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1. Genomic data resources of the Brain Somatic Mosaicism Network for neuropsychiatric diseases.

Author

Garrison, McKinzie, Jang, Yeongjun, Bae, Taejeong, Cherskov, Adriana, Emery, Sarah, Fasching, Liana, Jones, Attila, Moldovan, John, Molitor, Cindy, Pochareddy, Sirisha, Peters, Mette, Shin, Joo, Wang, Yifan, Yang, Xiaoxu, Akbarian, Schahram, Chess, Andrew, Gage, Fred, Gleeson, Joseph, Kidd, Jeffrey, McConnell, Michael, Mills, Ryan, Moran, John, Park, Peter, Sestan, Nenad, Urban, Alexander, Vaccarino, Flora, Walsh, Christopher, Weinberger, Daniel, Wheelan, Sarah, and Abyzov, Alexej

Subjects
Humans, Autism Spectrum Disorder, Mosaicism, Genome, Brain, Genomics
Abstract

Somatic mosaicism is defined as an occurrence of two or more populations of cells having genomic sequences differing at given loci in an individual who is derived from a single zygote. It is a characteristic of multicellular organisms that plays a crucial role in normal development and disease. To study the nature and extent of somatic mosaicism in autism spectrum disorder, bipolar disorder, focal cortical dysplasia, schizophrenia, and Tourette syndrome, a multi-institutional consortium called the Brain Somatic Mosaicism Network (BSMN) was formed through the National Institute of Mental Health (NIMH). In addition to genomic data of affected and neurotypical brains, the BSMN also developed and validated a best practices somatic single nucleotide variant calling workflow through the analysis of reference brain tissue. These resources, which include >400 terabytes of data from 1087 subjects, are now available to the research community via the NIMH Data Archive (NDA) and are described here.

Published
2023

4. Enhancing anomaly detection techniques for emerging threats

Author

Mills, Ryan

Abstract

Despite the Internet being an apex of human achievement for many years, criminal behaviour and malicious activity are continuing to propagate at an alarming rate. This juxtaposition can be loosely attributed to the myriad of vulnerabilities identified in existing software. Cyber criminals leverage these innovative infection and exploitation techniques to author pervasive malware and propagate devastating attacks. These malicious actors are motivated by the financial or political gain achieved upon successful infiltration into computer systems as the resources held within are often very valuable in nature. With the widespread developments in the Internet of Things (IoT), 5G, and Starlink satellites, unserved areas of the world will experience a pervasive expansion of connected devices to the Internet. Consequently, a barrage of potential new attack vectors and victims are unfolding which requires constant monitoring in order to manage this ever growing problem. Conventional rule-based intrusion detection mechanisms used by network management solutions rely on pre-defined attack signatures and hence are unable to identify new attacks. In parallel, anomaly detection solutions tend to suffer from high false positive rates due to the limited statistical validation of ground truth data, which is used for profiling normal network behaviour. When considering the explosive threat landscape and the expanse of connected devices, current security solutions also face challenges relating to the scale at which attacks need to be monitored and detected. However, recent innovations in Big Data processing have revealed a promising avenue in which scale is addressed through cluster computing and parallel processing. This thesis advances beyond current solutions and leverages the coupling of anomaly detection and Cyber Threat Intelligence (CTI) with parallel processing for the profiling and detection of emerging cyber attacks. This is demonstrated through the design, implementation, and evaluation of Citrus: a novel intrusion detection framework which is adept at tackling emerging threats through the collection and labelling of live attack data by utilising diverse Internet vantage points in order to detect and classify malicious behaviour using graph-based metrics, as well as a range of Machine Learning (ML) algorithms. This research provides innovative contributions to the cyber security field, including the public release of an open flow-based intrusion detection data set. This data set encompasses emerging attack patterns and is supported by a robust ground truth. Furthermore, Citrus advances the current state of the art through a novel ground truth development method. Citrus also enables both near real-time and offline detection of emerging cyber attacks under optimal computational costs. These properties demonstrate that it is a viable and practical solution for next generation network defence and resilience strategies.

Published
2022
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5. Comprehensive identification of somatic nucleotide variants in human brain tissue

Author

Wang, Yifan, Bae, Taejeong, Thorpe, Jeremy, Sherman, Maxwell A, Jones, Attila G, Cho, Sean, Daily, Kenneth, Dou, Yanmei, Ganz, Javier, Galor, Alon, Lobon, Irene, Pattni, Reenal, Rosenbluh, Chaggai, Tomasi, Simone, Tomasini, Livia, Yang, Xiaoxu, Zhou, Bo, Akbarian, Schahram, Ball, Laurel L, Bizzotto, Sara, Emery, Sarah B, Doan, Ryan, Fasching, Liana, Jang, Yeongjun, Juan, David, Lizano, Esther, Luquette, Lovelace J, Moldovan, John B, Narurkar, Rujuta, Oetjens, Matthew T, Rodin, Rachel E, Sekar, Shobana, Shin, Joo Heon, Soriano, Eduardo, Straub, Richard E, Zhou, Weichen, Chess, Andrew, Gleeson, Joseph G, Marquès-Bonet, Tomas, Park, Peter J, Peters, Mette A, Pevsner, Jonathan, Walsh, Christopher A, Weinberger, Daniel R, Vaccarino, Flora M, Moran, John V, Urban, Alexander E, Kidd, Jeffrey M, Mills, Ryan E, and Abyzov, Alexej

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Neurosciences, Human Genome, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Alleles, Brain, Chromosome Mapping, Computational Biology, Genetic Association Studies, Genetic Variation, Genomics, Germ Cells, High-Throughput Nucleotide Sequencing, Humans, Organ Specificity, Polymorphism, Single Nucleotide, Brain Somatic Mosaicism Network, Environmental Sciences, Information and Computing Sciences, Bioinformatics
Abstract

BackgroundPost-zygotic mutations incurred during DNA replication, DNA repair, and other cellular processes lead to somatic mosaicism. Somatic mosaicism is an established cause of various diseases, including cancers. However, detecting mosaic variants in DNA from non-cancerous somatic tissues poses significant challenges, particularly if the variants only are present in a small fraction of cells.ResultsHere, the Brain Somatic Mosaicism Network conducts a coordinated, multi-institutional study to examine the ability of existing methods to detect simulated somatic single-nucleotide variants (SNVs) in DNA mixing experiments, generate multiple replicates of whole-genome sequencing data from the dorsolateral prefrontal cortex, other brain regions, dura mater, and dural fibroblasts of a single neurotypical individual, devise strategies to discover somatic SNVs, and apply various approaches to validate somatic SNVs. These efforts lead to the identification of 43 bona fide somatic SNVs that range in variant allele fractions from ~ 0.005 to ~ 0.28. Guided by these results, we devise best practices for calling mosaic SNVs from 250× whole-genome sequencing data in the accessible portion of the human genome that achieve 90% specificity and sensitivity. Finally, we demonstrate that analysis of multiple bulk DNA samples from a single individual allows the reconstruction of early developmental cell lineage trees.ConclusionsThis study provides a unified set of best practices to detect somatic SNVs in non-cancerous tissues. The data and methods are freely available to the scientific community and should serve as a guide to assess the contributions of somatic SNVs to neuropsychiatric diseases.

