, Foster, Barbara A., Gillard, Bryan M., Karasik, Ellen, Kumar, Rachna, Miklos, Mark, Moser, Michael T., Jewell, Scott D., Montroy, Robert G., Rohrer, Daniel C., Valley, Dana R., Davis, David A., Mash, Deborah C., Undale, Anita H., Smith, Anna M., Tabor, David E., Roche, Nancy V., McLean, Jeffrey A., Vatanian, Negin, Robinson, Karna L., Sobin, Leslie, Barcus, Mary E., Valentino, Kimberly M., Qi, Liqun, Hunter, Steven, Hariharan, Pushpa, Singh, Shilpi, Um, Ki Sung, Matose, Takunda, Tomaszewski, Maria M., Barker, Laura K., Mosavel, Maghboeba, Siminoff, Laura A., Traino, Heather M., Flicek, Paul, Juettemann, Thomas, Ruffier, Magali, Sheppard, Dan, Taylor, Kieron, Trevanion, Stephen J., Zerbino, Daniel R., Craft, Brian, Goldman, Mary, Haeussler, Maximilian, Kent, W. James, Lee, Christopher M., Paten, Benedict, Rosenbloom, Kate R., Vivian, John, and Zhu, Jingchun

Subjects
Disease susceptibility -- Genetic aspects, Genetic variation -- Observations, Gene expression -- Observations, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Xin Li [1]; Yungil Kim [2]; Emily K. Tsang [1, 3]; Joe R. Davis [1, 4]; Farhan N. Damani [2]; Colby Chiang [5]; Gaelen T. Hess [4]; Zachary Zappala [...]

Published
2017
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15. Dynamic landscape and regulation of RNA editing in mammals

Author

Tan, Meng How, Li, Qin, Shanmugam, Raghuvaran, Piskol, Robert, Kohler, Jennefer, Young, Amy N., Liu, Kaiwen Ivy, Zhang, Rui, Ramaswami, Gokul, Ariyoshi, Kentaro, Gupte, Ankita, Keegan, Liam P., George, Cyril X., Ramu, Avinash, Huang, Ni, Pollina, Elizabeth A., Leeman, Dena S., Rustighi, Alessandra, Goh, Y. P. Sharon, Aguet, Franois, Ardlie, Kristin G., Cummings, Beryl B., Gelfand, Ellen T., Getz, Gad, Hadley, Kane, Handsaker, Robert E., Huang, Katherine H., Kashin, Seva, Karczewski, Konrad J., Lek, Monkol, Li, Xiao, MacArthur, Daniel G., Nedzel, Jared L., Nguyen, Duyen T., Noble, Michael S., Segr, Ayellet V., Trowbridge, Casandra A., Tukiainen, Taru, Abell, Nathan S., Balliu, Brunilda, Barshir, Ruth, Basha, Omer, Battle, Alexis, Bogu, Gireesh K., Brown, Andrew, Brown, Christopher D., Castel, Stephane E., Chen, Lin S., Chiang, Colby, Conrad, Donald F., Cox, Nancy J., Damani, Farhan N., Davis, Joe R., Delaneau, Olivier, Dermitzakis, Emmanouil T., Engelhardt, Barbara E., Eskin, Eleazar, Ferreira, Pedro G., Frsard, Laure, Gamazon, Eric R., Garrido-Martn, Diego, Gewirtz, Ariel D. H., Gliner, Genna, Gloudemans, Michael J., Guigo, Roderic, Hall, Ira M., Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Kyung Im, Hae, Jo, Brian, Yong Kang, Eun, Kim, Yungil, Kim-Hellmuth, Sarah, Lappalainen, Tuuli, Li, Gen, Li, Xin, Liu, Boxiang, Mangul, Serghei, McCarthy, Mark I., McDowell, Ian C., Mohammadi, Pejman, Monlong, Jean, Montgomery, Stephen B., Muoz-Aguirre, Manuel, Ndungu, Anne W., Nicolae, Dan L., Nobel, Andrew B., Oliva, Meritxell, Ongen, Halit, Palowitch, John J., Panousis, Nikolaos, Papasaikas, Panagiotis, Park, YoSon, Parsana, Princy, Payne, Anthony J., Peterson, Christine B., Quan, Jie, Reverter, Ferran, Sabatti, Chiara, Saha, Ashis, Sammeth, Michael, Scott, Alexandra J., Shabalin, Andrey A., Sodaei, Reza, Stephens, Matthew, Stranger, Barbara E., Strober, Benjamin J., Sul, Jae Hoon, Tsang, Emily K., Urbut, Sarah, van de Bunt, Martijn, Wang, Gao, Wen, Xiaoquan, Wright, Fred A., Xi, Hualin S., Yeger-Lotem, Esti, Zappala, Zachary, Zaugg, Judith B., Zhou, Yi-Hui, Akey, Joshua M., Bates, Daniel, Chan, Joanne, Claussnitzer, Melina, Demanelis, Kathryn, Diegel, Morgan, Doherty, Jennifer A., Feinberg, Andrew P., Fernando, Marian S., Halow, Jessica, Hansen, Kasper D., Haugen, Eric, Hickey, Peter F., Hou, Lei, Jasmine, Farzana, Jian, Ruiqi, Jiang, Lihua, Johnson, Audra, Kaul, Rajinder, Kellis, Manolis, Kibriya, Muhammad G., Lee, Kristen, Li, Jin Billy, Lin, Jessica, Lin, Shin, Linder, Sandra, Linke, Caroline, Liu, Yaping, Maurano, Matthew T., Molinie, Benoit, Nelson, Jemma, Neri, Fidencio J., Park, Yongjin, Pierce, Brandon L., Rinaldi, Nicola J., Rizzardi, Lindsay F., Sandstrom, Richard, Skol, Andrew, Smith, Kevin S., Snyder, Michael P., Stamatoyannopoulos, John, Tang, Hua, Wang, Li, Wang, Meng, Van Wittenberghe, Nicholas, Wu, Fan, Nierras, Concepcion R., Branton, Philip A., Carithers, Latarsha J., Guan, Ping, Moore, Helen M., Rao, Abhi, Vaught, Jimmie B., Gould, Sarah E., Lockart, Nicole C., Martin, Casey, Struewing, Jeffery P., Volpi, Simona, Addington, Anjene M., Koester, Susan E., Little, A. Roger, Brigham, Lori E., Hasz, Richard, Hunter, Marcus, Johns, Christopher, Johnson, Mark, Kopen, Gene, Leinweber, William F., Lonsdale, John T., McDonald, Alisa, Mestichelli, Bernadette, Myer, Kevin, Roe, Brian, Salvatore, Michael, Shad, Saboor, Thomas, Jeffrey A., Walters, Gary, Washington, Michael, Wheeler, Joseph, Bridge, Jason, Foster, Barbara A., Gillard, Bryan M., Karasik, Ellen, Kumar, Rachna, Miklos, Mark, Moser, Michael T., Jewell, Scott D., Montroy, Robert G., Rohrer, Daniel C., Valley, Dana R., Davis, David A., Mash, Deborah C., Undale, Anita H., Smith, Anna M., Tabor, David E., Roche, Nancy V., McLean, Jeffrey A., Vatanian, Negin, Robinson, Karna L., Sobin, Leslie, Barcus, Mary E., Valentino, Kimberly M., Qi, Liqun, Hunter, Steven, Hariharan, Pushpa, Singh, Shilpi, Um, Ki Sung, Matose, Takunda, Tomaszewski, Maria M., Barker, Laura K., Mosavel, Maghboeba, Siminoff, Laura A., Traino, Heather M., Flicek, Paul, Juettemann, Thomas, Ruffier, Magali, Sheppard, Dan, Taylor, Kieron, Trevanion, Stephen J., Zerbino, Daniel R., Craft, Brian, Goldman, Mary, Haeussler, Maximilian, Kent, W. James, Lee, Christopher M., Paten, Benedict, Rosenbloom, Kate R., Vivian, John, Zhu, Jingchun, Chawla, Ajay, Del Sal, Giannino, Peltz, Gary, Brunet, Anne, Samuel, Charles E., OConnell, Mary A., Walkley, Carl R., and Nishikura, Kazuko

Subjects
Genetic research, Mammals -- Genetic aspects, RNA processing -- Research, Genetic regulation, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Meng How Tan (corresponding author) [1, 2, 3]; Qin Li [1]; Raghuvaran Shanmugam [2, 3]; Robert Piskol [1]; Jennefer Kohler [1]; Amy N. Young [1]; Kaiwen Ivy Liu [3]; [...]

Published
2017
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16. Landscape of X chromosome inactivation across human tissues

Author

Tukiainen, Taru, Villani, Alexandra-Chlo, Yen, Angela, Rivas, Manuel A., Marshall, Jamie L., Satija, Rahul, Aguirre, Matt, Gauthier, Laura, Fleharty, Mark, Kirby, Andrew, Cummings, Beryl B., Castel, Stephane E., Karczewski, Konrad J., Aguet, Franois, Byrnes, Andrea, Ardlie, Kristin G., Gelfand, Ellen T., Getz, Gad, Hadley, Kane, Handsaker, Robert E., Huang, Katherine H., Kashin, Seva, Lek, Monkol, Li, Xiao, MacArthur, Daniel G., Nedzel, Jared L., Nguyen, Duyen T., Noble, Michael S., Segr, Ayellet V., Trowbridge, Casandra A., Abell, Nathan S., Balliu, Brunilda, Barshir, Ruth, Basha, Omer, Battle, Alexis, Bogu, Gireesh K., Brown, Andrew, Brown, Christopher D., Chen, Lin S., Chiang, Colby, Conrad, Donald F., Cox, Nancy J., Damani, Farhan N., Davis, Joe R., Delaneau, Olivier, Dermitzakis, Emmanouil T., Engelhardt, Barbara E., Eskin, Eleazar, Ferreira, Pedro G., Frsard, Laure, Gamazon, Eric R., Garrido-Martn, Diego, Gewirtz, Ariel D. H., Gliner, Genna, Gloudemans, Michael J., Guigo, Roderic, Hall, Ira M., Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Kyung Im, Hae, Jo, Brian, Yong Kang, Eun, Kim, Yungil, Kim-Hellmuth, Sarah, Lappalainen, Tuuli, Li, Gen, Li, Xin, Liu, Boxiang, Mangul, Serghei, McCarthy, Mark I., McDowell, Ian C., Mohammadi, Pejman, Monlong, Jean, Montgomery, Stephen B., Muoz-Aguirre, Manuel, Ndungu, Anne W., Nicolae, Dan L., Nobel, Andrew B., Oliva, Meritxell, Ongen, Halit, Palowitch, John J., Panousis, Nikolaos, Papasaikas, Panagiotis, Park, YoSon, Parsana, Princy, Payne, Anthony J., Peterson, Christine B., Quan, Jie, Reverter, Ferran, Sabatti, Chiara, Saha, Ashis, Sammeth, Michael, Scott, Alexandra J., Shabalin, Andrey A., Sodaei, Reza, Stephens, Matthew, Stranger, Barbara E., Strober, Benjamin J., Sul, Jae Hoon, Tsang, Emily K., Urbut, Sarah, van de Bunt, Martijn, Wang, Gao, Wen, Xiaoquan, Wright, Fred A., Xi, Hualin S., Yeger-Lotem, Esti, Zappala, Zachary, Zaugg, Judith B., Zhou, Yi-Hui, Akey, Joshua M., Bates, Daniel, Chan, Joanne, Claussnitzer, Melina, Demanelis, Kathryn, Diegel, Morgan, Doherty, Jennifer A., Feinberg, Andrew P., Fernando, Marian S., Halow, Jessica, Hansen, Kasper D., Haugen, Eric, Hickey, Peter F., Hou, Lei, Jasmine, Farzana, Jian, Ruiqi, Jiang, Lihua, Johnson, Audra, Kaul, Rajinder, Kellis, Manolis, Kibriya, Muhammad G., Lee, Kristen, Li, Jin Billy, Li, Qin, Lin, Jessica, Lin, Shin, Linder, Sandra, Linke, Caroline, Liu, Yaping, Maurano, Matthew T., Molinie, Benoit, Nelson, Jemma, Neri, Fidencio J., Park, Yongjin, Pierce, Brandon L., Rinaldi, Nicola J., Rizzardi, Lindsay F., Sandstrom, Richard, Skol, Andrew, Smith, Kevin S., Snyder, Michael P., Stamatoyannopoulos, John, Tang, Hua, Wang, Li, Wang, Meng, Van Wittenberghe, Nicholas, Wu, Fan, Zhang, Rui, Nierras, Concepcion R., Branton, Philip A., Carithers, Latarsha J., Guan, Ping, Moore, Helen M., Rao, Abhi, Vaught, Jimmie B., Gould, Sarah E., Lockart, Nicole C., Martin, Casey, Struewing, Jeffery P., Volpi, Simona, Addington, Anjene M., Koester, Susan E., Little, A. Roger, Brigham, Lori E., Hasz, Richard, Hunter, Marcus, Johns, Christopher, Johnson, Mark, Kopen, Gene, Leinweber, William F., Lonsdale, John T., McDonald, Alisa, Mestichelli, Bernadette, Myer, Kevin, Roe, Brian, Salvatore, Michael, Shad, Saboor, Thomas, Jeffrey A., Walters, Gary, Washington, Michael, Wheeler, Joseph, Bridge, Jason, Foster, Barbara A., Gillard, Bryan M., Karasik, Ellen, Kumar, Rachna, Miklos, Mark, Moser, Michael T., Jewell, Scott D., Montroy, Robert G., Rohrer, Daniel C., Valley, Dana R., Davis, David A., Mash, Deborah C., Undale, Anita H., Smith, Anna M., Tabor, David E., Roche, Nancy V., McLean, Jeffrey A., Vatanian, Negin, Robinson, Karna L., Sobin, Leslie, Barcus, Mary E., Valentino, Kimberly M., Qi, Liqun, Hunter, Steven, Hariharan, Pushpa, Singh, Shilpi, Um, Ki Sung, Matose, Takunda, Tomaszewski, Maria M., Barker, Laura K., Mosavel, Maghboeba, Siminoff, Laura A., Traino, Heather M., Flicek, Paul, Juettemann, Thomas, Ruffier, Magali, Sheppard, Dan, Taylor, Kieron, Trevanion, Stephen J., Zerbino, Daniel R., Craft, Brian, Goldman, Mary, Haeussler, Maximilian, Kent, W. James, Lee, Christopher M., Paten, Benedict, Rosenbloom, Kate R., Vivian, John, Zhu, Jingchun, Regev, Aviv, and Hacohen, Nir

Subjects
Chromosomes -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Taru Tukiainen (corresponding author) [1, 2]; Alexandra-Chlo Villani [2, 3]; Angela Yen [2, 4]; Manuel A. Rivas [1, 2, 5]; Jamie L. Marshall [1, 2]; Rahul Satija [2, 6, [...]

Published
2017
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17. Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations

Author

Merkle, Florian T., Ghosh, Sulagna, Kamitaki, Nolan, Mitchell, Jana, Avior, Yishai, Mello, Curtis, and Kashin, Seva

Subjects
Stem cells -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The authors surveyed whole-exome and RNA-sequencing data from 252 unique pluripotent stem cell lines, some of which are in the pipeline for clinical use, and found that approximately 5% of cell lines had acquired mutations in the TP53 gene that allow mutant cells to rapidly outcompete non-mutant cells, but do not prevent differentiation. Expansion of human pluripotent stem cells carrying P53 mutations Copy number variants at particular genomic locations have been shown to arise in human pluripotent stem cells (hPSCs) under certain culture conditions, but the extent of acquired mutations in such culture remains to be determined. Kevin Eggan and colleagues surveyed the exomes of 140 human embryonic stem cell (hESC) lines, some of which are in the pipeline for clinical use.They identified mosaic mutations in the TP53 gene in a subset of cells for five unrelated hESC lines and show that the cells carrying the mutations outcompeted the non-mutant cells and could readily differentiate. Similar mutations were also identified by mining published datasets for an additional 14 hESC lines and more than 100 human induced PSC lines. The study highlights the need for in-depth characterization of cells derived from hPSCs before their use in the clinic. Human pluripotent stem cells (hPS cells) can self-renew indefinitely, making them an attractive source for regenerative therapies. This expansion potential has been linked with the acquisition of large copy number variants that provide mutated cells with a growth advantage in culture.sup.1,2,3. The nature, extent and functional effects of other acquired genome sequence mutations in cultured hPS cells are not known. Here we sequence the protein-coding genes (exomes) of 140 independent human embryonic stem cell (hES cell) lines, including 26 lines prepared for potential clinical use.sup.4. We then apply computational strategies for identifying mutations present in a subset of cells in each hES cell line.sup.5. Although such mosaic mutations were generally rare, we identified five unrelated hES cell lines that carried six mutations in the TP53 gene that encodes the tumour suppressor P53. The TP53 mutations we observed are dominant negative and are the mutations most commonly seen in human cancers. We found that the TP53 mutant allelic fraction increased with passage number under standard culture conditions, suggesting that the P53 mutations confer selective advantage. We then mined published RNA sequencing data from 117 hPS cell lines, and observed another nine TP53 mutations, all resulting in coding changes in the DNA-binding domain of P53. In three lines, the allelic fraction exceeded 50%, suggesting additional selective advantage resulting from the loss of heterozygosity at the TP53 locus. As the acquisition and expansion of cancer-associated mutations in hPS cells may go unnoticed during most applications, we suggest that careful genetic characterization of hPS cells and their differentiated derivatives be carried out before clinical use., Author(s): Florian T. Merkle [sup.1] [sup.2] [sup.3] [sup.4] [sup.9] , Sulagna Ghosh [sup.1] [sup.2] [sup.3] [sup.4] , Nolan Kamitaki [sup.3] [sup.5] [sup.6] , Jana Mitchell [sup.1] [sup.2] [sup.3] [sup.4] , [...]

Published
2017
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18. A marmoset brain cell census reveals persistent influence of developmental origin on neurons

Author

Krienen, Fenna M., primary, Levandowski, Kirsten M., additional, Zaniewski, Heather, additional, del Rosario, Ricardo C.H., additional, Schroeder, Margaret E., additional, Goldman, Melissa, additional, Lutservitz, Alyssa, additional, Zhang, Qiangge, additional, Li, Katelyn X., additional, Beja-Glasser, Victoria F., additional, Sharma, Jitendra, additional, Shin, Tay Won, additional, Mauermann, Abigail, additional, Wysoker, Alec, additional, Nemesh, James, additional, Kashin, Seva, additional, Vergara, Josselyn, additional, Chelini, Gabriele, additional, Dimidschstein, Jordane, additional, Berretta, Sabina, additional, Boyden, Ed, additional, McCarroll, Steven A., additional, and Feng, Guoping, additional

Published
2022
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19. Genetic effects on gene expression across human tissues

Author

Aguet, François, Ardlie, Kristin G., Cummings, Beryl B., Gelfand, Ellen T., Getz, Gad, Hadley, Kane, Handsaker, Robert E., Huang, Katherine H., Kashin, Seva, Karczewski, Konrad J., Lek, Monkol, Li, Xiao, MacArthur, Daniel G., Nedzel, Jared L., Nguyen, Duyen T., Noble, Michael S., Segrè, Ayellet V., Trowbridge, Casandra A., Tukiainen, Taru, Abell, Nathan S., Balliu, Brunilda, Barshir, Ruth, Basha, Omer, Battle, Alexis, Bogu, Gireesh K., Brown, Andrew, Brown, Christopher D., Castel, Stephane E., Chen, Lin S., Chiang, Colby, Conrad, Donald F., Cox, Nancy J., Damani, Farhan N., Davis, Joe R., Delaneau, Olivier, Dermitzakis, Emmanouil T., Engelhardt, Barbara E., Eskin, Eleazar, Ferreira, Pedro G., Frésard, Laure, Gamazon, Eric R., Garrido-Martín, Diego, Gewirtz, Ariel D.H., Gliner, Genna, Gloudemans, Michael J., Guigo, Roderic, Hall, Ira M., Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Im, Hae Kyung, Jo, Brian, Kang, Eun Yong, Kim, Yungil, Kim-Hellmuth, Sarah, Lappalainen, Tuuli, Li, Gen, Li, Xin, Liu, Boxiang, Mangul, Serghei, McCarthy, Mark I., McDowell, Ian C., Mohammadi, Pejman, Monlong, Jean, Montgomery, Stephen B., Muñoz-Aguirre, Manuel, Ndungu, Anne W., Nicolae, Dan L., Nobel, Andrew B., Oliva, Meritxell, Ongen, Halit, Palowitch, John J., Panousis, Nikolaos, Papasaikas, Panagiotis, Park, YoSon, Parsana, Princy, Payne, Anthony J., Peterson, Christine B., Quan, Jie, Reverter, Ferran, Sabatti, Chiara, Saha, Ashis, Sammeth, Michael, Scott, Alexandra J., Shabalin, Andrey A., Sodaei, Reza, Stephens, Matthew, Stranger, Barbara E., Strober, Benjamin J., Sul, Jae Hoon, Tsang, Emily K., Urbut, Sarah, van de Bunt, Martijn, Wang, Gao, Wen, Xiaoquan, Wright, Fred A., Xi, Hualin S., Yeger-Lotem, Esti, Zappala, Zachary, Zaugg, Judith B., Zhou, Yi-Hui, Akey, Joshua M., Bates, Daniel, Chan, Joanne, Claussnitzer, Melina, Demanelis, Kathryn, Diegel, Morgan, Doherty, Jennifer A., Feinberg, Andrew P., Fernando, Marian S., Halow, Jessica, Hansen, Kasper D., Haugen, Eric, Hickey, Peter F., Hou, Lei, Jasmine, Farzana, Jian, Ruiqi, Jiang, Lihua, Johnson, Audra, Kaul, Rajinder, Kellis, Manolis, Kibriya, Muhammad G., Lee, Kristen, Li, Jin Billy, Li, Qin, Lin, Jessica, Lin, Shin, Linder, Sandra, Linke, Caroline, Liu, Yaping, Maurano, Matthew T., Molinie, Benoit, Nelson, Jemma, Neri, Fidencio J., Park, Yongjin, Pierce, Brandon L., Rinaldi, Nicola J., Rizzardi, Lindsay F., Sandstrom, Richard, Skol, Andrew, Smith, Kevin S., Snyder, Michael P., Stamatoyannopoulos, John, Tang, Hua, Wang, Li, Wang, Meng, Van Wittenberghe, Nicholas, Wu, Fan, Zhang, Rui, Nierras, Concepcion R., Branton, Philip A., Carithers, Latarsha J., Guan, Ping, Moore, Helen M., Rao, Abhi, Vaught, Jimmie B., Gould, Sarah E., Lockart, Nicole C., Martin, Casey, Struewing, Jeffery P., Volpi, Simona, Addington, Anjene M., Koester, Susan E., Little, Roger A., Brigham, Lori E., Hasz, Richard, Hunter, Marcus, Johns, Christopher, Johnson, Mark, Kopen, Gene, Leinweber, William F., Lonsdale, John T., McDonald, Alisa, Mestichelli, Bernadette, Myer, Kevin, Roe, Brian, Salvatore, Michael, Shad, Saboor, Thomas, Jeffrey A., Walters, Gary, Washington, Michael, Wheeler, Joseph, Bridge, Jason, Foster, Barbara A., Gillard, Bryan M., Karasik, Ellen, Kumar, Rachna, Miklos, Mark, Moser, Michael T., Jewell, Scott D., Montroy, Robert G., Rohrer, Daniel C., Valley, Dana R., Davis, David A., Mash, Deborah C., Undale, Anita H., Smith, Anna M., Tabor, David E., Roche, Nancy V., McLean, Jeffrey A., Vatanian, Negin, Robinson, Karna L., Sobin, Leslie, Barcus, Mary E., Valentino, Kimberly M., Qi, Liqun, Hunter, Steven, Hariharan, Pushpa, Singh, Shilpi, Um, Ki Sung, Matose, Takunda, Tomaszewski, Maria M., Barker, Laura K., Mosavel, Maghboeba, Siminoff, Laura A., Traino, Heather M., Flicek, Paul, Juettemann, Thomas, Ruffier, Magali, Sheppard, Dan, Taylor, Kieron, Trevanion, Stephen J., Zerbino, Daniel R., Craft, Brian, Goldman, Mary, Haeussler, Maximilian, Kent, James W., Lee, Christopher M., Paten, Benedict, Rosenbloom, Kate R., Vivian, John, Zhu, Jingchun, Brown, Andrew A., Nguyen, Duyen Y., Sullivan, Timothy J., Addington, Anjene, Koester, Susan, Lockhart, Nicole C., Roe, Bryan, Valley, Dana, Gewirtz, Ariel D. H., He, Amy Z., Quon, Gerald, Ripke, Stephan, Shimko, Tyler C., Teran, Nicole A., Zhang, Hailei, Bustamante, Carlos D., and Guigó, Roderic

Published
2017
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20. Whole-genome analysis of human embryonic stem cells enables rational line selection based on genetic variation

Author

Merkle, Florian T., primary, Ghosh, Sulagna, additional, Genovese, Giulio, additional, Handsaker, Robert E., additional, Kashin, Seva, additional, Meyer, Daniel, additional, Karczewski, Konrad J., additional, O’Dushlaine, Colm, additional, Pato, Carlos, additional, Pato, Michele, additional, MacArthur, Daniel G., additional, McCarroll, Steven A., additional, and Eggan, Kevin, additional

Published
2022
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21. Ascertaining cells’ synaptic connections and RNA expression simultaneously with massively barcoded rabies virus libraries

Author

Saunders, Arpiar, primary, Huang, Kee Wui, additional, Vondrak, Cassandra, additional, Hughes, Christina, additional, Smolyar, Karina, additional, Sen, Harsha, additional, Philson, Adrienne C., additional, Nemesh, James, additional, Wysoker, Alec, additional, Kashin, Seva, additional, Sabatini, Bernardo L., additional, and McCarroll, Steven A., additional

Published
2021
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22. A global reference for human genetic variation