Published
2021

6. Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

Author

Marshall, Christian R., Merico, Daniele, Thiruvahindrapuram, Bhooma, Wang, Zhouzhi, Scherer, Stephen W., Howrigan, Daniel P, Ripke, Stephan, Bulik-Sullivan, Brendan, Farh, Kai-How, Fromer, Menachem, Goldstein, Jacqueline I., Huang, Hailiang, Lee, Phil, Daly, Mark J., Neale, Benjamin M., Belliveau, Richard A., Jr., Bergen, Sarah E., Bevilacqua, Elizabeth, Chambert, Kimberley D., O'Dushlaine, Colm, Scolnick, Edward M., Smoller, Jordan W., Moran, Jennifer L., Palotie, Aarno, Petryshen, Tracey L., Wu, Wenting, Greer, Douglas S., Antaki, Danny, Shetty, Aniket, Gujral, Madhusudan, Brandler, William M., Malhotra, Dheeraj, Fuentes Fajarado, Karin V., Maile, Michelle S., Holmans, Peter A., Carrera, Noa, Craddock, Nick, Escott-Price, Valentina, Georgieva, Lyudmila, Hamshere, Marian L., Kavanagh, David, Legge, Sophie E., Pocklington, Andrew J., Richards, Alexander L., Ruderfer, Douglas M., Williams, Nigel M., Kirov, George, Owen, Michael J., Pinto, Dalila, Cai, Guiqing, Davis, Kenneth L., Drapeau, Elodie, Friedman, Joseph I, Haroutunian, Vahram, Parkhomenko, Elena, Reichenberg, Abraham, Silverman, Jeremy M., Buxbaum, Joseph D., Domenici, Enrico, Agartz, Ingrid, Djurovic, Srdjan, Mattingsdal, Morten, Melle, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Söderman, Erik, Albus, Margot, Alexander, Madeline, Laurent, Claudine, Levinson, Douglas F., Amin, Farooq, Atkins, Joshua, Cairns, Murray J., Scott, Rodney J., Tooney, Paul A., Wu, Jing Qin, Bacanu, Silviu A., Bigdeli, Tim B., Reimers, Mark A., Webb, Bradley T., Wolen, Aaron R., Wormley, Brandon K., Kendler, Kenneth S., Riley, Brien P., Kähler, Anna K., Magnusson, Patrik K.E., Hultman, Christina M., Bertalan, Marcelo, Hansen, Thomas, Olsen, Line, Rasmussen, Henrik B., Werge, Thomas, Mattheisen, Manuel, Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Roffman, Joshua L., Byerley, William, Cahn, Wiepke, Kahn, René S, Strengman, Eric, Ophoff, Roel A., Carr, Vaughan J., Catts, Stanley V., Henskens, Frans A., Loughland, Carmel M., Michie, Patricia T., Pantelis, Christos, Schall, Ulrich, Jablensky, Assen V., Kelly, Brian J., Campion, Dominique, Cantor, Rita M., Cheng, Wei, Cloninger, C. Robert, Svrakic, Dragan M, Cohen, David, Cormican, Paul, Donohoe, Gary, Morris, Derek W., Corvin, Aiden, Gill, Michael, Crespo-Facorro, Benedicto, Crowley, James J., Farrell, Martilias S., Giusti-Rodríguez, Paola, Kim, Yunjung, Szatkiewicz, Jin P., Williams, Stephanie, Curtis, David, Pimm, Jonathan, Gurling, Hugh, McQuillin, Andrew, Davidson, Michael, Weiser, Mark, Degenhardt, Franziska, Forstner, Andreas J., Herms, Stefan, Hoffmann, Per, Hofman, Andrea, Cichon, Sven, Nöthen, Markus M., Del Favero, Jurgen, DeLisi, Lynn E., McCarley, Robert W., Levy, Deborah L., Mesholam-Gately, Raquelle I., Seidman, Larry J., Dikeos, Dimitris, Papadimitriou, George N., Dinan, Timothy, Duan, Jubao, Sanders, Alan R., Gejman, Pablo V., Gershon, Elliot S., Dudbridge, Frank, Eichhammer, Peter, Eriksson, Johan, Salomaa, Veikko, Essioux, Laurent, Fanous, Ayman H., Knowles, James A., Pato, Michele T., Pato, Carlos N., Frank, Josef, Meier, Sandra, Schulze, Thomas G., Strohmaier, Jana, Witt, Stephanie H., Rietschel, Marcella, Franke, Lude, Karjalainen, Juha, Freedman, Robert, Olincy, Ann, Freimer, Nelson B., Purcell, Shaun M., Roussos, Panos, Stahl, Eli A., Sklar, Pamela, Giegling, Ina, Hartmann, Annette M., Konte, Bettina, Rujescu, Dan, Godard, Stephanie, Hirschhorn, Joel N., Pers, Tune H., Price, Alkes, Esko, Tõnu, Gratten, Jacob, Lee, S. Hong, Visscher, Peter M., Wray, Naomi R., Mowry, Bryan J., de Haan, Lieuwe, Meijer, Carin J., Hansen, Mark, Ikeda, Masashi, Iwata, Nakao, Joa, Inge, Kalaydjieva, Luba, Keller, Matthew C., Kennedy, James L., Zai, Clement C., Knight, Jo, Lerer, Bernard, Liang, Kung-Yee, Lieberman, Jeffrey, Stroup, T. Scott, Lönnqvist, Jouko, Suvisaari, Jaana, Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, McDonald, Colm, McIntosh, Andrew M., Blackwood, Douglas H.R., Metspalu, Andres, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Collier, David A., Müller-Myhsok, Bertram, Murphy, Kieran C., Murray, Robin M., Powell, John, Myin-Germeys, Inez, Van Os, Jim, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Pulver, Ann E., Nicodemus, Kristin K., Nisenbaum, Laura, Nordin, Annelie, Adolfsson, Rolf, O'Callaghan, Eadbhard, Oh, Sang-Yun, O'Neill, F. Anthony, Paunio, Tiina, Pietiläinen, Olli, Perkins, Diana O., Quested, Digby, Savitz, Adam, Li, Qingqin S., Schwab, Sibylle G., Shi, Jianxin, Spencer, Chris C.A., Thirumalai, Srinivas, Veijola, Juha, Waddington, John, Walsh, Dermot, Wildenauer, Dieter B., Bramon, Elvira, Darvasi, Ariel, Posthuma, Danielle, St. Clair, David, Shanta, Omar, Klein, Marieke, Park, Peter J., Weinberger, Daniel, Moran, John V., Gage, Fred H., Vaccarino, Flora M., Gleeson, Joseph, Mathern, Gary, Courchesne, Eric, Roy, Subhojit, Bizzotto, Sara, Coulter, Michael, Dias, Caroline, D'Gama, Alissa, Ganz, Javier, Hill, Robert, Huang, August Yue, Khoshkhoo, Sattar, Kim, Sonia, Lodato, Michael, Miller, Michael, Borges-Monroy, Rebeca, Rodin, Rachel, Zhou, Zinan, Bohrson, Craig, Chu, Chong, Cortes-Ciriano, Isidro, Dou, Yanmei, Galor, Alon, Gulhan, Doga, Kwon, Minseok, Luquette, Joe, Viswanadham, Vinay, Jones, Attila, Rosenbluh, Chaggai, Cho, Sean, Langmead, Ben, Thorpe, Jeremy, Erwin, Jennifer, Jaffe, Andrew, McConnell, Michael, Narurkar, Rujuta, Paquola, Apua, Shin, Jooheon, Straub, Richard, Abyzov, Alexej, Bae, Taejeong, Jang, Yeongjun, Wang, Yifan, Gage, Fred, Linker, Sara, Reed, Patrick, Wang, Meiyan, Urban, Alexander, Zhou, Bo, Zhu, Xiaowei, Pattni, Reenal, Amero, Aitor Serres, Juan, David, Lobon, Irene, Marques-Bonet, Tomas, Moruno, Manuel Solis, Perez, Raquel Garcia, Povolotskaya, Inna, Soriano, Eduardo, Averbuj, Dan, Ball, Laurel, Breuss, Martin, Yang, Xiaoxu, Chung, Changuk, Emery, Sarah B., Flasch, Diane A., Kidd, Jeffrey M., Kopera, Huira C., Kwan, Kenneth Y., Mills, Ryan E., Moldovan, John B., Sun, Chen, Zhao, Xuefang, Zhou, Weichen, Frisbie, Trenton J., Cherskov, Adriana, Fasching, Liana, Jourdon, Alexandre, Pochareddy, Sirisha, Scuderi, Soraya, Sestan, Nenad, Maury, Eduardo A., Sherman, Maxwell A., Genovese, Giulio, Gilgenast, Thomas G., Kamath, Tushar, Burris, S.J., Rajarajan, Prashanth, Flaherty, Erin, Akbarian, Schahram, Chess, Andrew, McCarroll, Steven A., Loh, Po-Ru, Phillips-Cremins, Jennifer E., Brennand, Kristen J., Macosko, Evan Z., Walters, James T.R., O’Donovan, Michael, Sullivan, Patrick, Sebat, Jonathan, Lee, Eunjung A., and Walsh, Christopher A.