Author

Altshuler, David M., (Co-Chair), Durbin, Richard M., (Co-Chair, Principal Investigator), Donnelly, Peter, Green, Eric D., Nickerson, Deborah A., Boerwinkle, Eric, Doddapaneni, Harsha, Han, Yi, Korchina, Viktoriya, Kovar, Christie, Lee, Sandra, Muzny, Donna, Reid, Jeffrey G., Zhu, Yiming, Wang, Jun, (Principal Investigator), Chang, Yuqi, Feng, Qiang, Fang, Xiaodong, Guo, Xiaosen, Jian, Min, Jiang, Hui, Jin, Xin, Lan, Tianming, Li, Guoqing, Li, Jingxiang, Li, Yingrui, Liu, Shengmao, Liu, Xiao, Lu, Yao, Ma, Xuedi, Tang, Meifang, Wang, Bo, Wang, Guangbiao, Wu, Honglong, Wu, Renhua, Xu, Xun, Yin, Ye, Zhang, Dandan, Zhang, Wenwei, Zhao, Jiao, Zhao, Meiru, Zheng, Xiaole, Lander, Eric S., (Principal Investigator), Gabriel, Stacey B., (Co-Chair), Gupta, Namrata, Gharani, Neda, Toji, Lorraine H., Gerry, Norman P., Resch, Alissa M., Barker, Jonathan, Gil, Laurent, Hunt, Sarah E., Kelman, Gavin, Kulesha, Eugene, Leinonen, Rasko, McLaren, William M., Radhakrishnan, Rajesh, Roa, Asier, Smirnov, Dmitriy, Smith, Richard E., Streeter, Ian, Thormann, Anja, Toneva, Iliana, Vaughan, Brendan, Zheng-Bradley, Xiangqun, Bentley, David R., (Principal Investigator), Grocock, Russell, Humphray, Sean, James, Terena, Kingsbury, Zoya, Lehrach, Hans, (Principal Investigator), Sudbrak, Ralf, (Project Leader), Albrecht, Marcus W., Amstislavskiy, Vyacheslav S., Borodina, Tatiana A., Lienhard, Matthias, Mertes, Florian, Sultan, Marc, Timmermann, Bernd, Yaspo, Marie-Laure, Mardis, Elaine R., (Co-Principal Investigator) (Co-Chair), Wilson, Richard K., (Co-Principal Investigator), Fulton, Lucinda, Fulton, Robert, Ananiev, Victor, Belaia, Zinaida, Beloslyudtsev, Dimitriy, Bouk, Nathan, Chen, Chao, Church, Deanna, Cohen, Robert, Cook, Charles, Garner, John, Hefferon, Timothy, Kimelman, Mikhail, Liu, Chunlei, Lopez, John, Meric, Peter, O’Sullivan, Chris, Ostapchuk, Yuri, Phan, Lon, Ponomarov, Sergiy, Schneider, Valerie, Shekhtman, Eugene, Sirotkin, Karl, Slotta, Douglas, Zhang, Hua, Balasubramaniam, Senduran, Burton, John, Danecek, Petr, Keane, Thomas M., Kolb-Kokocinski, Anja, McCarthy, Shane, Stalker, James, Quail, Michael, Schmidt, Jeanette P., (Principal Investigator), Davies, Christopher J., Gollub, Jeremy, Webster, Teresa, Wong, Brant, Zhan, Yiping, Auton, Adam, (Principal Investigator), Campbell, Christopher L., Kong, Yu, Marcketta, Anthony, Yu, Fuli, (Project Leader), Antunes, Lilian, Bainbridge, Matthew, Sabo, Aniko, Huang, Zhuoyi, Coin, Lachlan J. M., Fang, Lin, Li, Qibin, Li, Zhenyu, Lin, Haoxiang, Liu, Binghang, Luo, Ruibang, Shao, Haojing, Xie, Yinlong, Ye, Chen, Yu, Chang, Zhang, Fan, Zheng, Hancheng, Zhu, Hongmei, Alkan, Can, Dal, Elif, Kahveci, Fatma, Garrison, Erik P., (Project Lead), Kural, Deniz, Lee, Wan-Ping, Leong, Wen Fung, Stromberg, Michael, Ward, Alistair N., Wu, Jiantao, Zhang, Mengyao, Daly, Mark J., (Principal Investigator), DePristo, Mark A., (Project Leader), Handsaker, Robert E., (Project Leader), Banks, Eric, Bhatia, Gaurav, del Angel, Guillermo, Genovese, Giulio, Li, Heng, Kashin, Seva, Nemesh, James C., Poplin, Ryan E., Yoon, Seungtai C., (Principal Investigator), Lihm, Jayon, Makarov, Vladimir, Clark, Andrew G., (Principal Investigator), Gottipati, Srikanth, Keinan, Alon, Rodriguez-Flores, Juan L., Rausch, Tobias, (Project Leader), Fritz, Markus H., Stütz, Adrian M., Beal, Kathryn, Datta, Avik, Herrero, Javier, Ritchie, Graham R. S., Zerbino, Daniel, Sabeti, Pardis C., (Principal Investigator), Shlyakhter, Ilya, Schaffner, Stephen F., Vitti, Joseph, Cooper, David N., (Principal Investigator), Ball, Edward V., Stenson, Peter D., Barnes, Bret, Bauer, Markus, Cheetham, Keira R., Cox, Anthony, Eberle, Michael, Kahn, Scott, Murray, Lisa, Peden, John, Shaw, Richard, Kenny, Eimear E., (Principal Investigator), Batzer, Mark A., (Principal Investigator), Konkel, Miriam K., Walker, Jerilyn A., MacArthur, Daniel G., (Principal Investigator), Lek, Monkol, Herwig, Ralf, Koboldt, Daniel C., Larson, David, Ye, Kai, Gravel, Simon, Swaroop, Anand, Chew, Emily, Lappalainen, Tuuli, (Principal Investigator), Erlich, Yaniv, (Principal Investigator), Gymrek, Melissa, Willems, Thomas Frederick, Simpson, Jared T., Shriver, Mark D., (Principal Investigator), Rosenfeld, Jeffrey A., (Principal Investigator), Montgomery, Stephen B., (Principal Investigator), De La Vega, Francisco M., (Principal Investigator), Byrnes, Jake K., Carroll, Andrew W., DeGorter, Marianne K., Lacroute, Phil, Maples, Brian K., Martin, Alicia R., Moreno-Estrada, Andres, Shringarpure, Suyash S., Zakharia, Fouad, Halperin, Eran, (Principal Investigator), Baran, Yael, Cerveira, Eliza, Hwang, Jaeho, Malhotra, Ankit, (Co-Project Lead), Plewczynski, Dariusz, Radew, Kamen, Romanovitch, Mallory, Zhang, Chengsheng, (Co-Project Lead), Hyland, Fiona C. L., Craig, David W., (Principal Investigator), Christoforides, Alexis, Homer, Nils, Izatt, Tyler, Kurdoglu, Ahmet A., Sinari, Shripad A., Squire, Kevin, Xiao, Chunlin, Sebat, Jonathan, (Principal Investigator), Antaki, Danny, Gujral, Madhusudan, Noor, Amina, Ye, Kenny, Burchard, Esteban G., (Principal Investigator), Hernandez, Ryan D., (Principal Investigator), Gignoux, Christopher R., Haussler, David, (Principal Investigator), Katzman, Sol J., Kent, James W., Howie, Bryan, Ruiz-Linares, Andres, (Principal Investigator), Dermitzakis, Emmanouil T., (Principal Investigator), Devine, Scott E., (Principal Investigator), Abecasis, Gonçalo R., (Principal Investigator) (Co-Chair), Kang, Hyun Min, (Project Leader), Kidd, Jeffrey M., (Principal Investigator), Blackwell, Tom, Caron, Sean, Chen, Wei, Emery, Sarah, Fritsche, Lars, Fuchsberger, Christian, Jun, Goo, Li, Bingshan, Lyons, Robert, Scheller, Chris, Sidore, Carlo, Song, Shiya, Sliwerska, Elzbieta, Taliun, Daniel, Tan, Adrian, Welch, Ryan, Wing, Mary Kate, Zhan, Xiaowei, Awadalla, Philip, (Principal Investigator), Hodgkinson, Alan, Li, Yun, Shi, Xinghua, (Principal Investigator), Quitadamo, Andrew, Lunter, Gerton, (Principal Investigator), McVean, Gil A., (Principal Investigator) (Co-Chair), Marchini, Jonathan L., (Principal Investigator), Myers, Simon, (Principal Investigator), Churchhouse, Claire, Delaneau, Olivier, Gupta-Hinch, Anjali, Kretzschmar, Warren, Iqbal, Zamin, Mathieson, Iain, Menelaou, Androniki, Rimmer, Andy, Xifara, Dionysia K., Oleksyk, Taras K., (Principal Investigator), Fu, Yunxin, (Principal Investigator), Liu, Xiaoming, Xiong, Momiao, Jorde, Lynn, (Principal Investigator), Witherspoon, David, Xing, Jinchuan, Browning, Brian L., (Principal Investigator), Browning, Sharon R., (Principal Investigator), Hormozdiari, Fereydoun, Sudmant, Peter H., Khurana, Ekta, (Principal Investigator), Hurles, Matthew E., (Principal Investigator), Albers, Cornelis A., Ayub, Qasim, Chen, Yuan, Colonna, Vincenza, Jostins, Luke, Walter, Klaudia, Xue, Yali, Abyzov, Alexej, Balasubramanian, Suganthi, Chen, Jieming, Clarke, Declan, Fu, Yao, Harmanci, Arif O., Jin, Mike, Lee, Donghoon, Liu, Jeremy, Mu, Xinmeng Jasmine, Zhang, Jing, Zhang, Yan, McCarroll, Steven A., (Principal Investigator), Hartl, Chris, Shakir, Khalid, Degenhardt, Jeremiah, Korbel, Jan O., (Principal Investigator) (Co-Chair), Meiers, Sascha, Raeder, Benjamin, Casale, Francesco Paolo, Stegle, Oliver, Lameijer, Eric-Wubbo, Ding, Li, (Principal Investigator), Hall, Ira, Lee, Charles, (Principal Investigator) (Co-Chair), Bafna, Vineet, Michaelson, Jacob, Gardner, Eugene J., (Project Leader), Mills, Ryan E., (Principal Investigator), Dayama, Gargi, Chen, Ken, (Principle Investigator), Fan, Xian, Chong, Zechen, Chen, Tenghui, Eichler, Evan E., (Principal Investigator) (Co-Chair), Chaisson, Mark J., Huddleston, John, Malig, Maika, Nelson, Bradley J., Parrish, Nicholas F., Blackburne, Ben, Lindsay, Sarah J., Ning, Zemin, Zhang, Yujun, Lam, Hugo, Sisu, Cristina, Gibbs, Richard A., (Principal Investigator) (Co-Chair), Challis, Danny, Evani, Uday S., Lu, James, Nagaswamy, Uma, Yu, Jin, Li, Wangshen, Marth, Gabor T., (Principal Investigator) (Co-Chair), Habegger, Lukas, Yu, Haiyuan, (Principal Investigator), Cunningham, Fiona, Dunham, Ian, Lage, Kasper, (Principal Investigator), Jespersen, Jakob Berg, Horn, Heiko, Tyler-Smith, Chris, (Principal Investigator) (Co-Chair), Gerstein, Mark B., (Principal Investigator) (Co-Chair), Kim, Donghoon, Desalle, Rob, Narechania, Apurva, Wilson Sayres, Melissa A., Bustamante, Carlos D., (Principal Investigator) (Co-Chair), Mendez, Fernando L., Poznik, David G., Underhill, Peter A., Coin, Lachlan, (Principal Investigator), Mittelman, David, Banerjee, Ruby, Cerezo, Maria, Fitzgerald, Thomas W., Louzada, Sandra, Massaia, Andrea, Ritchie, Graham R., Yang, Fengtang, Kalra, Divya, Hale, Walker, Dan, Xu, Flicek, Paul, (Principal Investigator) (Co-Chair), Clarke, Laura, (Project Lead), Sherry, Stephen T., (Principal Investigator) (Co-Chair), Chakravarti, Aravinda, (Co-Chair), Knoppers, Bartha M., (Co-Chair), Barnes, Kathleen C., Beiswanger, Christine, Cai, Hongyu, Cao, Hongzhi, Henn, Brenna, Jones, Danielle, Kaye, Jane S., Kent, Alastair, Kerasidou, Angeliki, Mathias, Rasika, Ossorio, Pilar N., Parker, Michael, Rotimi, Charles N., Royal, Charmaine D., Sandoval, Karla, Su, Yeyang, Tian, Zhongming, Tishkoff, Sarah, Via, Marc, Wang, Yuhong, Yang, Ling, Zhu, Jiayong, Bodmer, Walter, Bedoya, Gabriel, Cai, Zhiming, Gao, Yang, Chu, Jiayou, Peltonen, Leena, Garcia-Montero, Andres, Orfao, Alberto, Dutil, Julie, Martinez-Cruzado, Juan C., Mathias, Rasika A., Hennis, Anselm, Watson, Harold, McKenzie, Colin, Qadri, Firdausi, LaRocque, Regina, Deng, Xiaoyan, Asogun, Danny, Folarin, Onikepe, Happi, Christian, Omoniwa, Omonwunmi, Stremlau, Matt, Tariyal, Ridhi, Jallow, Muminatou, Joof, Fatoumatta Sisay, Corrah, Tumani, Rockett, Kirk, Kwiatkowski, Dominic, Kooner, Jaspal, Hiê`n, Trâ`n Tinh, Dunstan, Sarah J., Hang, Nguyen Thuy, Fonnie, Richard, Garry, Robert, Kanneh, Lansana, Moses, Lina, Schieffelin, John, Grant, Donald S., Gallo, Carla, Poletti, Giovanni, Saleheen, Danish, Rasheed, Asif, Brooks, Lisa D., Felsenfeld, Adam L., McEwen, Jean E., Vaydylevich, Yekaterina, Duncanson, Audrey, Dunn, Michael, Schloss, Jeffery A., and Yang, Huanming

Published
2015
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23. Population-scale tissue transcriptomics maps long non-coding RNAs to complex disease

Author

de Goede, Olivia M., primary, Nachun, Daniel C., additional, Ferraro, Nicole M., additional, Gloudemans, Michael J., additional, Rao, Abhiram S., additional, Smail, Craig, additional, Eulalio, Tiffany Y., additional, Aguet, François, additional, Ng, Bernard, additional, Xu, Jishu, additional, Barbeira, Alvaro N., additional, Castel, Stephane E., additional, Kim-Hellmuth, Sarah, additional, Park, YoSon, additional, Scott, Alexandra J., additional, Strober, Benjamin J., additional, Brown, Christopher D., additional, Wen, Xiaoquan, additional, Hall, Ira M., additional, Battle, Alexis, additional, Lappalainen, Tuuli, additional, Im, Hae Kyung, additional, Ardlie, Kristin G., additional, Mostafavi, Sara, additional, Quertermous, Thomas, additional, Kirkegaard, Karla, additional, Montgomery, Stephen B., additional, Anand, Shankara, additional, Gabriel, Stacey, additional, Getz, Gad A., additional, Graubert, Aaron, additional, Hadley, Kane, additional, Handsaker, Robert E., additional, Huang, Katherine H., additional, Li, Xiao, additional, MacArthur, Daniel G., additional, Meier, Samuel R., additional, Nedzel, Jared L., additional, Nguyen, Duyen T., additional, Segrè, Ayellet V., additional, Todres, Ellen, additional, Balliu, Brunilda, additional, Bonazzola, Rodrigo, additional, Brown, Andrew, additional, Conrad, Donald F., additional, Cotter, Daniel J., additional, Cox, Nancy, additional, Das, Sayantan, additional, Dermitzakis, Emmanouil T., additional, Einson, Jonah, additional, Engelhardt, Barbara E., additional, Eskin, Eleazar, additional, Flynn, Elise D., additional, Fresard, Laure, additional, Gamazon, Eric R., additional, Garrido-Martín, Diego, additional, Gay, Nicole R., additional, Guigó, Roderic, additional, Hamel, Andrew R., additional, He, Yuan, additional, Hoffman, Paul J., additional, Hormozdiari, Farhad, additional, Hou, Lei, additional, Jo, Brian, additional, Kasela, Silva, additional, Kashin, Seva, additional, Kellis, Manolis, additional, Kwong, Alan, additional, Li, Xin, additional, Liang, Yanyu, additional, Mangul, Serghei, additional, Mohammadi, Pejman, additional, Muñoz-Aguirre, Manuel, additional, Nobel, Andrew B., additional, Oliva, Meritxell, additional, Park, Yongjin, additional, Parsana, Princy, additional, Reverter, Ferran, additional, Rouhana, John M., additional, Sabatti, Chiara, additional, Saha, Ashis, additional, Stephens, Matthew, additional, Stranger, Barbara E., additional, Teran, Nicole A., additional, Viñuela, Ana, additional, Wang, Gao, additional, Wright, Fred, additional, Wucher, Valentin, additional, Zou, Yuxin, additional, Ferreira, Pedro G., additional, Li, Gen, additional, Melé, Marta, additional, Yeger-Lotem, Esti, additional, Bradbury, Debra, additional, Krubit, Tanya, additional, McLean, Jeffrey A., additional, Qi, Liqun, additional, Robinson, Karna, additional, Roche, Nancy V., additional, Smith, Anna M., additional, Tabor, David E., additional, Undale, Anita, additional, Bridge, Jason, additional, Brigham, Lori E., additional, Foster, Barbara A., additional, Gillard, Bryan M., additional, Hasz, Richard, additional, Hunter, Marcus, additional, Johns, Christopher, additional, Johnson, Mark, additional, Karasik, Ellen, additional, Kopen, Gene, additional, Leinweber, William F., additional, McDonald, Alisa, additional, Moser, Michael T., additional, Myer, Kevin, additional, Ramsey, Kimberley D., additional, Roe, Brian, additional, Shad, Saboor, additional, Thomas, Jeffrey A., additional, Walters, Gary, additional, Washington, Michael, additional, Wheeler, Joseph, additional, Jewell, Scott D., additional, Rohrer, Daniel C., additional, Valley, Dana R., additional, Davis, David A., additional, Mash, Deborah C., additional, Barcus, Mary E., additional, Branton, Philip A., additional, Sobin, Leslie, additional, Barker, Laura K., additional, Gardiner, Heather M., additional, Mosavel, Maghboeba, additional, Siminoff, Laura A., additional, Flicek, Paul, additional, Haeussler, Maximilian, additional, Juettemann, Thomas, additional, Kent, W. James, additional, Lee, Christopher M., additional, Powell, Conner C., additional, Rosenbloom, Kate R., additional, Ruffier, Magali, additional, Sheppard, Dan, additional, Taylor, Kieron, additional, Trevanion, Stephen J., additional, Zerbino, Daniel R., additional, Abell, Nathan S., additional, Akey, Joshua, additional, Chen, Lin, additional, Demanelis, Kathryn, additional, Doherty, Jennifer A., additional, Feinberg, Andrew P., additional, Hansen, Kasper D., additional, Hickey, Peter F., additional, Jasmine, Farzana, additional, Jiang, Lihua, additional, Kaul, Rajinder, additional, Kibriya, Muhammad G., additional, Li, Jin Billy, additional, Li, Qin, additional, Lin, Shin, additional, Linder, Sandra E., additional, Pierce, Brandon L., additional, Rizzardi, Lindsay F., additional, Skol, Andrew D., additional, Smith, Kevin S., additional, Snyder, Michael, additional, Stamatoyannopoulos, John, additional, Tang, Hua, additional, Wang, Meng, additional, Carithers, Latarsha J., additional, Guan, Ping, additional, Koester, Susan E., additional, Little, A. Roger, additional, Moore, Helen M., additional, Nierras, Concepcion R., additional, Rao, Abhi K., additional, Vaught, Jimmie B., additional, and Volpi, Simona, additional

Published
2021
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24. Evolution of genes and genomes on the Drosophila phylogeny

Author

Clark, Andrew G., Eisen, Michael B., Smith, Douglas R., Bergman, Casey M., Oliver, Brian, Markow, Therese A., Kaufman, Thomas C., Kellis, Manolis, Gelbart, William, Iyer, Venky N., Pollard, Daniel A., Sackton, Timothy B., Larracuente, Amanda M., Singh, Nadia D., Abad, Jose P., Abt, Dawn N., Adryan, Boris, Aguade, Montserrat, Akashi, Hiroshi, Anderson, Wyatt W., Aquadro, Charles F., Ardell, David H., Arguello, Roman, Artieri, Carlo G., Barbash, Daniel A., Barker, Daniel, Barsanti, Paolo, Batterham, Phil, Batzoglou, Serafim, Begun, Dave, Bhutkar, Arjun, Blanco, Enrico, Bosak, Stephanie A., Bradley, Robert K., Brand, Adrianne D., Brent, Michael R., Brooks, Angela N., Brown, Randall H., Butlin, Roger K., Caggese, Corrado, Calvi, Brian R., Bernardo de Carvalho, A., Caspi, Anat, Castrezana, Sergio, Celniker, Susan E., Chang, Jean L., Chapple, Charles, Chatterji, Sourav, Chinwalla, Asif, Civetta, Alberto, Clifton, Sandra W., Comeron, Josep M., Costello, James C., Coyne, Jerry A., Daub, Jennifer, David, Robert G., Delcher, Arthur L., Delehaunty, Kim, Do, Chuong B., Ebling, Heather, Edwards, Kevin, Eickbush, Thomas, Evans, Jay D., Filipski, Alan, Findeiß, Sven, Freyhult, Eva, Fulton, Lucinda, Fulton, Robert, Garcia, Ana C. L., Gardiner, Anastasia, Garfield, David A., Garvin, Barry E., Gibson, Greg, Gilbert, Don, Gnerre, Sante, Godfrey, Jennifer, Good, Robert, Gotea, Valer, Gravely, Brenton, Greenberg, Anthony J., Griffiths-Jones, Sam, Gross, Samuel, Guigo, Roderic, Gustafson, Erik A., Haerty, Wilfried, Hahn, Matthew W., Halligan, Daniel L., Halpern, Aaron L., Halter, Gillian M., Han, Mira V., Heger, Andreas, Hillier, LaDeana, Hinrichs, Angie S., Holmes, Ian, Hoskins, Roger A., Hubisz, Melissa J., Hultmark, Dan, Huntley, Melanie A., Jaffe, David B., Jagadeeshan, Santosh, Jeck, William R., Johnson, Justin, Jones, Corbin D., Jordan, William C., Karpen, Gary H., Kataoka, Eiko, Keightley, Peter D., Kheradpour, Pouya, Kirkness, Ewen F., Koerich, Leonardo B., Kristiansen, Karsten, Kudrna, Dave, Kulathinal, Rob J., Kumar, Sudhir, Kwok, Roberta, Lander, Eric, Langley, Charles H., Lapoint, Richard, Lazzaro, Brian P., Lee, So-Jeong, Levesque, Lisa, Li, Ruiqiang, Lin, Chiao-Feng, Lin, Michael F., Lindblad-Toh, Kerstin, Llopart, Ana, Long, Manyuan, Low, Lloyd, Lozovsky, Elena, Lu, Jian, Luo, Meizhong, Machado, Carlos A., Makalowski, Wojciech, Marzo, Mar, Matsuda, Muneo, Matzkin, Luciano, McAllister, Bryant, McBride, Carolyn S., McKernan, Brendan, McKernan, Kevin, Mendez-Lago, Maria, Minx, Patrick, Mollenhauer, Michael U., Montooth, Kristi, Mount, Stephen M., Mu, Xu, Myers, Eugene, Negre, Barbara, Newfeld, Stuart, Nielsen, Rasmus, Noor, Mohamed A. F., O'Grady, Patrick, Pachter, Lior, Papaceit, Montserrat, Parisi, Matthew J., Parisi, Michael, Parts, Leopold, Pedersen, Jakob S., Pesole, Graziano, Phillippy, Adam M., Ponting, Chris P., Pop, Mihai, Porcelli, Damiano, Powell, Jeffrey R., Prohaska, Sonja, Pruitt, Kim, Puig, Marta, Quesneville, Hadi, Ravi Ram, Kristipati, Rand, David, Rasmussen, Matthew D., Reed, Laura K., Reenan, Robert, Reily, Amy, Remington, Karin A., Rieger, Tania T., Ritchie, Michael G., Robin, Charles, Rogers, Yu-Hui, Rohde, Claudia, Rozas, Julio, Rubenfield, Marc J., Ruiz, Alfredo, Russo, Susan, Salzberg, Steven L., Sanchez-Gracia, Alejandro, Saranga, David J., Sato, Hajime, Schaeffer, Stephen W., Schatz, Michael C., Schlenke, Todd, Schwartz, Russell, Segarra, Carmen, Singh, Rama S., Sirot, Laura, Sirota, Marina, Sisneros, Nicholas B., Smith, Chris D., Smith, Temple F., Spieth, John, Stage, Deborah E., Stark, Alexander, Stephan, Wolfgang, Strausberg, Robert L., Strempel, Sebastian, Sturgill, David, Sutton, Granger, Sutton, Granger G., Tao, Wei, Teichmann, Sarah, Tobari, Yoshiko N., Tomimura, Yoshihiko, Tsolas, Jason M., Valente, Vera L. S., Venter, Eli, Craig Venter, J., Vicario, Saverio, Vieira, Filipe G., Vilella, Albert J., Villasante, Alfredo, Walenz, Brian, Wang, Jun, Wasserman, Marvin, Watts, Thomas, Wilson, Derek, Wilson, Richard K., Wing, Rod A., Wolfner, Mariana F., Wong, Alex, Ka-Shu Wong, Gane, Wu, Chung-I, Wu, Gabriel, Yamamoto, Daisuke, Yang, Hsiao-Pei, Yang, Shiaw-Pyng, Yorke, James A., Yoshida, Kiyohito, Zdobnov, Evgeny, Zhang, Peili, Zhang, Yu, Zimin, Aleksey V., Baldwin, Jennifer, Abdouelleil, Amr, Abdulkadir, Jamal, Abebe, Adal, Abera, Brikti, Abreu, Justin, Christophe Acer, St, Aftuck, Lynne, Alexander, Allen, An, Peter, Anderson, Erica, Anderson, Scott, Arachi, Harindra, Azer, Marc, Bachantsang, Pasang, Barry, Andrew, Bayul, Tashi, Berlin, Aaron, Bessette, Daniel, Bloom, Toby, Blye, Jason, Boguslavskiy, Leonid, Bonnet, Claude, Boukhgalter, Boris, Bourzgui, Imane, Brown, Adam, Cahill, Patrick, Channer, Sheridon, Cheshatsang, Yama, Chuda, Lisa, Citroen, Mieke, Collymore, Alville, Cooke, Patrick, Costello, Maura, D'Aco, Katie, Daza, Riza, De Haan, Georgius, DeGray, Stuart, DeMaso, Christina, Dhargay, Norbu, Dooley, Kimberly, Dooley, Erin, Doricent, Missole, Dorje, Passang, Dorjee, Kunsang, Dupes, Alan, Elong, Richard, Falk, Jill, Farina, Abderrahim, Faro, Susan, Ferguson, Diallo, Fisher, Sheila, Foley, Chelsea D., Franke, Alicia, Friedrich, Dennis, Gadbois, Loryn, Gearin, Gary, Gearin, Christina R., Giannoukos, Georgia, Goode, Tina, Graham, Joseph, Grandbois, Edward, Grewal, Sharleen, Gyaltsen, Kunsang, Hafez, Nabil, Hagos, Birhane, Hall, Jennifer, Henson, Charlotte, Hollinger, Andrew, Honan, Tracey, Huard, Monika D., Hughes, Leanne, Hurhula, Brian, Erii Husby, M, Kamat, Asha, Kanga, Ben, Kashin, Seva, Khazanovich, Dmitry, Kisner, Peter, Lance, Krista, Lara, Marcia, Lee, William, Lennon, Niall, Letendre, Frances, LeVine, Rosie, Lipovsky, Alex, Liu, Xiaohong, Liu, Jinlei, Liu, Shangtao, Lokyitsang, Tashi, Lokyitsang, Yeshi, Lubonja, Rakela, Lui, Annie, MacDonald, Pen, Magnisalis, Vasilia, Maru, Kebede, Matthews, Charles, McCusker, William, McDonough, Susan, Mehta, Teena, Meldrim, James, Meneus, Louis, Mihai, Oana, Mihalev, Atanas, Mihova, Tanya, Mittelman, Rachel, Mlenga, Valentine, Montmayeur, Anna, Mulrain, Leonidas, Navidi, Adam, Naylor, Jerome, Negash, Tamrat, Nguyen, Thu, Nguyen, Nga, Nicol, Robert, Norbu, Choe, Norbu, Nyima, Novod, Nathaniel, O'Neill, Barry, Osman, Sahal, Markiewicz, Eva, Oyono, Otero L., Patti, Christopher, Phunkhang, Pema, Pierre, Fritz, Priest, Margaret, Raghuraman, Sujaa, Rege, Filip, Reyes, Rebecca, Rise, Cecil, Rogov, Peter, Ross, Keenan, Ryan, Elizabeth, Settipalli, Sampath, Shea, Terry, Sherpa, Ngawang, Shi, Lu, Shih, Diana, Sparrow, Todd, Spaulding, Jessica, Stalker, John, Stange-Thomann, Nicole, Stavropoulos, Sharon, Stone, Catherine, Strader, Christopher, Tesfaye, Senait, Thomson, Talene, Thoulutsang, Yama, Thoulutsang, Dawa, Topham, Kerri, Topping, Ira, Tsamla, Tsamla, Vassiliev, Helen, Vo, Andy, Wangchuk, Tsering, Wangdi, Tsering, Weiand, Michael, Wilkinson, Jane, Wilson, Adam, Yadav, Shailendra, Young, Geneva, Yu, Qing, Zembek, Lisa, Zhong, Danni, Zimmer, Andrew, Zwirko, Zac, Alvarez, Pablo, Brockman, Will, Butler, Jonathan, Chin, CheeWhye, Grabherr, Manfred, Kleber, Michael, Mauceli, Evan, and MacCallum, Iain

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Drosophila 12 Genomes Consortium; Project Leaders; Andrew G. Clark (corresponding author) [1]; Michael B. Eisen (corresponding author) [2, 3]; Douglas R. Smith (corresponding author) [4]; Casey M. Bergman (corresponding [...]

Published
2007
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25. Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequences

Author

Mikkelsen, Tarjei S., Wakefield, Matthew J., Aken, Bronwen, Amemiya, Chris T., Chang, Jean L., Duke, Shannon, Garber, Manuel, Gentles, Andrew J., Goodstadt, Leo, Heger, Andreas, Jurka, Jerzy, Kamal, Michael, Mauceli, Evan, Searle, Stephen M. J., Sharpe, Ted, Baker, Michelle L., Batzer, Mark A., Benos, Panayiotis V., Belov, Katherine, Clamp, Michele, Cook, April, Cuff, James, Das, Radhika, Davidow, Lance, Deakin, Janine E., Fazzari, Melissa J., Glass, Jacob L., Grabherr, Manfred, Greally, John M., Gu, Wanjun, Hore, Timothy A., Huttley, Gavin A., Kleber, Michael, Jirtle, Randy L., Koina, Edda, Lee, Jeannie T., Mahony, Shaun, Marra, Marco A., Miller, Robert D., Nicholls, Robert D., Oda, Mayumi, Papenfuss, Anthony T., Parra, Zuly E., Pollock, David D., Ray, David A., Schein, Jacqueline E., Speed, Terence P., Thompson, Katherine, VandeBerg, John L., Wade, Claire M., Walker, Jerilyn A., Waters, Paul D., Webber, Caleb, Weidman, Jennifer R., Xie, Xiaohui, Zody, Michael C., Baldwin, Jennifer, Abdouelleil, Amr, Abdulkadir, Jamal, Abebe, Adal, Abera, Brikti, Abreu, Justin, Acer, St Christophe, Aftuck, Lynne, Alexander, Allen, An, Peter, Anderson, Erica, Anderson, Scott, Arachi, Harindra, Azer, Marc, Bachantsang, Pasang, Barry, Andrew, Bayul, Tashi, Berlin, Aaron, Bessette, Daniel, Bloom, Toby, Blye, Jason, Boguslavskiy, Leonid, Bonnet, Claude, Boukhgalter, Boris, Bourzgui, Imane, Brown, Adam, Cahill, Patrick, Channer, Sheridon, Cheshatsang, Yama, Chuda, Lisa, Citroen, Mieke, Collymore, Alville, Cooke, Patrick, Costello, Maura, D'Aco, Katie, Daza, Riza, De Haan, Georgius, DeGray, Stuart, DeMaso, Christina, Dhargay, Norbu, Dooley, Kimberly, Dooley, Erin, Doricent, Missole, Dorje, Passang, Dorjee, Kunsang, Dupes, Alan, Elong, Richard, Falk, Jill, Farina, Abderrahim, Faro, Susan, Ferguson, Diallo, Fisher, Sheila, Foley, Chelsea D., Franke, Alicia, Friedrich, Dennis, Gadbois, Loryn, Gearin, Gary, Gearin, Christina R., Giannoukos, Georgia, Goode, Tina, Graham, Joseph, Grandbois, Edward, Grewal, Sharleen, Gyaltsen, Kunsang, Hafez, Nabil, Hagos, Birhane, Hall, Jennifer, Henson, Charlotte, Hollinger, Andrew, Honan, Tracey, Huard, Monika D., Hughes, Leanne, Hurhula, Brian, Husby, M. Erii, Kamat, Asha, Kanga, Ben, Kashin, Seva, Khazanovich, Dmitry, Kisner, Peter, Lance, Krista, Lara, Marcia, Lee, William, Lennon, Niall, Letendre, Frances, LeVine, Rosie, Lipovsky, Alex, Liu, Xiaohong, Liu, Jinlei, Liu, Shangtao, Lokyitsang, Tashi, Lokyitsang, Yeshi, Lubonja, Rakela, Lui, Annie, MacDonald, Pen, Magnisalis, Vasilia, Maru, Kebede, Matthews, Charles, McCusker, William, McDonough, Susan, Mehta, Teena, Meldrim, James, Meneus, Louis, Mihai, Oana, Mihalev, Atanas, Mihova, Tanya, Mittelman, Rachel, Mlenga, Valentine, Montmayeur, Anna, Mulrain, Leonidas, Navidi, Adam, Naylor, Jerome, Negash, Tamrat, Nguyen, Thu, Nguyen, Nga, Nicol, Robert, Norbu, Choe, Norbu, Nyima, Novod, Nathaniel, O'Neill, Barry, Osman, Sahal, Markiewicz, Eva, Oyono, Otero L., Patti, Christopher, Phunkhang, Pema, Pierre, Fritz, Priest, Margaret, Raghuraman, Sujaa, Rege, Filip, Reyes, Rebecca, Rise, Cecil, Rogov, Peter, Ross, Keenan, Ryan, Elizabeth, Settipalli, Sampath, Shea, Terry, Sherpa, Ngawang, Shi, Lu, Shih, Diana, Sparrow, Todd, Spaulding, Jessica, Stalker, John, Stange-Thomann, Nicole, Stavropoulos, Sharon, Stone, Catherine, Strader, Christopher, Tesfaye, Senait, Thomson, Talene, Thoulutsang, Yama, Thoulutsang, Dawa, Topham, Kerri, Topping, Ira, Tsamla, Tsamla, Vassiliev, Helen, Vo, Andy, Wangchuk, Tsering, Wangdi, Tsering, Weiand, Michael, Wilkinson, Jane, Wilson, Adam, Yadav, Shailendra, Young, Geneva, Yu, Qing, Zembek, Lisa, Zhong, Danni, Zimmer, Andrew, Zwirko, Zac, Jaffe, David B., Alvarez, Pablo, Brockman, Will, Butler, Jonathan, Chin, CheeWhye, Gnerre, Sante, MacCallum, Iain, Graves, Jennifer A. Marshall, Ponting, Chris P., Breen, Matthew, Samollow, Paul B., Lander, Eric S., and Lindblad-Toh, Kerstin

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Tarjei S. Mikkelsen (corresponding author) [1, 2]; Matthew J. Wakefield [3]; Bronwen Aken [4]; Chris T. Amemiya [5]; Jean L. Chang [1]; Shannon Duke [6]; Manuel Garber [1]; Andrew [...]