Published
2023
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7. A robust benchmark for detection of germline large deletions and insertions

Author

Zook, Justin M, Hansen, Nancy F, Olson, Nathan D, Chapman, Lesley, Mullikin, James C, Xiao, Chunlin, Sherry, Stephen, Koren, Sergey, Phillippy, Adam M, Boutros, Paul C, Sahraeian, Sayed Mohammad E, Huang, Vincent, Rouette, Alexandre, Alexander, Noah, Mason, Christopher E, Hajirasouliha, Iman, Ricketts, Camir, Lee, Joyce, Tearle, Rick, Fiddes, Ian T, Barrio, Alvaro Martinez, Wala, Jeremiah, Carroll, Andrew, Ghaffari, Noushin, Rodriguez, Oscar L, Bashir, Ali, Jackman, Shaun, Farrell, John J, Wenger, Aaron M, Alkan, Can, Soylev, Arda, Schatz, Michael C, Garg, Shilpa, Church, George, Marschall, Tobias, Chen, Ken, Fan, Xian, English, Adam C, Rosenfeld, Jeffrey A, Zhou, Weichen, Mills, Ryan E, Sage, Jay M, Davis, Jennifer R, Kaiser, Michael D, Oliver, John S, Catalano, Anthony P, Chaisson, Mark JP, Spies, Noah, Sedlazeck, Fritz J, and Salit, Marc

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Diploidy, Genomic Structural Variation, Germ-Line Mutation, Humans, INDEL Mutation, Molecular Sequence Annotation, Sequence Analysis, DNA
Abstract

New technologies and analysis methods are enabling genomic structural variants (SVs) to be detected with ever-increasing accuracy, resolution and comprehensiveness. To help translate these methods to routine research and clinical practice, we developed a sequence-resolved benchmark set for identification of both false-negative and false-positive germline large insertions and deletions. To create this benchmark for a broadly consented son in a Personal Genome Project trio with broadly available cells and DNA, the Genome in a Bottle Consortium integrated 19 sequence-resolved variant calling methods from diverse technologies. The final benchmark set contains 12,745 isolated, sequence-resolved insertion (7,281) and deletion (5,464) calls ≥50 base pairs (bp). The Tier 1 benchmark regions, for which any extra calls are putative false positives, cover 2.51 Gbp and 5,262 insertions and 4,095 deletions supported by ≥1 diploid assembly. We demonstrate that the benchmark set reliably identifies false negatives and false positives in high-quality SV callsets from short-, linked- and long-read sequencing and optical mapping.

Published
2020

8. Author Correction: A robust benchmark for detection of germline large deletions and insertions

Author

Zook, Justin M, Hansen, Nancy F, Olson, Nathan D, Chapman, Lesley, Mullikin, James C, Xiao, Chunlin, Sherry, Stephen, Koren, Sergey, Phillippy, Adam M, Boutros, Paul C, Sahraeian, Sayed Mohammad E, Huang, Vincent, Rouette, Alexandre, Alexander, Noah, Mason, Christopher E, Hajirasouliha, Iman, Ricketts, Camir, Lee, Joyce, Tearle, Rick, Fiddes, Ian T, Barrio, Alvaro Martinez, Wala, Jeremiah, Carroll, Andrew, Ghaffari, Noushin, Rodriguez, Oscar L, Bashir, Ali, Jackman, Shaun, Farrell, John J, Wenger, Aaron M, Alkan, Can, Soylev, Arda, Schatz, Michael C, Garg, Shilpa, Church, George, Marschall, Tobias, Chen, Ken, Fan, Xian, English, Adam C, Rosenfeld, Jeffrey A, Zhou, Weichen, Mills, Ryan E, Sage, Jay M, Davis, Jennifer R, Kaiser, Michael D, Oliver, John S, Catalano, Anthony P, Chaisson, Mark JP, Spies, Noah, Sedlazeck, Fritz J, and Salit, Marc

Subjects
Control Engineering, Mechatronics and Robotics, Engineering
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020

9. Multi-platform discovery of haplotype-resolved structural variation in human genomes.

Author

Chaisson, Mark JP, Sanders, Ashley D, Zhao, Xuefang, Malhotra, Ankit, Porubsky, David, Rausch, Tobias, Gardner, Eugene J, Rodriguez, Oscar L, Guo, Li, Collins, Ryan L, Fan, Xian, Wen, Jia, Handsaker, Robert E, Fairley, Susan, Kronenberg, Zev N, Kong, Xiangmeng, Hormozdiari, Fereydoun, Lee, Dillon, Wenger, Aaron M, Hastie, Alex R, Antaki, Danny, Anantharaman, Thomas, Audano, Peter A, Brand, Harrison, Cantsilieris, Stuart, Cao, Han, Cerveira, Eliza, Chen, Chong, Chen, Xintong, Chin, Chen-Shan, Chong, Zechen, Chuang, Nelson T, Lambert, Christine C, Church, Deanna M, Clarke, Laura, Farrell, Andrew, Flores, Joey, Galeev, Timur, Gorkin, David U, Gujral, Madhusudan, Guryev, Victor, Heaton, William Haynes, Korlach, Jonas, Kumar, Sushant, Kwon, Jee Young, Lam, Ernest T, Lee, Jong Eun, Lee, Joyce, Lee, Wan-Ping, Lee, Sau Peng, Li, Shantao, Marks, Patrick, Viaud-Martinez, Karine, Meiers, Sascha, Munson, Katherine M, Navarro, Fabio CP, Nelson, Bradley J, Nodzak, Conor, Noor, Amina, Kyriazopoulou-Panagiotopoulou, Sofia, Pang, Andy WC, Qiu, Yunjiang, Rosanio, Gabriel, Ryan, Mallory, Stütz, Adrian, Spierings, Diana CJ, Ward, Alistair, Welch, AnneMarie E, Xiao, Ming, Xu, Wei, Zhang, Chengsheng, Zhu, Qihui, Zheng-Bradley, Xiangqun, Lowy, Ernesto, Yakneen, Sergei, McCarroll, Steven, Jun, Goo, Ding, Li, Koh, Chong Lek, Ren, Bing, Flicek, Paul, Chen, Ken, Gerstein, Mark B, Kwok, Pui-Yan, Lansdorp, Peter M, Marth, Gabor T, Sebat, Jonathan, Shi, Xinghua, Bashir, Ali, Ye, Kai, Devine, Scott E, Talkowski, Michael E, Mills, Ryan E, Marschall, Tobias, Korbel, Jan O, Eichler, Evan E, and Lee, Charles