Published
2007
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26. Biological insights from the whole genome analysis of human embryonic stem cells

Author

Merkle, Florian T., primary, Ghosh, Sulagna, additional, Genovese, Giulio, additional, Handsaker, Robert E., additional, Kashin, Seva, additional, Karczewski, Konrad, additional, O’Dushlaine, Colm, additional, Pato, Carlos, additional, Pato, Michele, additional, MacArthur, Daniel G., additional, McCarroll, Steven A., additional, and Eggan, Kevin, additional

Published
2020
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27. A Quantitative Proteome Map of the Human Body

Author

Jiang, Lihua, primary, Wang, Meng, additional, Lin, Shin, additional, Jian, Ruiqi, additional, Li, Xiao, additional, Chan, Joanne, additional, Dong, Guanlan, additional, Fang, Huaying, additional, Robinson, Aaron E., additional, Snyder, Michael P., additional, Aguet, François, additional, Anand, Shankara, additional, Ardlie, Kristin G., additional, Gabriel, Stacey, additional, Getz, Gad, additional, Graubert, Aaron, additional, Hadley, Kane, additional, Handsaker, Robert E., additional, Huang, Katherine H., additional, Kashin, Seva, additional, MacArthur, Daniel G., additional, Meier, Samuel R., additional, Nedzel, Jared L., additional, Nguyen, Duyen Y., additional, Segrè, Ayellet V., additional, Todres, Ellen, additional, Balliu, Brunilda, additional, Barbeira, Alvaro N., additional, Battle, Alexis, additional, Bonazzola, Rodrigo, additional, Brown, Andrew, additional, Brown, Christopher D., additional, Castel, Stephane E., additional, Conrad, Don, additional, Cotter, Daniel J., additional, Cox, Nancy, additional, Das, Sayantan, additional, de Goede, Olivia M., additional, Dermitzakis, Emmanouil T., additional, Engelhardt, Barbara E., additional, Eskin, Eleazar, additional, Eulalio, Tiffany Y., additional, Ferraro, Nicole M., additional, Flynn, Elise, additional, Fresard, Laure, additional, Gamazon, Eric R., additional, Garrido-Martín, Diego, additional, Gay, Nicole R., additional, Guigó, Roderic, additional, Hamel, Andrew R., additional, He, Yuan, additional, Hoffman, Paul J., additional, Hormozdiari, Farhad, additional, Hou, Lei, additional, Im, Hae Kyung, additional, Jo, Brian, additional, Kasela, Silva, additional, Kellis, Manolis, additional, Kim-Hellmuth, Sarah, additional, Kwong, Alan, additional, Lappalainen, Tuuli, additional, Li, Xin, additional, Liang, Yanyu, additional, Mangul, Serghei, additional, Mohammadi, Pejman, additional, Montgomery, Stephen B., additional, Muñoz-Aguirre, Manuel, additional, Nachun, Daniel C., additional, Nobel, Andrew B., additional, Oliva, Meritxell, additional, Park, YoSon, additional, Park, Yongjin, additional, Parsana, Princy, additional, Reverter, Ferran, additional, Rouhana, John M., additional, Sabatti, Chiara, additional, Saha, Ashis, additional, Skol, Andrew D., additional, Stephens, Matthew, additional, Stranger, Barbara E., additional, Strober, Benjamin J., additional, Teran, Nicole A., additional, Viñuela, Ana, additional, Wang, Gao, additional, Wen, Xiaoquan, additional, Wright, Fred, additional, Wucher, Valentin, additional, Zou, Yuxin, additional, Ferreira, Pedro G., additional, Li, Gen, additional, Melé, Marta, additional, Yeger-Lotem, Esti, additional, Barcus, Mary E., additional, Bradbury, Debra, additional, Krubit, Tanya, additional, McLean, Jeffrey A., additional, Qi, Liqun, additional, Robinson, Karna, additional, Roche, Nancy V., additional, Smith, Anna M., additional, Sobin, Leslie, additional, Tabor, David E., additional, Undale, Anita, additional, Bridge, Jason, additional, Brigham, Lori E., additional, Foster, Barbara A., additional, Gillard, Bryan M., additional, Hasz, Richard, additional, Hunter, Marcus, additional, Johns, Christopher, additional, Johnson, Mark, additional, Karasik, Ellen, additional, Kopen, Gene, additional, Leinweber, William F., additional, McDonald, Alisa, additional, Moser, Michael T., additional, Myer, Kevin, additional, Ramsey, Kimberley D., additional, Roe, Brian, additional, Shad, Saboor, additional, Thomas, Jeffrey A., additional, Walters, Gary, additional, Washington, Michael, additional, Wheeler, Joseph, additional, Jewell, Scott D., additional, Rohrer, Daniel C., additional, Valley, Dana R., additional, Davis, David A., additional, Mash, Deborah C., additional, Branton, Philip A., additional, Barker, Laura K., additional, Gardiner, Heather M., additional, Mosavel, Maghboeba, additional, Siminoff, Laura A., additional, Flicek, Paul, additional, Haeussler, Maximilian, additional, Juettemann, Thomas, additional, Kent, W. James, additional, Lee, Christopher M., additional, Powell, Conner C., additional, Rosenbloom, Kate R., additional, Ruffier, Magali, additional, Sheppard, Dan, additional, Taylor, Kieron, additional, Trevanion, Stephen J., additional, Zerbino, Daniel R., additional, Abell, Nathan S., additional, Akey, Joshua, additional, Chen, Lin, additional, Demanelis, Kathryn, additional, Doherty, Jennifer A., additional, Feinberg, Andrew P., additional, Hansen, Kasper D., additional, Hickey, Peter F., additional, Jasmine, Farzana, additional, Kaul, Rajinder, additional, Kibriya, Muhammad G., additional, Li, Jin Billy, additional, Li, Qin, additional, Linder, Sandra E., additional, Pierce, Brandon L., additional, Rizzardi, Lindsay F., additional, Smith, Kevin S., additional, Stamatoyannopoulos, John, additional, Tang, Hua, additional, Carithers, Latarsha J., additional, Guan, Ping, additional, Koester, Susan E., additional, Little, A. Roger, additional, Moore, Helen M., additional, Nierras, Concepcion R., additional, Rao, Abhi K., additional, Vaught, Jimmie B., additional, and Volpi, Simona, additional

Published
2020
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29. The GTEx Consortium atlas of genetic regulatory effects across human tissues

Author

Aguet, François, Barbeira, Alvaro N, Bonazzola, Rodrigo, Brown, Andrew, Castel, Stephane E, Jo, Brian, Kasela, Silva, Kim-Hellmuth, Sarah, Liang, Yanyu, Oliva, Meritxell, Parsana, Princy E, Flynn, Elise, Fresard, Laure, Gaamzon, Eric R, Hamel, Andrew R, He, Yuan, Hormozdiari, Farhad, Mohammadi, Pejman, Muñoz-Aguirre, Manuel, Park, YoSon, Saha, Ashis, Segrć, Ayellet V, Strober, Benjamin J, Wen, Xiaoquan, Wucher, Valentin, Das, Sayantan, Garrido-Martín, Diego, Gay, Nicole R, Handsaker, Robert E, Hoffman, Paul J, Kashin, Seva, Kwong, Alan, Li, Xiao, MacArthur, Daniel, Rouhana, John M, Stephens, Matthew, Todres, Ellen, Viñuela, Ana, Wang, Gao, Zou, Yuxin, Brown, Christopher D, Cox, Nancy, Dermitzakis, Emmanouil, Engelhardt, Barbara E, Getz, Gad, Guigo, Roderic, Montgomery, Stephen B, Stranger, Barbara E, Im, Hae Kyung, Battle, Alexis, Ardlie, Kristin G, Lappalainen, Tuuli, and Universitat Politècnica de Catalunya. Doctorat en Estadística i Investigació Operativa

Subjects
Enginyeria química::Biotecnologia [Àrees temàtiques de la UPC], 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Genotype-Tissue Expression, Atlas (topology), Genetics, Computational biology, Biology, Genètica, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues, and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the v8 data, based on 17,382 RNA-sequencing samples from 54 tissues of 948 post-mortem donors. We comprehensively characterize genetic associations for gene expression and splicing incisandtrans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue-specificity of genetic effects, and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.

Published
2019

30. Landscape of X chromosome inactivation across human tissues

Author

Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Yen, Angela, Regev, Aviv, Tukiainen, Taru, Villani, Alexandra-Chloé, Rivas, Manuel A., Marshall, Jamie L., Satija, Rahul, Aguirre, Matt, Gauthier, Laura, Fleharty, Mark, Kirby, Andrew, Cummings, Beryl B., Castel, Stephane E., Karczewski, Konrad J., Aguet, François, Byrnes, Andrea, Ardlie, Kristin G., Gelfand, Ellen T., Getz, Gad, Hadley, Kane, Handsaker, Robert E., Huang, Katherine H., Kashin, Seva, Lek, Monkol, Li, Xiao, MacArthur, Daniel G., Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Yen, Angela, Regev, Aviv, Tukiainen, Taru, Villani, Alexandra-Chloé, Rivas, Manuel A., Marshall, Jamie L., Satija, Rahul, Aguirre, Matt, Gauthier, Laura, Fleharty, Mark, Kirby, Andrew, Cummings, Beryl B., Castel, Stephane E., Karczewski, Konrad J., Aguet, François, Byrnes, Andrea, Ardlie, Kristin G., Gelfand, Ellen T., Getz, Gad, Hadley, Kane, Handsaker, Robert E., Huang, Katherine H., Kashin, Seva, Lek, Monkol, Li, Xiao, and MacArthur, Daniel G.

Abstract

X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of 'escape' from inactivation varying between genes and individuals1,2. The extent to which XCI is shared between cells and tissues remains poorly characterized3,4, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression5 and phenotypic traits6. Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity6,7. Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI.

Published
2018

31. An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder.

Author

Werling, Donna, Werling, Donna, Brand, Harrison, An, Joon-Yong, Stone, Matthew, Zhu, Lingxue, Glessner, Joseph, Collins, Ryan, Dong, Shan, Layer, Ryan, Markenscoff-Papadimitriou, Eirene, Farrell, Andrew, Schwartz, Grace, Wang, Harold, Currall, Benjamin, Zhao, Xuefang, Dea, Jeanselle, Duhn, Clif, Erdman, Carolyn, Gilson, Michael, Yadav, Rachita, Handsaker, Robert, Kashin, Seva, Klei, Lambertus, Mandell, Jeffrey, Nowakowski, Tomasz, Liu, Yuwen, Pochareddy, Sirisha, Smith, Louw, Waterman, Matthew, He, Xin, Sestan, Nenad, McCarroll, Steven, Neale, Benjamin, Coon, Hilary, Buxbaum, Joseph, Daly, Mark, State, Matthew, Quinlan, Aaron, Marth, Gabor, Roeder, Kathryn, Devlin, Bernie, Talkowski, Michael, Kriegstein, Arnold, Rubenstein, John, Sanders, Stephan, Willsey, Arthur, Walker, Michael, Werling, Donna, Werling, Donna, Brand, Harrison, An, Joon-Yong, Stone, Matthew, Zhu, Lingxue, Glessner, Joseph, Collins, Ryan, Dong, Shan, Layer, Ryan, Markenscoff-Papadimitriou, Eirene, Farrell, Andrew, Schwartz, Grace, Wang, Harold, Currall, Benjamin, Zhao, Xuefang, Dea, Jeanselle, Duhn, Clif, Erdman, Carolyn, Gilson, Michael, Yadav, Rachita, Handsaker, Robert, Kashin, Seva, Klei, Lambertus, Mandell, Jeffrey, Nowakowski, Tomasz, Liu, Yuwen, Pochareddy, Sirisha, Smith, Louw, Waterman, Matthew, He, Xin, Sestan, Nenad, McCarroll, Steven, Neale, Benjamin, Coon, Hilary, Buxbaum, Joseph, Daly, Mark, State, Matthew, Quinlan, Aaron, Marth, Gabor, Roeder, Kathryn, Devlin, Bernie, Talkowski, Michael, Kriegstein, Arnold, Rubenstein, John, Sanders, Stephan, Willsey, Arthur, and Walker, Michael

Abstract

Genomic association studies of common or rare protein-coding variation have established robust statistical approaches to account for multiple testing. Here we present a comparable framework to evaluate rare and de novo noncoding single-nucleotide variants, insertion/deletions, and all classes of structural variation from whole-genome sequencing (WGS). Integrating genomic annotations at the level of nucleotides, genes, and regulatory regions, we define 51,801 annotation categories. Analyses of 519 autism spectrum disorder families did not identify association with any categories after correction for 4,123 effective tests. Without appropriate correction, biologically plausible associations are observed in both cases and controls. Despite excluding previously identified gene-disrupting mutations, coding regions still exhibited the strongest associations. Thus, in autism, the contribution of de novo noncoding variation is probably modest in comparison to that of de novo coding variants. Robust results from future WGS studies will require large cohorts and comprehensive analytical strategies that consider the substantial multiple-testing burden.

Published
2018

32. Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations

Author

Merkle, Florian T, Ghosh, Sulagna, Kamitaki, Nolan, Mitchell, Jana, Avior, Yishai, Mello, Curtis, Kashin, Seva, Mekhoubad, Shila, Ilic, Dusko, Charlton, Maura, Saphier, Genevieve, Handsaker, Robert E, Genovese, Giulio, Bar, Shiran, Benvenisty, Nissim, McCarroll, Steven A, Eggan, Kevin, Merkle, Florian [0000-0002-8513-2998], and Apollo - University of Cambridge Repository

Subjects
Mosaicism, DNA Mutational Analysis, Human Embryonic Stem Cells, Induced Pluripotent Stem Cells, Loss of Heterozygosity, Cell Count, Cell Differentiation, DNA, Genes, p53, Cell Line, Protein Domains, Neoplasms, Mutation, Humans, Exome, Selection, Genetic, Tumor Suppressor Protein p53, Alleles, Cell Division, Genes, Dominant
Abstract

Human pluripotent stem cells (hPS cells) can self-renew indefinitely, making them an attractive source for regenerative therapies. This expansion potential has been linked with the acquisition of large copy number variants that provide mutated cells with a growth advantage in culture. The nature, extent and functional effects of other acquired genome sequence mutations in cultured hPS cells are not known. Here we sequence the protein-coding genes (exomes) of 140 independent human embryonic stem cell (hES cell) lines, including 26 lines prepared for potential clinical use. We then apply computational strategies for identifying mutations present in a subset of cells in each hES cell line. Although such mosaic mutations were generally rare, we identified five unrelated hES cell lines that carried six mutations in the TP53 gene that encodes the tumour suppressor P53. The TP53 mutations we observed are dominant negative and are the mutations most commonly seen in human cancers. We found that the TP53 mutant allelic fraction increased with passage number under standard culture conditions, suggesting that the P53 mutations confer selective advantage. We then mined published RNA sequencing data from 117 hPS cell lines, and observed another nine TP53 mutations, all resulting in coding changes in the DNA-binding domain of P53. In three lines, the allelic fraction exceeded 50%, suggesting additional selective advantage resulting from the loss of heterozygosity at the TP53 locus. As the acquisition and expansion of cancer-associated mutations in hPS cells may go unnoticed during most applications, we suggest that careful genetic characterization of hPS cells and their differentiated derivatives be carried out before clinical use.