Subjects
Humans, Chromosome Mapping, Genomics, Haplotypes, Genome, Human, Algorithms, Databases, Genetic, INDEL Mutation, Genomic Structural Variation, High-Throughput Nucleotide Sequencing, Whole Genome Sequencing, Genome, Human, Databases, Genetic
Abstract

The incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (

Published
2019

10. Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate over time in fibroblasts.

Author

Zhou, Weichen, Karan, Kalpita R., Gu, Wenjin, Klein, Hans-Ulrich, Sturm, Gabriel, De Jager, Philip L., Bennett, David A., Hirano, Michio, Picard, Martin, and Mills, Ryan E.

Subjects
HORIZONTAL gene transfer, WHOLE genome sequencing, NUCLEAR DNA, GENETIC transformation, PREFRONTAL cortex
Abstract

The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in nonhuman species and recently demonstrated to occur in rare instances from one human generation to the next. Here, we investigated numtogenesis dynamics in humans in 2 ways. First, we quantified Numts in 1,187 postmortem brain and blood samples from different individuals. Compared to circulating immune cells (n = 389), postmitotic brain tissue (n = 798) contained more Numts, consistent with their potential somatic accumulation. Within brain samples, we observed a 5.5-fold enrichment of somatic Numt insertions in the dorsolateral prefrontal cortex (DLPFC) compared to cerebellum samples, suggesting that brain Numts arose spontaneously during development or across the lifespan. Moreover, an increase in the number of brain Numts was linked to earlier mortality. The brains of individuals with no cognitive impairment (NCI) who died at younger ages carried approximately 2 more Numts per decade of life lost than those who lived longer. Second, we tested the dynamic transfer of Numts using a repeated-measures whole-genome sequencing design in a human fibroblast model that recapitulates several molecular hallmarks of aging. These longitudinal experiments revealed a gradual accumulation of 1 Numt every ~13 days. Numtogenesis was independent of large-scale genomic instability and unlikely driven by cell clonality. Targeted pharmacological perturbations including chronic glucocorticoid signaling or impairing mitochondrial oxidative phosphorylation (OxPhos) only modestly increased the rate of numtogenesis, whereas patient-derived SURF1-mutant cells exhibiting mtDNA instability accumulated Numts 4.7-fold faster than healthy donors. Combined, our data document spontaneous numtogenesis in human cells and demonstrate an association between brain cortical somatic Numts and human lifespan. These findings open the possibility that mito-nuclear horizontal gene transfer among human postmitotic tissues produces functionally relevant human Numts over timescales shorter than previously assumed. Somatic nuclear mitochondrial DNA (Numt) insertions are mito-nuclear gene transfer events that can arise in the germline and in cancer. This study shows that Numt insertions arise spontaneously and accumulate in brain tissues during development or over the human lifespan. [ABSTRACT FROM AUTHOR]

Published
2024
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12. Rapid, ultra low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy

Author

Hovelson, Daniel H, Liu, Chia-Jen, Wang, Yugang, Kang, Qing, Henderson, James, Gursky, Amy, Brockman, Scott, Ramnath, Nithya, Krauss, John C, Talpaz, Moshe, Kandarpa, Malathi, Chugh, Rashmi, Tuck, Missy, Herman, Kirk, Grasso, Catherine S, Quist, Michael J, Feng, Felix Y, Haakenson, Christine, Langmore, John, Kamberov, Emmanuel, Tesmer, Tim, Husain, Hatim, Lonigro, Robert J, Robinson, Dan, Smith, David C, Alva, Ajjai S, Hussain, Maha H, Chinnaiyan, Arul M, Tewari, Muneesh, Mills, Ryan E, Morgan, Todd M, and Tomlins, Scott A

Subjects
Human Genome, Cancer, Prostate Cancer, Biotechnology, Genetics, Good Health and Well Being, cell-free DNA, precision oncology, prostate cancer, whole genome sequencing, copy-number analysis, Oncology and Carcinogenesis
Abstract

Current cell-free DNA (cfDNA) next generation sequencing (NGS) precision oncology workflows are typically limited to targeted and/or disease-specific applications. In advanced cancer, disease burden and cfDNA tumor content are often elevated, yielding unique precision oncology opportunities. We sought to demonstrate the utility of a pan-cancer, rapid, inexpensive, whole genome NGS of cfDNA approach (PRINCe) as a precision oncology screening strategy via ultra-low coverage (~0.01x) tumor content determination through genome-wide copy number alteration (CNA) profiling. We applied PRINCe to a retrospective cohort of 124 cfDNA samples from 100 patients with advanced cancers, including 76 men with metastatic castration-resistant prostate cancer (mCRPC), enabling cfDNA tumor content approximation and actionable focal CNA detection, while facilitating concordance analyses between cfDNA and tissue-based NGS profiles and assessment of cfDNA alteration associations with mCRPC treatment outcomes. Therapeutically relevant focal CNAs were present in 42 (34%) cfDNA samples, including 36 of 93 (39%) mCRPC patient samples harboring AR amplification. PRINCe identified pre-treatment cfDNA CNA profiles facilitating disease monitoring. Combining PRINCe with routine targeted NGS of cfDNA enabled mutation and CNA assessment with coverages tuned to cfDNA tumor content. In mCRPC, genome-wide PRINCe cfDNA and matched tissue CNA profiles showed high concordance (median Pearson correlation = 0.87), and PRINCe detectable AR amplifications predicted reduced time on therapy, independent of therapy type (Kaplan-Meier log-rank test, chi-square = 24.9, p < 0.0001). Our screening approach enables robust, broadly applicable cfDNA-based precision oncology for patients with advanced cancer through scalable identification of therapeutically relevant CNAs and pre-/post-treatment genomic profiles, enabling cfDNA- or tissue-based precision oncology workflow optimization.

Published
2017

14. How to Count Like Florida: In the Sunshine State, the voting is easy and the results are quick

Author

Mills, Ryan

Subjects
Voting-machines -- Social aspects, Elections -- Forecasts and trends, Voting -- Forecasts and trends -- Social aspects, Market trend/market analysis, Political science
Abstract

The day after the 2020 general election, Florida governor Ron DeSantis crowed about his state's performance. While vote-counting in other states was slow going and the results in several key [...]

Published
2022

15. The Walker Wager: Can the vivid former football player defeat Raphael Warnock?

Author

Mills, Ryan

Subjects
Electioneering -- Forecasts and trends, Political campaigns -- Forecasts and trends, Congressional candidates -- Political activity -- Public opinion -- Beliefs, opinions and attitudes, Market trend/market analysis, Political science
Abstract

Trenton, Ga. There are two pieces of white paper taped to the front door of Jeffrey Johnston's sales office, which is draped in a Donald Trump banner. One sheet provides [...]

Published
2022

17. Covid Cash: Schools are awash in relief funds; maybe they could spend them on education

Author

Mills, Ryan

Subjects
Expenditures, Public -- Laws, regulations and rules, Epidemics -- Control -- Educational aspects -- United States, School districts -- Government finance -- Forecasts and trends, Government regulation, Market trend/market analysis, Political science
Abstract

Presented with more than $139 million in Covid-19 relief money, J. A. Gonzalez, the superintendent of the McAllen Independent School District in South Texas, vowed last year to spend the [...]

Published
2022

18. 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

25. Constitutively Higher Level of GSTT2 in Esophageal Tissues From African Americans Protects Cells Against DNA Damage

Author

Ferrer-Torres, Daysha, Nancarrow, Derek J., Steinberg, Hannah, Wang, Zhuwen, Kuick, Rork, Weh, Katherine M., Mills, Ryan E., Ray, Dipankar, Ray, Paramita, Lin, Jules, Chang, Andrew C., Reddy, Rishindra M., Orringer, Mark B., Canto, Marcia I., Shaheen, Nicholas J., Kresty, Laura A., Chak, Amitabh, Wang, Thomas D., Rubenstein, Joel H., and Beer, David G.

Published
2019
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27. Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

Author

Maury, Eduardo A., primary, Sherman, Maxwell A., additional, Genovese, Giulio, additional, Gilgenast, Thomas G., additional, Kamath, Tushar, additional, Burris, S.J., additional, Rajarajan, Prashanth, additional, Flaherty, Erin, additional, Akbarian, Schahram, additional, Chess, Andrew, additional, McCarroll, Steven A., additional, Loh, Po-Ru, additional, Phillips-Cremins, Jennifer E., additional, Brennand, Kristen J., additional, Macosko, Evan Z., additional, Walters, James T.R., additional, O’Donovan, Michael, additional, Sullivan, Patrick, additional, Sebat, Jonathan, additional, Lee, Eunjung A., additional, Walsh, Christopher A., additional, Marshall, Christian R., additional, Merico, Daniele, additional, Thiruvahindrapuram, Bhooma, additional, Wang, Zhouzhi, additional, Scherer, Stephen W., additional, Howrigan, Daniel P, additional, Ripke, Stephan, additional, Bulik-Sullivan, Brendan, additional, Farh, Kai-How, additional, Fromer, Menachem, additional, Goldstein, Jacqueline I., additional, Huang, Hailiang, additional, Lee, Phil, additional, Daly, Mark J., additional, Neale, Benjamin M., additional, Belliveau, Richard A., additional, Bergen, Sarah E., additional, Bevilacqua, Elizabeth, additional, Chambert, Kimberley D., additional, O'Dushlaine, Colm, additional, Scolnick, Edward M., additional, Smoller, Jordan W., additional, Moran, Jennifer L., additional, Palotie, Aarno, additional, Petryshen, Tracey L., additional, Wu, Wenting, additional, Greer, Douglas S., additional, Antaki, Danny, additional, Shetty, Aniket, additional, Gujral, Madhusudan, additional, Brandler, William M., additional, Malhotra, Dheeraj, additional, Fuentes Fajarado, Karin V., additional, Maile, Michelle S., additional, Holmans, Peter A., additional, Carrera, Noa, additional, Craddock, Nick, additional, Escott-Price, Valentina, additional, Georgieva, Lyudmila, additional, Hamshere, Marian L., additional, Kavanagh, David, additional, Legge, Sophie E., additional, Pocklington, Andrew J., additional, Richards, Alexander L., additional, Ruderfer, Douglas M., additional, Williams, Nigel M., additional, Kirov, George, additional, Owen, Michael J., additional, Pinto, Dalila, additional, Cai, Guiqing, additional, Davis, Kenneth L., additional, Drapeau, Elodie, additional, Friedman, Joseph I, additional, Haroutunian, Vahram, additional, Parkhomenko, Elena, additional, Reichenberg, Abraham, additional, Silverman, Jeremy M., additional, Buxbaum, Joseph D., additional, Domenici, Enrico, additional, Agartz, Ingrid, additional, Djurovic, Srdjan, additional, Mattingsdal, Morten, additional, Melle, Ingrid, additional, Andreassen, Ole A., additional, Jönsson, Erik G., additional, Söderman, Erik, additional, Albus, Margot, additional, Alexander, Madeline, additional, Laurent, Claudine, additional, Levinson, Douglas F., additional, Amin, Farooq, additional, Atkins, Joshua, additional, Cairns, Murray J., additional, Scott, Rodney J., additional, Tooney, Paul A., additional, Wu, Jing Qin, additional, Bacanu, Silviu A., additional, Bigdeli, Tim B., additional, Reimers, Mark A., additional, Webb, Bradley T., additional, Wolen, Aaron R., additional, Wormley, Brandon K., additional, Kendler, Kenneth S., additional, Riley, Brien P., additional, Kähler, Anna K., additional, Magnusson, Patrik K.E., additional, Hultman, Christina M., additional, Bertalan, Marcelo, additional, Hansen, Thomas, additional, Olsen, Line, additional, Rasmussen, Henrik B., additional, Werge, Thomas, additional, Mattheisen, Manuel, additional, Black, Donald W., additional, Bruggeman, Richard, additional, Buccola, Nancy G., additional, Buckner, Randy L., additional, Roffman, Joshua L., additional, Byerley, William, additional, Cahn, Wiepke, additional, Kahn, René S, additional, Strengman, Eric, additional, Ophoff, Roel A., additional, Carr, Vaughan J., additional, Catts, Stanley V., additional, Henskens, Frans A., additional, Loughland, Carmel M., additional, Michie, Patricia T., additional, Pantelis, Christos, additional, Schall, Ulrich, additional, Jablensky, Assen V., additional, Kelly, Brian J., additional, Campion, Dominique, additional, Cantor, Rita M., additional, Cheng, Wei, additional, Cloninger, C. Robert, additional, Svrakic, Dragan M, additional, Cohen, David, additional, Cormican, Paul, additional, Donohoe, Gary, additional, Morris, Derek W., additional, Corvin, Aiden, additional, Gill, Michael, additional, Crespo-Facorro, Benedicto, additional, Crowley, James J., additional, Farrell, Martilias S., additional, Giusti-Rodríguez, Paola, additional, Kim, Yunjung, additional, Szatkiewicz, Jin P., additional, Williams, Stephanie, additional, Curtis, David, additional, Pimm, Jonathan, additional, Gurling, Hugh, additional, McQuillin, Andrew, additional, Davidson, Michael, additional, Weiser, Mark, additional, Degenhardt, Franziska, additional, Forstner, Andreas J., additional, Herms, Stefan, additional, Hoffmann, Per, additional, Hofman, Andrea, additional, Cichon, Sven, additional, Nöthen, Markus M., additional, Del Favero, Jurgen, additional, DeLisi, Lynn E., additional, McCarley, Robert W., additional, Levy, Deborah