Published
2017

33. Genetic effects on gene expression across human tissues

Author

Haugen, Eric, He, Yuan, Chen, Lin S., Dermitzakis, Emmanouil T., Branton, Philip A., Nobel, Andrew B., Park, YoSon, McLean, Jeffrey A., Neri, Fidencio J., Tabor, David E., Saha, Ashis, Sobin, Leslie, Doherty, Jennifer A., Rosenbloom, Kate R., Quan, Jie, Strober, Benjamin J., Liu, Yaping, Valley, Dana, Basha, Omer, Barshir, Ruth, Trowbridge, Casandra A., Segrè, Ayellet V., Skol, Andrew, Karasik, Ellen, Bridge, Jason, Kent, W. James, Chiang, Colby, Damani, Farhan N., Karczewski, Konrad J., Barcus, Mary E., Oliva, Meritxell, Papasaikas, Panagiotis, Nelson, Jemma, Linke, Caroline, Paten, Benedict, Gelfand, Ellen T., Zhu, Jingchun, Wright, Fred A., Smith, Kevin S., Halow, Jessica, Kim-Hellmuth, Sarah, Salvatore, Michael, Hunter, Steven, Noble, Michael S., Goldman, Mary, Nguyen, Duyen Y., Singh, Shilpi, Rohrer, Daniel C., Cox, Nancy J., Hickey, Peter F., Battle, Alexis, Claussnitzer, Melina, Molinie, Benoit, Aguet, François, Balliu, Brunilda, Thomas, Jeffrey A., Hormozdiari, Farhad, Hou, Lei, Kaul, Rajinder, Peterson, Christine B., Lin, Jessica, Barker, Laura K., Brown, Christopher D., Guan, Ping, Lee, Kristen, Gloudemans, Michael J., Ripke, Stephan, Moser, Michael T., Muñoz-Aguirre, Manuel, Haeussler, Maximilian, Vatanian, Negin, Gewirtz, Ariel D.H., Castel, Stephane E., Monlong, Jean, Scott, Alexandra J., Stamatoyannopoulos, John, Ruffier, Magali, Zappala, Zachary, Li, Xiao, Ferreira, Pedro G., Nierras, Concepcion R., Yeger-Lotem, Esti, Wen, Xiaoquan, Struewing, Jeffery P., Delaneau, Olivier, Tukiainen, Taru, Tomaszewski, Maria M., Jo, Brian, Park, Yongjin, Martin, Casey, Bogu, Gireesh K., Pierce, Brandon L., Zhou, Yi-Hui, Eskin, Eleazar, Reverter, Ferran, Guigó, Roderic, Teran, Nicole A., Lek, Monkol, Leinweber, William F., Ardlie, Kristin G., Kopen, Gene, Ongen, Halit, Lonsdale, John T., Hall, Ira M., Bustamante, Carlos D., Quon, Gerald, Han, Buhm, Mohammadi, Pejman, Nicolae, Dan L., Kellis, Manolis, Vivian, John, Robinson, Karna L., Davis, David A., Washington, Michael, Montroy, Robert G., Craft, Brian, Wang, Gao, Garrido-Martín, Diego, Taylor, Kieron, Linder, Sandra, Hadley, Kane, Addington, Anjene M., Davis, Joe R., Siminoff, Laura A., Miklos, Mark, Tsang, Emily K., Diegel, Morgan, Mash, Deborah C., McDowell, Ian C., Lockhart, Nicole C., Payne, Anthony J., Abell, Nathan S., Cummings, Beryl B., Wheeler, Joseph, Matose, Takunda, Demanelis, Kathryn, Gliner, Genna, Stephens, Matthew, McDonald, Alisa, Rao, Abhi, Foster, Barbara A., Frésard, Laure, Brown, Andrew A., Zhang, Rui, Rinaldi, Nicola J., Gillard, Bryan M., Zerbino, Daniel R., Sabatti, Chiara, Moore, Helen M., Hasz, Richard, Brigham, Lori E., Zaugg, Judith B., Jian, Ruiqi, Conrad, Donald F., Snyder, Michael P., Im, Hae Kyung, Wu, Fan, MacArthur, Daniel G., Liu, Boxiang, Gamazon, Eric R., Jiang, Lihua, Sammeth, Michael, Johns, Christopher, Maurano, Matthew T., Hansen, Kasper D., Kang, Eun Yong, Myer, Kevin, Tang, Hua, Johnson, Mark, Fernando, Marian S., Smith, Anna M., Urbut, Sarah, Gould, Sarah E., Van Wittenberghe, Nicholas, Lee, Christopher M., Engelhardt, Barbara E., Panousis, Nikolaos, Palowitch, John J., Kibriya, Muhammad G., Sheppard, Dan, McCarthy, Mark I., Ndungu, Anne W., Valentino, Kimberly M., Sodaei, Reza, Sandstrom, Richard, Parsana, Princy, Kim, Yungil, Kumar, Rachna, Chan, Joanne, Little, A. Roger, Shimko, Tyler C., Volpi, Simona, Li, Qin, Akey, Joshua M., Walters, Gary, Roe, Bryan, Undale, Anita H., Van De Bunt, Martijn, Getz, Gad, Li, Jin Billy, Mangul, Serghei, Feinberg, Andrew P., Sul, Jae Hoon, Rizzardi, Lindsay F., Nguyen, Duyen T., Stranger, Barbara E., Um, Ki Sung, Flicek, Paul, Trevanion, Stephen J., Vaught, Jimmie B., Lockart, Nicole C., Nedzel, Jared L., Handsaker, Robert E., Hunter, Marcus, Xi, Hualin S., Bates, Daniel, Howald, Cedric, Roche, Nancy V., Koester, Susan, Huang, Katherine H., Sullivan, Timothy J., Wang, Meng, Shabalin, Andrey A., Shad, Saboor, Hariharan, Pushpa, He, Amy Z., Qi, Liqun, Lappalainen, Tuuli, Li, Xin, Carithers, Latarsha J., Mestichelli, Bernadette, Kashin, Seva, Li, Gen, Jasmine, Farzana, Juettemann, Thomas, Montgomery, Stephen B., Zhang, Hailei, Traino, Heather M., Mosavel, Maghboeba, Koester, Susan E., Lin, Shin, Jewell, Scott D., Johnson, Audra, and Wang, Li

Abstract

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease.

Published
2017
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34. A vast resource of allelic expression data spanning human tissues.

Author

Castel, Stephane E., Aguet, François, Mohammadi, Pejman, GTEx Consortium, Anand, Shankara, Ardlie, Kristin G., Gabriel, Stacey, Getz, Gad A., Graubert, Aaron, Hadley, Kane, Handsaker, Robert E., Huang, Katherine H., Kashin, Seva, Li, Xiao, MacArthur, Daniel G., Meier, Samuel R., Nedzel, Jared L., Nguyen, Duyen T., Segrè, Ayellet V., and Todres, Ellen

Published
2020
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35. A global reference for human genetic variation

Author

Institute for Medical Engineering and Science, Broad Institute of MIT and Harvard, Lincoln Laboratory, Massachusetts Institute of Technology. Department of Biology, Gabriel, Stacey, Lander, Eric Steven, Daly, Mark J, Banks, Eric, Bhatia, Gaurav, Kashin, Seva, McCarroll, Steven A, Nemesh, James, Poplin, Ryan E., Sabeti, Pardis, Shlyakhter, Ilya, Schaffner, Stephen F, Vitti, Joseph, Gymrek, Melissa A, Hartler, Christina M., Tariyal, Ridhi, The 1000 Genomes Project Consortium, Institute for Medical Engineering and Science, Broad Institute of MIT and Harvard, Lincoln Laboratory, Massachusetts Institute of Technology. Department of Biology, Gabriel, Stacey, Lander, Eric Steven, Daly, Mark J, Banks, Eric, Bhatia, Gaurav, Kashin, Seva, McCarroll, Steven A, Nemesh, James, Poplin, Ryan E., Sabeti, Pardis, Shlyakhter, Ilya, Schaffner, Stephen F, Vitti, Joseph, Gymrek, Melissa A, Hartler, Christina M., Tariyal, Ridhi, and The 1000 Genomes Project Consortium

Abstract

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies., Wellcome Trust (London, England) (Core Award 090532/Z/09/Z), Wellcome Trust (London, England) (Senior Investigator Award 095552/Z/11/Z ), Wellcome Trust (London, England) (WT095908), Wellcome Trust (London, England) (WT109497), Wellcome Trust (London, England) (WT098051), Wellcome Trust (London, England) (WT086084/Z/08/Z), Wellcome Trust (London, England) (WT100956/Z/13/Z ), Wellcome Trust (London, England) (WT097307), Wellcome Trust (London, England) (WT0855322/Z/08/Z ), Wellcome Trust (London, England) (WT090770/Z/09/Z ), Wellcome Trust (London, England) (Major Overseas program in Vietnam grant 089276/Z.09/Z), Medical Research Council (Great Britain) (grant G0801823), Biotechnology and Biological Sciences Research Council (Great Britain) (grant BB/I02593X/1), Biotechnology and Biological Sciences Research Council (Great Britain) (grant BB/I021213/1), Zhongguo ke xue ji shu qing bao yan jiu suo. Office of 863 Programme of China (2012AA02A201), National Basic Research Program of China (2011CB809201), National Basic Research Program of China (2011CB809202), National Basic Research Program of China (2011CB809203), National Natural Science Foundation of China (31161130357), Shenzhen Municipal Government of China (grant ZYC201105170397A), Canadian Institutes of Health Research (grant 136855), Quebec Ministry of Economic Development, Innovation, and Exports (PSR-SIIRI-195), Germany. Bundesministerium für Bildung und Forschung (0315428A), Germany. Bundesministerium für Bildung und Forschung (01GS08201), Germany. Bundesministerium für Bildung und Forschung (BMBF-EPITREAT grant 0316190A), Deutsche Forschungsgemeinschaft (Emmy Noether Grant KO4037/1-1), Beatriu de Pinos Program (2006 BP-A 10144), Beatriu de Pinos Program (2009 BP-B 00274), Spanish National Institute for Health (grant PRB2 IPT13/0001-ISCIII-SGEFI/FEDER), Japan Society for the Promotion of Science (fellowship number PE13075), Marie Curie Actions Career Integration (grant 303772), Fonds National Suisse del la Recherche, SNSF, Scientifique (31003A_130342), National Center for Biotechnology Information (U.S.) (U54HG3067), National Center for Biotechnology Information (U.S.) (U54HG3273), National Center for Biotechnology Information (U.S.) (U01HG5211), National Center for Biotechnology Information (U.S.) (U54HG3079), National Center for Biotechnology Information (U.S.) (R01HG2898), National Center for Biotechnology Information (U.S.) (R01HG2385), National Center for Biotechnology Information (U.S.) (RC2HG5552), National Center for Biotechnology Information (U.S.) (U01HG6513), National Center for Biotechnology Information (U.S.) (U01HG5214), National Center for Biotechnology Information (U.S.) (U01HG5715), National Center for Biotechnology Information (U.S.) (U01HG5718), National Center for Biotechnology Information (U.S.) (U01HG5728), National Center for Biotechnology Information (U.S.) (U41HG7635), National Center for Biotechnology Information (U.S.) (U41HG7497), National Center for Biotechnology Information (U.S.) (R01HG4960), National Center for Biotechnology Information (U.S.) (R01HG5701), National Center for Biotechnology Information (U.S.) (R01HG5214), National Center for Biotechnology Information (U.S.) (R01HG6855), National Center for Biotechnology Information (U.S.) (R01HG7068), National Center for Biotechnology Information (U.S.) (R01HG7644), National Center for Biotechnology Information (U.S.) (DP2OD6514), National Center for Biotechnology Information (U.S.) (DP5OD9154), National Center for Biotechnology Information (U.S.) (R01CA166661), National Center for Biotechnology Information (U.S.) (R01CA172652), National Center for Biotechnology Information (U.S.) (P01GM99568), National Center for Biotechnology Information (U.S.) (R01GM59290), National Center for Biotechnology Information (U.S.) (R01GM104390), National Center for Biotechnology Information (U.S.) (T32GM7790), National Center for Biotechnology Information (U.S.) (R01HL87699), National Center for Biotechnology Information (U.S.) (R01HL104608), National Center for Biotechnology Information (U.S.) (T32HL94284), National Center for Biotechnology Information (U.S.) (HHSN268201100040C), National Center for Biotechnology Information (U.S.) (HHSN272201000025C), Lundbeck Foundation (grant R170-2014-1039, Simons Foundation (SFARI award SF51), National Science Foundation (U.S.) (Research Fellowship DGE-1147470)

Published
2017

36. Limited contribution of rare, noncoding variation to autism spectrum disorder from sequencing of 2,076 genomes in quartet families

Author

Werling, Donna M., primary, Brand, Harrison, additional, An, Joon-Yong, additional, Stone, Matthew R., additional, Glessner, Joseph T., additional, Zhu, Lingxue, additional, Collins, Ryan L., additional, Dong, Shan, additional, Layer, Ryan M., additional, Markenscoff-Papadimitriou, Eirene, additional, Farrell, Andrew, additional, Schwartz, Grace B., additional, Currall, Benjamin B., additional, Dea, Jeanselle, additional, Duhn, Clif, additional, Erdman, Carolyn, additional, Gilson, Michael, additional, Handsaker, Robert E., additional, Kashin, Seva, additional, Klei, Lambertus, additional, Mandell, Jeffrey D., additional, Nowakowski, Tomasz J., additional, Liu, Yuwen, additional, Pochareddy, Sirisha, additional, Smith, Louw, additional, Walker, Michael F., additional, Wang, Harold Z., additional, Waterman, Mathew J., additional, He, Xin, additional, Kriegstein, Arnold R., additional, Rubenstein, John L., additional, Sestan, Nenad, additional, McCarroll, Steven A., additional, Neale, Ben M., additional, Coon, Hilary, additional, Willsey, A. Jeremy, additional, Buxbaum, Joseph D., additional, Daly, Mark J., additional, State, Matthew W., additional, Quinlan, Aaron, additional, Marth, Gabor T., additional, Roeder, Kathryn, additional, Devlin, Bernie, additional, Talkowski, Michael E., additional, and Sanders, Stephan J., additional

Published
2017
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37. Structural forms of the human amylase locus and their relationships to SNPs, haplotypes and obesity

Author

Usher, Christina L, primary, Handsaker, Robert E, additional, Esko, Tõnu, additional, Tuke, Marcus A, additional, Weedon, Michael N, additional, Hastie, Alex R, additional, Cao, Han, additional, Moon, Jennifer E, additional, Kashin, Seva, additional, Fuchsberger, Christian, additional, Metspalu, Andres, additional, Pato, Carlos N, additional, Pato, Michele T, additional, McCarthy, Mark I, additional, Boehnke, Michael, additional, Altshuler, David M, additional, Frayling, Timothy M, additional, Hirschhorn, Joel N, additional, and McCarroll, Steven A, additional

Published
2015
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39. Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics

Author

Barbeira, Alvaro N., Dickinson, Scott P., Bonazzola, Rodrigo, Zheng, Jiamao, Wheeler, Heather E., Torres, Jason M., Torstenson, Eric S., Shah, Kaanan P., Garcia, Tzintzuni, Edwards, Todd L., Stahl, Eli A., Huckins, Laura M., Aguet, François, Ardlie, Kristin G., Cummings, Beryl B., Gelfand, Ellen T., Getz, Gad, Hadley, Kane, Handsaker, Robert E., Huang, Katherine H., Kashin, Seva, Karczewski, Konrad J., Lek, Monkol, Li, Xiao, MacArthur, Daniel G., Nedzel, Jared L., Nguyen, Duyen T., Noble, Michael S., Segrè, Ayellet V., Trowbridge, Casandra A., Tukiainen, Taru, Abell, Nathan S., Balliu, Brunilda, Barshir, Ruth, Basha, Omer, Battle, Alexis, Bogu, Gireesh K., Brown, Andrew, Brown, Christopher D., Castel, Stephane E., Chen, Lin S., Chiang, Colby, Conrad, Donald F., Damani, Farhan N., Davis, Joe R., Delaneau, Olivier, Dermitzakis, Emmanouil T., Engelhardt, Barbara E., Eskin, Eleazar, Ferreira, Pedro G., Frésard, Laure, Gamazon, Eric R., Garrido-Martín, Diego, Gewirtz, Ariel D. H., Gliner, Genna, Gloudemans, Michael J., Guigo, Roderic, Hall, Ira M., Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Jo, Brian, Kang, Eun Yong, Kim, Yungil, Kim-Hellmuth, Sarah, Lappalainen, Tuuli, Li, Gen, Li, Xin, Liu, Boxiang, Mangul, Serghei, McCarthy, Mark I., McDowell, Ian C., Mohammadi, Pejman, Monlong, Jean, Montgomery, Stephen B., Muñoz-Aguirre, Manuel, Ndungu, Anne W., Nobel, Andrew B., Oliva, Meritxell, Ongen, Halit, Palowitch, John J., Panousis, Nikolaos, Papasaikas, Panagiotis, Park, YoSon, Parsana, Princy, Payne, Anthony J., Peterson, Christine B., Quan, Jie, Reverter, Ferran, Sabatti, Chiara, Saha, Ashis, Sammeth, Michael, Scott, Alexandra J., Shabalin, Andrey A., Sodaei, Reza, Stephens, Matthew, Stranger, Barbara E., Strober, Benjamin J., Sul, Jae Hoon, Tsang, Emily K., Urbut, Sarah, van de Bunt, Martijn, Wang, Gao, Wen, Xiaoquan, Wright, Fred A., Xi, Hualin S., Yeger-Lotem, Esti, Zappala, Zachary, Zaugg, Judith B., Zhou, Yi-Hui, Akey, Joshua M., Bates, Daniel, Chan, Joanne, Claussnitzer, Melina, Demanelis, Kathryn, Diegel, Morgan, Doherty, Jennifer A., Feinberg, Andrew P., Fernando, Marian S., Halow, Jessica, Hansen, Kasper D., Haugen, Eric, Hickey, Peter F., Hou, Lei, Jasmine, Farzana, Jian, Ruiqi, Jiang, Lihua, Johnson, Audra, Kaul, Rajinder, Kellis, Manolis, Kibriya, Muhammad G., Lee, Kristen, Li, Jin Billy, Li, Qin, Lin, Jessica, Lin, Shin, Linder, Sandra, Linke, Caroline, Liu, Yaping, Maurano, Matthew T., Molinie, Benoit, Nelson, Jemma, Neri, Fidencio J., Park, Yongjin, Pierce, Brandon L., Rinaldi, Nicola J., Rizzardi, Lindsay F., Sandstrom, Richard, Skol, Andrew, Smith, Kevin S., Snyder, Michael P., Stamatoyannopoulos, John, Tang, Hua, Wang, Li, Wang, Meng, Van Wittenberghe, Nicholas, Wu, Fan, Zhang, Rui, Nierras, Concepcion R., Branton, Philip A., Carithers, Latarsha J., Guan, Ping, Moore, Helen M., Rao, Abhi, Vaught, Jimmie B., Gould, Sarah E., Lockart, Nicole C., Martin, Casey, Struewing, Jeffery P., Volpi, Simona, Addington, Anjene M., Koester, Susan E., Little, A. Roger, Brigham, Lori E., Hasz, Richard, Hunter, Marcus, Johns, Christopher, Johnson, Mark, Kopen, Gene, Leinweber, William F., Lonsdale, John T., McDonald, Alisa, Mestichelli, Bernadette, Myer, Kevin, Roe, Brian, Salvatore, Michael, Shad, Saboor, Thomas, Jeffrey A., Walters, Gary, Washington, Michael, Wheeler, Joseph, Bridge, Jason, Foster, Barbara A., Gillard, Bryan M., Karasik, Ellen, Kumar, Rachna, Miklos, Mark, Moser, Michael T., Jewell, Scott D., Montroy, Robert G., Rohrer, Daniel C., Valley, Dana R., Davis, David A., Mash, Deborah C., Undale, Anita H., Smith, Anna M., Tabor, David E., Roche, Nancy V., McLean, Jeffrey A., Vatanian, Negin, Robinson, Karna L., Sobin, Leslie, Barcus, Mary E., Valentino, Kimberly M., Qi, Liqun, Hunter, Steven, Hariharan, Pushpa, Singh, Shilpi, Um, Ki Sung, Matose, Takunda, Tomaszewski, Maria M., Barker, Laura K., Mosavel, Maghboeba, Siminoff, Laura A., Traino, Heather M., Flicek, Paul, Juettemann, Thomas, Ruffier, Magali, Sheppard, Dan, Taylor, Kieron, Trevanion, Stephen J., Zerbino, Daniel R., Craft, Brian, Goldman, Mary, Haeussler, Maximilian, Kent, W. James, Lee, Christopher M., Paten, Benedict, Rosenbloom, Kate R., Vivian, John, Zhu, Jingchun, Nicolae, Dan L., Cox, Nancy J., and Im, Hae Kyung