L., additional, Mesholam-Gately, Raquelle I., additional, Seidman, Larry J., additional, Dikeos, Dimitris, additional, Papadimitriou, George N., additional, Dinan, Timothy, additional, Duan, Jubao, additional, Sanders, Alan R., additional, Gejman, Pablo V., additional, Gershon, Elliot S., additional, Dudbridge, Frank, additional, Eichhammer, Peter, additional, Eriksson, Johan, additional, Salomaa, Veikko, additional, Essioux, Laurent, additional, Fanous, Ayman H., additional, Knowles, James A., additional, Pato, Michele T., additional, Pato, Carlos N., additional, Frank, Josef, additional, Meier, Sandra, additional, Schulze, Thomas G., additional, Strohmaier, Jana, additional, Witt, Stephanie H., additional, Rietschel, Marcella, additional, Franke, Lude, additional, Karjalainen, Juha, additional, Freedman, Robert, additional, Olincy, Ann, additional, Freimer, Nelson B., additional, Purcell, Shaun M., additional, Roussos, Panos, additional, Stahl, Eli A., additional, Sklar, Pamela, additional, Giegling, Ina, additional, Hartmann, Annette M., additional, Konte, Bettina, additional, Rujescu, Dan, additional, Godard, Stephanie, additional, Hirschhorn, Joel N., additional, Pers, Tune H., additional, Price, Alkes, additional, Esko, Tõnu, additional, Gratten, Jacob, additional, Lee, S. Hong, additional, Visscher, Peter M., additional, Wray, Naomi R., additional, Mowry, Bryan J., additional, de Haan, Lieuwe, additional, Meijer, Carin J., additional, Hansen, Mark, additional, Ikeda, Masashi, additional, Iwata, Nakao, additional, Joa, Inge, additional, Kalaydjieva, Luba, additional, Keller, Matthew C., additional, Kennedy, James L., additional, Zai, Clement C., additional, Knight, Jo, additional, Lerer, Bernard, additional, Liang, Kung-Yee, additional, Lieberman, Jeffrey, additional, Stroup, T. Scott, additional, Lönnqvist, Jouko, additional, Suvisaari, Jaana, additional, Maher, Brion S., additional, Maier, Wolfgang, additional, Mallet, Jacques, additional, McDonald, Colm, additional, McIntosh, Andrew M., additional, Blackwood, Douglas H.R., additional, Metspalu, Andres, additional, Milani, Lili, additional, Milanova, Vihra, additional, Mokrab, Younes, additional, Collier, David A., additional, Müller-Myhsok, Bertram, additional, Murphy, Kieran C., additional, Murray, Robin M., additional, Powell, John, additional, Myin-Germeys, Inez, additional, Van Os, Jim, additional, Nenadic, Igor, additional, Nertney, Deborah A., additional, Nestadt, Gerald, additional, Pulver, Ann E., additional, Nicodemus, Kristin K., additional, Nisenbaum, Laura, additional, Nordin, Annelie, additional, Adolfsson, Rolf, additional, O'Callaghan, Eadbhard, additional, Oh, Sang-Yun, additional, O'Neill, F. Anthony, additional, Paunio, Tiina, additional, Pietiläinen, Olli, additional, Perkins, Diana O., additional, Quested, Digby, additional, Savitz, Adam, additional, Li, Qingqin S., additional, Schwab, Sibylle G., additional, Shi, Jianxin, additional, Spencer, Chris C.A., additional, Thirumalai, Srinivas, additional, Veijola, Juha, additional, Waddington, John, additional, Walsh, Dermot, additional, Wildenauer, Dieter B., additional, Bramon, Elvira, additional, Darvasi, Ariel, additional, Posthuma, Danielle, additional, St. Clair, David, additional, Shanta, Omar, additional, Klein, Marieke, additional, Park, Peter J., additional, Weinberger, Daniel, additional, Moran, John V., additional, Gage, Fred H., additional, Vaccarino, Flora M., additional, Gleeson, Joseph, additional, Mathern, Gary, additional, Courchesne, Eric, additional, Roy, Subhojit, additional, Bizzotto, Sara, additional, Coulter, Michael, additional, Dias, Caroline, additional, D'Gama, Alissa, additional, Ganz, Javier, additional, Hill, Robert, additional, Huang, August Yue, additional, Khoshkhoo, Sattar, additional, Kim, Sonia, additional, Lodato, Michael, additional, Miller, Michael, additional, Borges-Monroy, Rebeca, additional, Rodin, Rachel, additional, Zhou, Zinan, additional, Bohrson, Craig, additional, Chu, Chong, additional, Cortes-Ciriano, Isidro, additional, Dou, Yanmei, additional, Galor, Alon, additional, Gulhan, Doga, additional, Kwon, Minseok, additional, Luquette, Joe, additional, Viswanadham, Vinay, additional, Jones, Attila, additional, Rosenbluh, Chaggai, additional, Cho, Sean, additional, Langmead, Ben, additional, Thorpe, Jeremy, additional, Erwin, Jennifer, additional, Jaffe, Andrew, additional, McConnell, Michael, additional, Narurkar, Rujuta, additional, Paquola, Apua, additional, Shin, Jooheon, additional, Straub, Richard, additional, Abyzov, Alexej, additional, Bae, Taejeong, additional, Jang, Yeongjun, additional, Wang, Yifan, additional, Gage, Fred, additional, Linker, Sara, additional, Reed, Patrick, additional, Wang, Meiyan, additional, Urban, Alexander, additional, Zhou, Bo, additional, Zhu, Xiaowei, additional, Pattni, Reenal, additional, Amero, Aitor Serres, additional, Juan, David, additional, Lobon, Irene, additional, Marques-Bonet, Tomas, additional, Moruno, Manuel Solis, additional, Perez, Raquel Garcia, additional, Povolotskaya, Inna, additional, Soriano, Eduardo, additional, Averbuj, Dan, additional, Ball, Laurel, additional, Breuss, Martin, additional, Yang, Xiaoxu, additional, Chung, Changuk, additional, Emery, Sarah B., additional, Flasch, Diane A., additional, Kidd, Jeffrey M., additional, Kopera, Huira C., additional, Kwan, Kenneth Y., additional, Mills, Ryan E., additional, Moldovan, John B., additional, Sun, Chen, additional, Zhao, Xuefang, additional, Zhou, Weichen, additional, Frisbie, Trenton J., additional, Cherskov, Adriana, additional, Fasching, Liana, additional, Jourdon, Alexandre, additional, Pochareddy, Sirisha, additional, Scuderi, Soraya, additional, and Sestan, Nenad, additional

Published
2023
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28. Officer Exodus: Departments around the country are losing staff and struggling to recruit

Author

Mills, Ryan

Subjects
Police administration -- Recruiting -- Officials and employees, Racism -- Forecasts and trends, Law enforcement -- Forecasts and trends -- Social aspects, Police -- Recruiting -- Practice -- Supply and demand, Industry hiring, Market trend/market analysis, Political science
Abstract

Asheville, N. C. After the police department in this midsize mountain city lost more than a third of its force to resignations and retirements last year, bringing in seven new [...]