Abstract

Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression to compute PrediXcan (a gene mapping approach) results using summary data (S-PrediXcan) and show its accuracy and general robustness to misspecified reference sets. We apply this framework to 44 GTEx tissues and 100+ phenotypes from GWAS and meta-analysis studies, creating a growing public catalog of associations that seeks to capture the effects of gene expression variation on human phenotypes. Replication in an independent cohort is shown. Most of the associations are tissue specific, suggesting context specificity of the trait etiology. Colocalized significant associations in unexpected tissues underscore the need for an agnostic scanning of multiple contexts to improve our ability to detect causal regulatory mechanisms. Monogenic disease genes are enriched among significant associations for related traits, suggesting that smaller alterations of these genes may cause a spectrum of milder phenotypes.

Published
2018
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40. Punctuated bursts in human male demography inferred from 1,244 worldwide Y-chromosome sequences

Author

Poznik, G David, Xue, Yali, Mendez, Fernando L, Willems, Thomas F, Massaia, Andrea, Wilson Sayres, Melissa A, Ayub, Qasim, McCarthy, Shane A, Narechania, Apurva, Kashin, Seva, Chen, Yuan, Banerjee, Ruby, Rodriguez-Flores, Juan L, Cerezo, Maria, Shao, Haojing, Gymrek, Melissa, Malhotra, Ankit, Louzada, Sandra, Desalle, Rob, Ritchie, Graham R S, Cerveira, Eliza, Fitzgerald, Tomas W, Garrison, Erik, Marcketta, Anthony, Mittelman, David, Romanovitch, Mallory, Zhang, Chengsheng, Zheng-Bradley, Xiangqun, Abecasis, Gonçalo R, McCarroll, Steven A, Flicek, Paul, Underhill, Peter A, Coin, Lachlan, Zerbino, Daniel R, Yang, Fengtang, Lee, Charles, Clarke, Laura, Auton, Adam, Erlich, Yaniv, Handsaker, Robert E, Bustamante, Carlos D, and Tyler-Smith, Chris

Abstract

We report the sequences of 1,244 human Y chromosomes randomly ascertained from 26 worldwide populations by the 1000 Genomes Project. We discovered more than 65,000 variants, including single-nucleotide variants, multiple-nucleotide variants, insertions and deletions, short tandem repeats, and copy number variants. Of these, copy number variants contribute the greatest predicted functional impact. We constructed a calibrated phylogenetic tree on the basis of binary single-nucleotide variants and projected the more complex variants onto it, estimating the number of mutations for each class. Our phylogeny shows bursts of extreme expansion in male numbers that have occurred independently among each of the five continental superpopulations examined, at times of known migrations and technological innovations.

Published
2016
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41. Structural forms of the human amylase locus and their relationships to SNPs, haplotypes, and obesity

Author

Usher, Christina L, Handsaker, Robert E, Esko, Tõnu, Tuke, Marcus A, Weedon, Michael N, Hastie, Alex R, Cao, Han, Moon, Jennifer E, Kashin, Seva, Fuchsberger, Christian, Metspalu, Andres, Pato, Carlos N, Pato, Michele T, McCarthy, Mark I, Boehnke, Michael, Altshuler, David M, Frayling, Timothy M, Hirschhorn, Joel N, and McCarroll, Steven A

Abstract

Hundreds of genes reside in structurally complex, poorly understood regions of the human genome1-3. One such region contains the three amylase genes (AMY2B, AMY2A, and AMY1) responsible for digesting starch into sugar. The copy number of AMY1 is reported to be the genome’s largest influence on obesity4, though genome-wide association studies for obesity have found this locus unremarkable. Using whole genome sequence analysis3,5, droplet digital PCR6, and genome mapping7, we identified eight common structural haplotypes of the amylase locus that suggest its mutational history. We found that AMY1 copy number in individuals’ genomes is generally even (rather than odd) and partially correlates to nearby SNPs, which do not associate with BMI. We measured amylase gene copy number in 1,000 obese or lean Estonians and in two other cohorts totaling ~3,500 individuals. We had 99% power to detect the lower bound of the reported effects on BMI4, yet found no association.

Published
2016
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42. An integrated map of structural variation in 2,504 human genomes

Author

Sudmant, Peter H., Rausch, Tobias, Gardner, Eugene J., Handsaker, Robert E., Abyzov, Alexej, Huddleston, John, Zhang, Yan, Ye, Kai, Jun, Goo, Fritz, Markus Hsi-Yang, Konkel, Miriam K., Malhotra, Ankit, Stütz, Adrian M., Shi, Xinghua, Casale, Francesco Paolo, Chen, Jieming, Hormozdiari, Fereydoun, Dayama, Gargi, Chen, Ken, Malig, Maika, Chaisson, Mark J.P., Walter, Klaudia, Meiers, Sascha, Kashin, Seva, Garrison, Erik, Auton, Adam, Lam, Hugo Y. K., Mu, Xinmeng Jasmine, Alkan, Can, Antaki, Danny, Bae, Taejeong, Cerveira, Eliza, Chines, Peter, Chong, Zechen, Clarke, Laura, Dal, Elif, Ding, Li, Emery, Sarah, Fan, Xian, Gujral, Madhusudan, Kahveci, Fatma, Kidd, Jeffrey M., Kong, Yu, Lameijer, Eric-Wubbo, McCarthy, Shane, Flicek, Paul, Gibbs, Richard A., Marth, Gabor, Mason, Christopher E., Menelaou, Androniki, Muzny, Donna M., Nelson, Bradley J., Noor, Amina, Parrish, Nicholas F., Pendleton, Matthew, Quitadamo, Andrew, Raeder, Benjamin, Schadt, Eric E., Romanovitch, Mallory, Schlattl, Andreas, Sebra, Robert, Shabalin, Andrey A., Untergasser, Andreas, Walker, Jerilyn A., Wang, Min, Yu, Fuli, Zhang, Chengsheng, Zhang, Jing, Zheng-Bradley, Xiangqun, Zhou, Wanding, Zichner, Thomas, Sebat, Jonathan, Batzer, Mark A., McCarroll, Steven A., Mills, Ryan E., Gerstein, Mark B., Bashir, Ali, Stegle, Oliver, Devine, Scott E., Lee, Charles, Eichler, Evan E., and Korbel, Jan O.

Abstract

Summary Structural variants (SVs) are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight SV classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype-blocks in 26 human populations. Analyzing this set, we identify numerous gene-intersecting SVs exhibiting population stratification and describe naturally occurring homozygous gene knockouts suggesting the dispensability of a variety of human genes. We demonstrate that SVs are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of SV complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex SVs with multiple breakpoints likely formed through individual mutational events. Our catalog will enhance future studies into SV demography, functional impact and disease association.

Published
2015
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43. Large multi-allelic copy number variations in humans

Author

Handsaker, Robert E., Van Doren, Vanessa, Berman, Jennifer R., Genovese, Giulio, Kashin, Seva, Boettger, Linda M., and McCarroll, Steven A.

Abstract

Thousands of genome segments appear to be present in widely varying copy number in different human genomes. We developed ways to use increasingly abundant whole genome sequence data to identify the copy numbers, alleles and haplotypes present at most large, multi-allelic CNVs (mCNVs). We analyzed 849 genomes sequenced by the 1000 Genomes Project to identify most large (>5 kb) mCNVs, including 3,878 duplications, of which 1,356 appear to have three or more segregating alleles. We find that mCNVs give rise to most human gene-dosage variation – exceeding sevenfold the contribution of deletions and biallelic duplications – and that this variation in gene dosage generates abundant variation in gene expression. We describe “runaway duplication haplotypes” in which genes, including HPR and ORM1, have mutated to high copy number on specific haplotypes. We describe partially successful initial strategies for analyzing mCNVs via imputation and provide an initial data resource to support such analyses.

Published
2015
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44. Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations

Author

Merkle, Florian T, Ghosh, Sulagna, Kamitaki, Nolan, Mitchell, Jana, Avior, Yishai, Mello, Curtis, Kashin, Seva, Mekhoubad, Shila, Ilic, Dusko, Charlton, Maura, Saphier, Genevieve, Handsaker, Robert E, Genovese, Giulio, Bar, Shiran, Benvenisty, Nissim, McCarroll, Steven A, and Eggan, Kevin

Subjects
Mosaicism, DNA Mutational Analysis, Human Embryonic Stem Cells, Induced Pluripotent Stem Cells, Loss of Heterozygosity, Cell Count, Cell Differentiation, DNA, Genes, p53, 3. Good health, Cell Line, Protein Domains, Neoplasms, Mutation, Humans, Exome, Selection, Genetic, Tumor Suppressor Protein p53, Alleles, Cell Division, Genes, Dominant
Abstract

Human pluripotent stem cells (hPS cells) can self-renew indefinitely, making them an attractive source for regenerative therapies. This expansion potential has been linked with the acquisition of large copy number variants that provide mutated cells with a growth advantage in culture. The nature, extent and functional effects of other acquired genome sequence mutations in cultured hPS cells are not known. Here we sequence the protein-coding genes (exomes) of 140 independent human embryonic stem cell (hES cell) lines, including 26 lines prepared for potential clinical use. We then apply computational strategies for identifying mutations present in a subset of cells in each hES cell line. Although such mosaic mutations were generally rare, we identified five unrelated hES cell lines that carried six mutations in the TP53 gene that encodes the tumour suppressor P53. The TP53 mutations we observed are dominant negative and are the mutations most commonly seen in human cancers. We found that the TP53 mutant allelic fraction increased with passage number under standard culture conditions, suggesting that the P53 mutations confer selective advantage. We then mined published RNA sequencing data from 117 hPS cell lines, and observed another nine TP53 mutations, all resulting in coding changes in the DNA-binding domain of P53. In three lines, the allelic fraction exceeded 50%, suggesting additional selective advantage resulting from the loss of heterozygosity at the TP53 locus. As the acquisition and expansion of cancer-associated mutations in hPS cells may go unnoticed during most applications, we suggest that careful genetic characterization of hPS cells and their differentiated derivatives be carried out before clinical use.

45. A global reference for human genetic variation

Author

Colonna V. (1000 Genomes Project Consortium) Adam Auton, Gonçalo R Abecasis, David M Altshuler, Richard M Durbin, David R Bentley, Aravinda Chakravarti, Andrew G Clark, Peter Donnelly, Evan E Eichler, Paul Flicek, Stacey B Gabriel, Richard A Gibbs, Eric D Green, Matthew E Hurles, Bartha M Knoppers, Jan O Korbel, Eric S Lander, Charles Lee, Hans Lehrach, Elaine R Mardis, Gabor T Marth, Gil A McVean, Deborah A Nickerson, Jeanette P Schmidt, Stephen T Sherry, Jun Wang, Richard K Wilson, Eric Boerwinkle, Harsha Doddapaneni, Yi Han, Viktoriya Korchina, Christie Kovar, Sandra Lee, Donna Muzny, Jeffrey G Reid, Yiming Zhu, Yuqi Chang, Qiang Feng, Xiaodong Fang, Xiaosen Guo, Min Jian, Hui Jiang, Xin Jin, Tianming Lan, Guoqing Li, Jingxiang Li, Yingrui Li, Shengmao Liu, Xiao Liu, Yao Lu, Xuedi Ma, Meifang Tang, Bo Wang, Guangbiao Wang, Honglong Wu, Renhua Wu, Xun Xu, Ye Yin, Dandan Zhang, Wenwei Zhang, Jiao Zhao, Meiru Zhao, Xiaole Zheng, Namrata Gupta, Neda Gharani, Lorraine H Toji, Norman P Gerry, Alissa M Resch, Jonathan Barker, Laura Clarke, Laurent Gil, Sarah E Hunt, Gavin Kelman, Eugene Kulesha, Rasko Leinonen, William M McLaren, Rajesh Radhakrishnan, Asier Roa, Dmitriy Smirnov, Richard E Smith, Ian Streeter, Anja Thormann, Iliana Toneva, Brendan Vaughan, Xiangqun Zheng-Bradley, Russell Grocock, Sean Humphray, Terena James, Zoya Kingsbury, Ralf Sudbrak, Marcus W Albrecht, Vyacheslav S Amstislavskiy, Tatiana A Borodina, Matthias Lienhard, Florian Mertes, Marc Sultan, Bernd Timmermann, Marie-Laure Yaspo, Lucinda Fulton, Robert Fulton, Victor Ananiev, Zinaida Belaia, Dimitriy Beloslyudtsev, Nathan Bouk, Chao Chen, Deanna Church, Robert Cohen, Charles Cook, John Garner, Timothy Hefferon, Mikhail Kimelman, Chunlei Liu, John Lopez, Peter Meric, Chris O'Sullivan, Yuri Ostapchuk, Lon Phan, Sergiy Ponomarov, Valerie Schneider, Eugene Shekhtman, Karl Sirotkin, Douglas Slotta, Hua Zhang, Senduran Balasubramaniam, John Burton, Petr Danecek, Thomas M Keane, Anja Kolb-Kokocinski, Shane McCarthy, James Stalker, Michael Quail, Christopher J Davies, Jeremy Gollub, Teresa Webster, Brant Wong, Yiping Zhan, Adam Auton, Christopher L Campbell, Yu Kong, Anthony Marcketta, Fuli Yu, Lilian Antunes, Matthew Bainbridge, Aniko Sabo, Zhuoyi Huang, Lachlan J M Coin, Lin Fang, Qibin Li, Zhenyu Li, Haoxiang Lin, Binghang Liu, Ruibang Luo, Haojing Shao, Yinlong Xie, Chen Ye, Chang Yu, Fan Zhang, Hancheng Zheng, Hongmei Zhu, Can Alkan, Elif Dal, Fatma Kahveci, Erik P Garrison, Deniz Kural, Wan-Ping Lee, Wen Fung Leong, Michael Stromberg, Alistair N Ward, Jiantao Wu, Mengyao Zhang, Mark J Daly, Mark A DePristo, Robert E Handsaker, Eric Banks, Gaurav Bhatia, Guillermo Del Angel, Giulio Genovese, Heng Li, Seva Kashin, Steven A McCarroll, James C Nemesh, Ryan E Poplin, Seungtai C Yoon, Jayon Lihm, Vladimir Makarov, Srikanth Gottipati, Alon Keinan, Juan L Rodriguez-Flores, Tobias Rausch, Markus H Fritz, Adrian M Stütz, Kathryn Beal, Avik Datta, Javier Herrero, Graham R S Ritchie, Daniel Zerbino, Pardis C Sabeti, Ilya Shlyakhter, Stephen F Schaffner, Joseph Vitti, David N Cooper, Edward V Ball, Peter D Stenson, Bret Barnes, Markus Bauer, R Keira Cheetham, Anthony Cox, Michael Eberle, Scott Kahn, Lisa Murray, John Peden, Richard Shaw, Eimear E Kenny, Mark A Batzer, Miriam K Konkel, Jerilyn A Walker, Daniel G MacArthur, Monkol Lek, Ralf Herwig, Li Ding, Daniel C Koboldt, David Larson, Kai Ye, Simon Gravel, Anand Swaroop, Emily Chew, Tuuli Lappalainen, Yaniv Erlich, Melissa Gymrek, Thomas Frederick Willems, Jared T Simpson, Mark D Shriver, Jeffrey A Rosenfeld, Carlos D Bustamante, Stephen B Montgomery, Francisco M De La Vega, Jake K Byrnes, Andrew W Carroll, Marianne K DeGorter, Phil Lacroute, Brian K Maples, Alicia R Martin, Andres Moreno-Estrada, Suyash S Shringarpure, Fouad Zakharia, Eran Halperin, Yael Baran, Eliza Cerveira, Jaeho Hwang, Ankit Malhotra, Dariusz Plewczynski, Kamen Radew, Mallory Romanovitch, Chengsheng Zhang, Fiona C L Hyland, David W Craig, Alexis Christoforides, Nils Homer, Tyler Izatt, Ahmet A Kurdoglu, Shripad A Sinari, Kevin Squire, Chunlin Xiao, Jonathan Sebat, Danny Antaki, Madhusudan Gujral, Amina Noor, Kenny Ye, Esteban G Burchard, Ryan D Hernandez, Christopher R Gignoux, David Haussler, Sol J Katzman, W James Kent, Bryan Howie, Andres Ruiz-Linares, Emmanouil T Dermitzakis, Scott E Devine, Hyun Min Kang, Jeffrey M Kidd, Tom Blackwell, Sean Caron, Wei Chen, Sarah Emery, Lars Fritsche, Christian Fuchsberger, Goo Jun, Bingshan Li, Robert Lyons, Chris Scheller, Carlo Sidore, Shiya Song, Elzbieta Sliwerska, Daniel Taliun, Adrian Tan, Ryan Welch, Mary Kate Wing, Xiaowei Zhan, Philip Awadalla, Alan Hodgkinson, Yun Li, Xinghua Shi, Andrew Quitadamo, Gerton Lunter, Jonathan L Marchini, Simon Myers, Claire Churchhouse, Olivier Delaneau, Anjali Gupta-Hinch, Warren Kretzschmar, Zamin Iqbal, Iain Mathieson, Androniki Menelaou, Andy Rimmer, Dionysia K Xifara, Taras K Oleksyk, Yunxin Fu, Xiaoming Liu, Momiao Xiong, Lynn Jorde, David Witherspoon, Jinchuan Xing, Brian L Browning, Sharon R Browning, Fereydoun Hormozdiari, Peter H Sudmant, Ekta Khurana, Chris Tyler-Smith, Cornelis A Albers, Qasim Ayub, Yuan Chen, Vincenza Colonna, Luke Jostins, Klaudia Walter, Yali Xue, Mark B Gerstein, Alexej Abyzov, Suganthi Balasubramanian, Jieming Chen, Declan Clarke, Yao Fu, Arif O Harmanci, Mike Jin, Donghoon Lee, Jeremy Liu, Xinmeng Jasmine Mu, Jing Zhang, Yan Zhang, Chris Hartl, Khalid Shakir, Jeremiah Degenhardt, Sascha Meiers, Benjamin Raeder, Francesco Paolo Casale, Oliver Stegle, Eric-Wubbo Lameijer, Ira Hall, Vineet Bafna, Jacob Michaelson, Eugene J Gardner, Ryan E Mills, Gargi Dayama, Ken Chen, Xian Fan, Zechen Chong, Tenghui Chen, Mark J Chaisson, John Huddleston, Maika Malig, Bradley J Nelson, Nicholas F Parrish, Ben Blackburne, Sarah J Lindsay, Zemin Ning, Yujun Zhang, Hugo Lam, Cristina Sisu, Danny Challis, Uday S Evani, James Lu, Uma Nagaswamy, Jin Yu, Wangshen Li, Lukas Habegger, Haiyuan Yu, Fiona Cunningham, Ian Dunham, Kasper Lage, Jakob Berg Jespersen, Heiko Horn, Donghoon Kim, Rob Desalle, Apurva Narechania, Melissa A Wilson Sayres, Fernando L Mendez, G David Poznik, Peter A Underhill, Lachlan Coin, David Mittelman, Ruby Banerjee, Maria Cerezo, Thomas W Fitzgerald, Sandra Louzada, Andrea Massaia, Graham R Ritchie, Fengtang Yang, Divya Kalra, Walker Hale, Xu Dan, Kathleen C Barnes, Christine Beiswanger, Hongyu Cai, Hongzhi Cao, Brenna Henn, Danielle Jones, Jane S Kaye, Alastair Kent, Angeliki Kerasidou, Rasika Mathias, Pilar N Ossorio, Michael Parker, Charles N Rotimi, Charmaine D Royal, Karla Sandoval, Yeyang Su, Zhongming Tian, Sarah Tishkoff, Marc Via, Yuhong Wang, Huanming Yang, Ling Yang, Jiayong Zhu, Walter Bodmer, Gabriel Bedoya, Zhiming Cai, Yang Gao, Jiayou Chu, Leena Peltonen, Andres Garcia-Montero, Alberto Orfao, Julie Dutil, Juan C Martinez-Cruzado, Rasika A Mathias, Anselm Hennis, Harold Watson, Colin McKenzie, Firdausi Qadri, Regina LaRocque, Xiaoyan Deng, Danny Asogun, Onikepe Folarin, Christian Happi, Omonwunmi Omoniwa, Matt Stremlau, Ridhi Tariyal, Muminatou Jallow, Fatoumatta Sisay Joof, Tumani Corrah, Kirk Rockett, Dominic Kwiatkowski, Jaspal Kooner, Trân T?nh Hiên, Sarah J Dunstan, Nguyen Thuy Hang, Richard Fonnie, Robert Garry, Lansana Kanneh, Lina Moses, John Schieffelin, Donald S Grant, Carla Gallo, Giovanni Poletti, Danish Saleheen, Asif Rasheed, Lisa D Brooks, Adam L Felsenfeld, Jean E McEwen, Yekaterina Vaydylevich, Audrey Duncanson, Michael Dunn, Jeffery A Schloss, 1000 Genomes Project Consortium, Institute for Medical Engineering and Science, Broad Institute of MIT and Harvard, Lincoln Laboratory, Massachusetts Institute of Technology. Department of Biology, Gabriel, Stacey, Lander, Eric Steven, Daly, Mark J, Banks, Eric, Bhatia, Gaurav, Kashin, Seva, McCarroll, Steven A, Nemesh, James, Poplin, Ryan E., Sabeti, Pardis, Shlyakhter, Ilya, Schaffner, Stephen F, Vitti, Joseph, Gymrek, Melissa A, Hartler, Christina M., and Tariyal, Ridhi

Subjects
demography, genetic association, genotype, Human genomics, Genome-wide association study, Review, SUSCEPTIBILITY, DISEASE, polymorphism, 0302 clinical medicine, quantitative trait locus, INDEL Mutation, genetics, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), MUTATION, Exome sequencing, 0303 health sciences, public health, Sequence analysis, High-Throughput Nucleotide Sequencing, standard, Genomics, Reference Standards, Physical Chromosome Mapping, 3. Good health, priority journal, Science & Technology - Other Topics, BAYES FACTORS, Molecular Developmental Biology, Genotype, Genetics, Medical, Quantitative Trait Loci, DNA sequence, rare disease, human genetics, information processing, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, POPULATION HISTORY, human genome, Humans, retroposon, Genetic variability, human, GENOME-WIDE ASSOCIATION, 1000 Genomes Project, Demography, Science & Technology, ancestry, disease predisposition, Genetic Variation, MACULAR DEGENERATION, major clinical study, gene linkage disequilibrium, purl.org/pe-repo/ocde/ford#3.01.02 [https], Genetics, Population, 030217 neurology & neurosurgery, haplotype, Internationality, VARIANT, Datasets as Topic, Human genetic variation, COMPLEMENT FACTOR-H, single nucleotide polymorphism, genetic variability, Exome, chromosome map, Genetics, Variant Call Format, Genome, Multidisciplinary, 1000 Genomes Project Consortium, international cooperation, Multidisciplinary Sciences, standards, Disease Susceptibility, medical genetics, General Science & Technology, Population, Computational biology, Biology, gene frequency, Polymorphism, Single Nucleotide, high throughput sequencing, Rare Diseases, promoter region, MD Multidisciplinary, Genetic variation, QH426, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genome, Human, population genetics, population structure, Sequence Analysis, DNA, gene structure, INDIVIDUALS, Haplotypes, Genome-Wide Association Study, purl.org/pe-repo/ocde/ford#1.06.07 [https]
Abstract

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies., Wellcome Trust (London, England) (Core Award 090532/Z/09/Z), Wellcome Trust (London, England) (Senior Investigator Award 095552/Z/11/Z ), Wellcome Trust (London, England) (WT095908), Wellcome Trust (London, England) (WT109497), Wellcome Trust (London, England) (WT098051), Wellcome Trust (London, England) (WT086084/Z/08/Z), Wellcome Trust (London, England) (WT100956/Z/13/Z ), Wellcome Trust (London, England) (WT097307), Wellcome Trust (London, England) (WT0855322/Z/08/Z ), Wellcome Trust (London, England) (WT090770/Z/09/Z ), Wellcome Trust (London, England) (Major Overseas program in Vietnam grant 089276/Z.09/Z), Medical Research Council (Great Britain) (grant G0801823), Biotechnology and Biological Sciences Research Council (Great Britain) (grant BB/I02593X/1), Biotechnology and Biological Sciences Research Council (Great Britain) (grant BB/I021213/1), Zhongguo ke xue ji shu qing bao yan jiu suo. Office of 863 Programme of China (2012AA02A201), National Basic Research Program of China (2011CB809201), National Basic Research Program of China (2011CB809202), National Basic Research Program of China (2011CB809203), National Natural Science Foundation of China (31161130357), Shenzhen Municipal Government of China (grant ZYC201105170397A), Canadian Institutes of Health Research (grant 136855), Quebec Ministry of Economic Development, Innovation, and Exports (PSR-SIIRI-195), Germany. Bundesministerium für Bildung und Forschung (0315428A), Germany. Bundesministerium für Bildung und Forschung (01GS08201), Germany. Bundesministerium für Bildung und Forschung (BMBF-EPITREAT grant 0316190A), Deutsche Forschungsgemeinschaft (Emmy Noether Grant KO4037/1-1), Beatriu de Pinos Program (2006 BP-A 10144), Beatriu de Pinos Program (2009 BP-B 00274), Spanish National Institute for Health (grant PRB2 IPT13/0001-ISCIII-SGEFI/FEDER), Japan Society for the Promotion of Science (fellowship number PE13075), Marie Curie Actions Career Integration (grant 303772), Fonds National Suisse del la Recherche, SNSF, Scientifique (31003A_130342), National Center for Biotechnology Information (U.S.) (U54HG3067), National Center for Biotechnology Information (U.S.) (U54HG3273), National Center for Biotechnology Information (U.S.) (U01HG5211), National Center for Biotechnology Information (U.S.) (U54HG3079), National Center for Biotechnology Information (U.S.) (R01HG2898), National Center for Biotechnology Information (U.S.) (R01HG2385), National Center for Biotechnology Information (U.S.) (RC2HG5552), National Center for Biotechnology Information (U.S.) (U01HG6513), National Center for Biotechnology Information (U.S.) (U01HG5214), National Center for Biotechnology Information (U.S.) (U01HG5715), National Center for Biotechnology Information (U.S.) (U01HG5718), National Center for Biotechnology Information (U.S.) (U01HG5728), National Center for Biotechnology Information (U.S.) (U41HG7635), National Center for Biotechnology Information (U.S.) (U41HG7497), National Center for Biotechnology Information (U.S.) (R01HG4960), National Center for Biotechnology Information (U.S.) (R01HG5701), National Center for Biotechnology Information (U.S.) (R01HG5214), National Center for Biotechnology Information (U.S.) (R01HG6855), National Center for Biotechnology Information (U.S.) (R01HG7068), National Center for Biotechnology Information (U.S.) (R01HG7644), National Center for Biotechnology Information (U.S.) (DP2OD6514), National Center for Biotechnology Information (U.S.) (DP5OD9154), National Center for Biotechnology Information (U.S.) (R01CA166661), National Center for Biotechnology Information (U.S.) (R01CA172652), National Center for Biotechnology Information (U.S.) (P01GM99568), National Center for Biotechnology Information (U.S.) (R01GM59290), National Center for Biotechnology Information (U.S.) (R01GM104390), National Center for Biotechnology Information (U.S.) (T32GM7790), National Center for Biotechnology Information (U.S.) (R01HL87699), National Center for Biotechnology Information (U.S.) (R01HL104608), National Center for Biotechnology Information (U.S.) (T32HL94284), National Center for Biotechnology Information (U.S.) (HHSN268201100040C), National Center for Biotechnology Information (U.S.) (HHSN272201000025C), Lundbeck Foundation (grant R170-2014-1039, Simons Foundation (SFARI award SF51), National Science Foundation (U.S.) (Research Fellowship DGE-1147470)

Published
2015

46. Concerted neuron-astrocyte gene expression declines in aging and schizophrenia.

Author

Ling E, Nemesh J, Goldman M, Kamitaki N, Reed N, Handsaker RE, Genovese G, Vogelgsang JS, Gerges S, Kashin S, Ghosh S, Esposito JM, French K, Meyer D, Lutservitz A, Mullally CD, Wysoker A, Spina L, Neumann A, Hogan M, Ichihara K, Berretta S, and McCarroll SA

Abstract

Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a striking relationship between people's cortical neurons and cortical astrocytes. We used single-nucleus RNA-seq to analyze the prefrontal cortex of 191 human donors ages 22-97 years, including healthy individuals and persons with schizophrenia. Latent-factor analysis of these data revealed that in persons whose cortical neurons more strongly expressed genes for synaptic components, cortical astrocytes more strongly expressed distinct genes with synaptic functions and genes for synthesizing cholesterol, an astrocyte-supplied component of synaptic membranes. We call this relationship the Synaptic Neuron-and-Astrocyte Program (SNAP). In schizophrenia and aging - two conditions that involve declines in cognitive flexibility and plasticity 1,2 - cells had divested from SNAP: astrocytes, glutamatergic (excitatory) neurons, and GABAergic (inhibitory) neurons all reduced SNAP expression to corresponding degrees. The distinct astrocytic and neuronal components of SNAP both involved genes in which genetic risk factors for schizophrenia were strongly concentrated. SNAP, which varies quantitatively even among healthy persons of similar age, may underlie many aspects of normal human interindividual differences and be an important point of convergence for multiple kinds of pathophysiology., Competing Interests: COMPETING INTERESTS The authors declare no competing interests.

Published
2024
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