Published
2021

29. Mapping copy number variation by population-scale genome sequencing.

Author

Mills, Ryan, Walter, Klaudia, Stewart, Chip, Handsaker, Robert, Chen, Ken, Alkan, Can, Abyzov, Alexej, Yoon, Seungtai, Ye, Kai, Cheetham, R, Chinwalla, Asif, Conrad, Donald, Fu, Yutao, Grubert, Fabian, Hajirasouliha, Iman, Hormozdiari, Fereydoun, Iakoucheva, Lilia, Iqbal, Zamin, Kang, Shuli, Kidd, Jeffrey, Konkel, Miriam, Korn, Joshua, Khurana, Ekta, Kural, Deniz, Lam, Hugo, Leng, Jing, Li, Ruiqiang, Li, Yingrui, Lin, Chang-Yun, Luo, Ruibang, Mu, Xinmeng, Nemesh, James, Peckham, Heather, Rausch, Tobias, Scally, Aylwyn, Shi, Xinghua, Stromberg, Michael, Stütz, Adrian, Urban, Alexander, Walker, Jerilyn, Wu, Jiantao, Zhang, Yujun, Zhang, Zhengdong, Batzer, Mark, Ding, Li, Marth, Gabor, McVean, Gil, Sebat, Jonathan, Snyder, Michael, Wang, Jun, Ye, Kenny, Eichler, Evan, Gerstein, Mark, Hurles, Matthew, Lee, Charles, McCarroll, Steven, and Korbel, Jan

Subjects
DNA Copy Number Variations, Gene Duplication, Genetic Predisposition to Disease, Genetics, Population, Genome, Human, Genomics, Genotype, Humans, Mutagenesis, Insertional, Reproducibility of Results, Sequence Analysis, DNA, Sequence Deletion
Abstract

Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies.

Published
2011

30. Intersection of diverse neuronal genomes and neuropsychiatric disease : The Brain Somatic Mosaicism Network

Author

Brain Somatic Mosaicism Network, McConnell, Michael J., Moran, John V., Abyzov, Alexej, Akbarian, Schahram, Bae, Taejeong, Cortes-Ciriano, Isidro, Erwin, Jennifer A., Fasching, Liana, Flasch, Diane A., Freed, Donald, Ganz, Javier, Jaffe, Andrew E., Kwan, Kenneth Y., Kwon, Minseok, Lodato, Michael A., Mills, Ryan E., Paquola, Apua C. M., Rodin, Rachel E., Rosenbluh, Chaggai, Sestan, Nenad, Sherman, Maxwell A., Shin, Joo Heon, Song, Saera, Straub, Richard E., Thorpe, Jeremy, Weinberger, Daniel R., Urban, Alexander E., Zhou, Bo, Gage, Fred H., Lehner, Thomas, Senthil, Geetha, A. Walsh, Christopher, Chess, Andrew, Courchesne, Eric, Gleeson, Joseph G., Kidd, Jeffrey M., Park, Peter J., Pevsner, Jonathan, and Vaccarino, Flora M.

Published
2017

31. Candida albicans selection for human commensalism results in substantial within-host diversity without decreasing fitness for invasive disease

Author

Anderson, Faith M., primary, Visser, Noelle D., additional, Amses, Kevin R., additional, Hodgins-Davis, Andrea, additional, Weber, Alexandra M., additional, Metzner, Katura M., additional, McFadden, Michael J., additional, Mills, Ryan E., additional, O’Meara, Matthew J., additional, James, Timothy Y., additional, and O’Meara, Teresa R., additional

Published
2023
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34. Supplementary table 3 from Early HPV ctDNA Kinetics and Imaging Biomarkers Predict Therapeutic Response in p16+ Oropharyngeal Squamous Cell Carcinoma

Author

Cao, Yue, primary, Haring, Catherine T., primary, Brummel, Collin, primary, Bhambhani, Chandan, primary, Aryal, Madhava, primary, Lee, Choonik, primary, Heft Neal, Molly, primary, Bhangale, Apurva, primary, Gu, Wenjin, primary, Casper, Keith, primary, Malloy, Kelly, primary, Sun, Yilun, primary, Shuman, Andrew, primary, Prince, Mark E., primary, Spector, Matthew E., primary, Chinn, Steven, primary, Shah, Jennifer, primary, Schonewolf, Caitlin, primary, McHugh, Jonathan B., primary, Mills, Ryan E., primary, Tewari, Muneesh, primary, Worden, Francis P., primary, Swiecicki, Paul L., primary, Mierzwa, Michelle, primary, and Brenner, J. Chad, primary

Published
2023
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35. Supplementary Data from Early HPV ctDNA Kinetics and Imaging Biomarkers Predict Therapeutic Response in p16+ Oropharyngeal Squamous Cell Carcinoma

Author

Cao, Yue, primary, Haring, Catherine T., primary, Brummel, Collin, primary, Bhambhani, Chandan, primary, Aryal, Madhava, primary, Lee, Choonik, primary, Heft Neal, Molly, primary, Bhangale, Apurva, primary, Gu, Wenjin, primary, Casper, Keith, primary, Malloy, Kelly, primary, Sun, Yilun, primary, Shuman, Andrew, primary, Prince, Mark E., primary, Spector, Matthew E., primary, Chinn, Steven, primary, Shah, Jennifer, primary, Schonewolf, Caitlin, primary, McHugh, Jonathan B., primary, Mills, Ryan E., primary, Tewari, Muneesh, primary, Worden, Francis P., primary, Swiecicki, Paul L., primary, Mierzwa, Michelle, primary, and Brenner, J. Chad, primary

Published
2023
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36. Supplementary figure and table legends from Early HPV ctDNA Kinetics and Imaging Biomarkers Predict Therapeutic Response in p16+ Oropharyngeal Squamous Cell Carcinoma

Author

Cao, Yue, primary, Haring, Catherine T., primary, Brummel, Collin, primary, Bhambhani, Chandan, primary, Aryal, Madhava, primary, Lee, Choonik, primary, Heft Neal, Molly, primary, Bhangale, Apurva, primary, Gu, Wenjin, primary, Casper, Keith, primary, Malloy, Kelly, primary, Sun, Yilun, primary, Shuman, Andrew, primary, Prince, Mark E., primary, Spector, Matthew E., primary, Chinn, Steven, primary, Shah, Jennifer, primary, Schonewolf, Caitlin, primary, McHugh, Jonathan B., primary, Mills, Ryan E., primary, Tewari, Muneesh, primary, Worden, Francis P., primary, Swiecicki, Paul L., primary, Mierzwa, Michelle, primary, and Brenner, J. Chad, primary

Published
2023
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37. Supplementary table 6 from Early HPV ctDNA Kinetics and Imaging Biomarkers Predict Therapeutic Response in p16+ Oropharyngeal Squamous Cell Carcinoma

Author

Cao, Yue, primary, Haring, Catherine T., primary, Brummel, Collin, primary, Bhambhani, Chandan, primary, Aryal, Madhava, primary, Lee, Choonik, primary, Heft Neal, Molly, primary, Bhangale, Apurva, primary, Gu, Wenjin, primary, Casper, Keith, primary, Malloy, Kelly, primary, Sun, Yilun, primary, Shuman, Andrew, primary, Prince, Mark E., primary, Spector, Matthew E., primary, Chinn, Steven, primary, Shah, Jennifer, primary, Schonewolf, Caitlin, primary, McHugh, Jonathan B., primary, Mills, Ryan E., primary, Tewari, Muneesh, primary, Worden, Francis P., primary, Swiecicki, Paul L., primary, Mierzwa, Michelle, primary, and Brenner, J. Chad, primary

Published
2023
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38. Supplementary table 2 from Early HPV ctDNA Kinetics and Imaging Biomarkers Predict Therapeutic Response in p16+ Oropharyngeal Squamous Cell Carcinoma

Author

Cao, Yue, primary, Haring, Catherine T., primary, Brummel, Collin, primary, Bhambhani, Chandan, primary, Aryal, Madhava, primary, Lee, Choonik, primary, Heft Neal, Molly, primary, Bhangale, Apurva, primary, Gu, Wenjin, primary, Casper, Keith, primary, Malloy, Kelly, primary, Sun, Yilun, primary, Shuman, Andrew, primary, Prince, Mark E., primary, Spector, Matthew E., primary, Chinn, Steven, primary, Shah, Jennifer, primary, Schonewolf, Caitlin, primary, McHugh, Jonathan B., primary, Mills, Ryan E., primary, Tewari, Muneesh, primary, Worden, Francis P., primary, Swiecicki, Paul L., primary, Mierzwa, Michelle, primary, and Brenner, J. Chad, primary

Published
2023
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39. Supplementary figure 1 from Early HPV ctDNA Kinetics and Imaging Biomarkers Predict Therapeutic Response in p16+ Oropharyngeal Squamous Cell Carcinoma

Author

Cao, Yue, primary, Haring, Catherine T., primary, Brummel, Collin, primary, Bhambhani, Chandan, primary, Aryal, Madhava, primary, Lee, Choonik, primary, Heft Neal, Molly, primary, Bhangale, Apurva, primary, Gu, Wenjin, primary, Casper, Keith, primary, Malloy, Kelly, primary, Sun, Yilun, primary, Shuman, Andrew, primary, Prince, Mark E., primary, Spector, Matthew E., primary, Chinn, Steven, primary, Shah, Jennifer, primary, Schonewolf, Caitlin, primary, McHugh, Jonathan B., primary, Mills, Ryan E., primary, Tewari, Muneesh, primary, Worden, Francis P., primary, Swiecicki, Paul L., primary, Mierzwa, Michelle, primary, and Brenner, J. Chad, primary

Published
2023
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40. Supplementary table 7 from Early HPV ctDNA Kinetics and Imaging Biomarkers Predict Therapeutic Response in p16+ Oropharyngeal Squamous Cell Carcinoma

Author

Cao, Yue, primary, Haring, Catherine T., primary, Brummel, Collin, primary, Bhambhani, Chandan, primary, Aryal, Madhava, primary, Lee, Choonik, primary, Heft Neal, Molly, primary, Bhangale, Apurva, primary, Gu, Wenjin, primary, Casper, Keith, primary, Malloy, Kelly, primary, Sun, Yilun, primary, Shuman, Andrew, primary, Prince, Mark E., primary, Spector, Matthew E., primary, Chinn, Steven, primary, Shah, Jennifer, primary, Schonewolf, Caitlin, primary, McHugh, Jonathan B., primary, Mills, Ryan E., primary, Tewari, Muneesh, primary, Worden, Francis P., primary, Swiecicki, Paul L., primary, Mierzwa, Michelle, primary, and Brenner, J. Chad, primary

Published
2023
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41. Supplementary table 4 from Early HPV ctDNA Kinetics and Imaging Biomarkers Predict Therapeutic Response in p16+ Oropharyngeal Squamous Cell Carcinoma

Author

Cao, Yue, primary, Haring, Catherine T., primary, Brummel, Collin, primary, Bhambhani, Chandan, primary, Aryal, Madhava, primary, Lee, Choonik, primary, Heft Neal, Molly, primary, Bhangale, Apurva, primary, Gu, Wenjin, primary, Casper, Keith, primary, Malloy, Kelly, primary, Sun, Yilun, primary, Shuman, Andrew, primary, Prince, Mark E., primary, Spector, Matthew E., primary, Chinn, Steven, primary, Shah, Jennifer, primary, Schonewolf, Caitlin, primary, McHugh, Jonathan B., primary, Mills, Ryan E., primary, Tewari, Muneesh, primary, Worden, Francis P., primary, Swiecicki, Paul L., primary, Mierzwa, Michelle, primary, and Brenner, J. Chad, primary

Published
2023
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42. Supplementary table 5 from Early HPV ctDNA Kinetics and Imaging Biomarkers Predict Therapeutic Response in p16+ Oropharyngeal Squamous Cell Carcinoma

Author

Cao, Yue, primary, Haring, Catherine T., primary, Brummel, Collin, primary, Bhambhani, Chandan, primary, Aryal, Madhava, primary, Lee, Choonik, primary, Heft Neal, Molly, primary, Bhangale, Apurva, primary, Gu, Wenjin, primary, Casper, Keith, primary, Malloy, Kelly, primary, Sun, Yilun, primary, Shuman, Andrew, primary, Prince, Mark E., primary, Spector, Matthew E., primary, Chinn, Steven, primary, Shah, Jennifer, primary, Schonewolf, Caitlin, primary, McHugh, Jonathan B., primary, Mills, Ryan E., primary, Tewari, Muneesh, primary, Worden, Francis P., primary, Swiecicki, Paul L., primary, Mierzwa, Michelle, primary, and Brenner, J. Chad, primary

Published
2023
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43. Supplementary table 1 from Early HPV ctDNA Kinetics and Imaging Biomarkers Predict Therapeutic Response in p16+ Oropharyngeal Squamous Cell Carcinoma

Author

Cao, Yue, primary, Haring, Catherine T., primary, Brummel, Collin, primary, Bhambhani, Chandan, primary, Aryal, Madhava, primary, Lee, Choonik, primary, Heft Neal, Molly, primary, Bhangale, Apurva, primary, Gu, Wenjin, primary, Casper, Keith, primary, Malloy, Kelly, primary, Sun, Yilun, primary, Shuman, Andrew, primary, Prince, Mark E., primary, Spector, Matthew E., primary, Chinn, Steven, primary, Shah, Jennifer, primary, Schonewolf, Caitlin, primary, McHugh, Jonathan B., primary, Mills, Ryan E., primary, Tewari, Muneesh, primary, Worden, Francis P., primary, Swiecicki, Paul L., primary, Mierzwa, Michelle, primary, and Brenner, J. Chad, primary

Published
2023
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46. Mapping the Complex Genetic Landscape of Human Neurons

Author

Sun, Chen, Kathuria, Kunal, Emery, Sarah B, Kim, ByungJun, Burbulis, Ian E., Shin, Joo Heon, Weinberger, Daniel R., Moran, John V., Kidd, Jeffrey M., Mills, Ryan E., and McConnell, Michael J.

Subjects
Article
Abstract

When somatic cells acquire complex karyotypes, they are removed by the immune system. Mutant somatic cells that evade immune surveillance can lead to cancer. Neurons with complex karyotypes arise during neurotypical brain development, but neurons are almost never the origin of brain cancers. Instead, somatic mutations in neurons can bring about neurodevelopmental disorders, and contribute to the polygenic landscape of neuropsychiatric and neurodegenerative disease. A subset of human neurons harbors idiosyncratic copy number variants (CNVs, “CNV neurons”), but previous analyses of CNV neurons have been limited by relatively small sample sizes. Here, we developed an allele-based validation approach, SCOVAL, to corroborate or reject read-depth based CNV calls in single human neurons. We applied this approach to 2,125 frontal cortical neurons from a neurotypical human brain. This approach identified 226 CNV neurons, as well as a class of CNV neurons with complex karyotypes containing whole or substantial losses on multiple chromosomes. Moreover, we found that CNV location appears to be nonrandom. Recurrent regions of neuronal genome rearrangement contained fewer, but longer, genes.

Published
2023

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