Search

Your search keyword '"Downie, Jonathan M."' showing total 28 results
Start Over Author "Downie, Jonathan M."
28 results on '"Downie, Jonathan M."'

1. Supplementary Figure from Incident Cancer Risk and Signatures Among Older MUTYH Carriers: Analysis of Population-Based and Genomic Cohorts

Author

Downie, Jonathan M., primary, Riaz, Moeen, primary, Xie, Jing, primary, Lee, Minyi, primary, Chan, Andrew T., primary, Gibbs, Peter, primary, Orchard, Suzanne G., primary, Mahady, Suzanne E., primary, Sebra, Robert P., primary, Murray, Anne M., primary, Macrae, Finlay, primary, Schadt, Eric, primary, Woods, Robyn L., primary, McNeil, John J., primary, Lacaze, Paul, primary, and Gala, Manish, primary

Published
2023
Full Text
View/download PDF

2. Data from Incident Cancer Risk and Signatures Among Older MUTYH Carriers: Analysis of Population-Based and Genomic Cohorts

Author

Downie, Jonathan M., primary, Riaz, Moeen, primary, Xie, Jing, primary, Lee, Minyi, primary, Chan, Andrew T., primary, Gibbs, Peter, primary, Orchard, Suzanne G., primary, Mahady, Suzanne E., primary, Sebra, Robert P., primary, Murray, Anne M., primary, Macrae, Finlay, primary, Schadt, Eric, primary, Woods, Robyn L., primary, McNeil, John J., primary, Lacaze, Paul, primary, and Gala, Manish, primary

Published
2023
Full Text
View/download PDF

3. Incident Cancer Risk and Signatures Among Older MUTYH Carriers: Analysis of Population-Based and Genomic Cohorts

Author

Downie, Jonathan M., primary, Riaz, Moeen, additional, Xie, Jing, additional, Lee, Minyi, additional, Chan, Andrew T., additional, Gibbs, Peter, additional, Orchard, Suzanne G., additional, Mahady, Suzanne E., additional, Sebra, Robert P., additional, Murray, Anne M., additional, Macrae, Finlay, additional, Schadt, Eric, additional, Woods, Robyn L., additional, McNeil, John J., additional, Lacaze, Paul, additional, and Gala, Manish, additional

Published
2022
Full Text
View/download PDF

6. MFN2 Influences Amyotrophic Lateral Sclerosis Pathology

Author

Russell, Kristi, primary, Downie, Jonathan M., additional, Gibson, Summer, additional, Figueroa, Patty, additional, Steely, Cody J, additional, Bromberg, Mark, additional, Murtaugh, Lewis Charles, additional, Jorde, Lynn B., additional, and Pulst, Stefan M, additional

Published
2021
Full Text
View/download PDF

7. S280 Incident Cancer Risk and Mutation Signatures Among Elderly MUTYH Carriers: Analysis of Population-Based and Genomic Cohorts

Author

Downie, Jonathan M., primary, Riaz, Moeen, additional, Xie, Sophia, additional, Lee, Minyi, additional, Chan, Andrew T., additional, Gibbs, Peter, additional, Orchard, Suzanne, additional, Mahady, Suzanne, additional, Sebra, Robert, additional, Murray, Anne, additional, Macrae, Finlay, additional, Schadt, Eric, additional, Woods, Robyn, additional, McNeil, John, additional, Lacaze, Paul, additional, and Gala, Manish, additional

Published
2021
Full Text
View/download PDF

8. Association of Combined Focal 22q11.22 Deletion and IKZF1 Alterations With Outcomes in Childhood Acute Lymphoblastic Leukemia

Author

Mangum, David Spencer, primary, Meyer, Julia A., additional, Mason, Clinton C., additional, Shams, Soheil, additional, Maese, Luke D., additional, Gardiner, Jamie D., additional, Downie, Jonathan M., additional, Pei, Deqing, additional, Cheng, Cheng, additional, Gleason, Adam, additional, Luo, Minjie, additional, Pui, Ching-Hon, additional, Aplenc, Richard, additional, Hunger, Stephen P., additional, Loh, Mignon, additional, Greaves, Mel, additional, Trede, Nikolaus, additional, Raetz, Elizabeth, additional, Frazer, J. Kimble, additional, Mullighan, Charles G., additional, Engel, Michael E., additional, Miles, Rodney R., additional, Rabin, Karen R., additional, and Schiffman, Joshua D., additional

Published
2021
Full Text
View/download PDF

9. Pathogenic Effect ofTP73Gene Variants in People With Amyotrophic Lateral Sclerosis

Author

Russell, Kristi L., primary, Downie, Jonathan M., additional, Gibson, Summer B., additional, Tsetsou, Spyridoula, additional, Keefe, Matthew D., additional, Duran, Jerry A., additional, Figueroa, Karla P., additional, Bromberg, Mark B., additional, Murtaugh, L. Charles, additional, Bonkowsky, Joshua L., additional, Pulst, Stefan M., additional, and Jorde, Lynn B., additional

Published
2021
Full Text
View/download PDF

13. Surveying the Genetic Risk Landscape Of Amyotrophic Lateral Sclerosis in The Era of Next-Generation Sequencing

Author

Downie, Jonathan M.

Subjects
Physiology, FOS: Clinical medicine, FOS: Biological sciences, Neurosciences, Genetics, Medicine
Abstract

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is an adult-onset fatal disease in which the upper and lower motor neurons of the body progressively degenerate. Efforts to understand the pathophysiology of ALS over the past two decades have shown that mutations in genes involved in a wide variety of cellular processes can cause ALS. Patients who develop ALS and have a family history of the disease are termed familial ALS (FALS) and represent 10% of ALS cases. However, similar genetic mutations occur in patients with no family history of ALS, which suggests genetic factors also play a role in sporadic ALS (SALS). Studies that utilize low-resolution single nucleotide variant (SNV) and microsatellite assays have identified over 30 ALS-associated genes. However, only 68% of FALS and 11% of SALS cases have an identifiable genetic cause. The identification of the genetic factors responsible for these unexplained ALS cases has been challenging because of the technological limitations of SNV and microsatellite assays. The increasing availability of next-generation sequencing (NGS) allows for the potential identification of such elusive disease-causing genetic variants. The aim of this dissertation is to better understand ALS genetic risk factors using NGS technology and computational methods. The first chapter will review ALS and the importance of genetic factors in its pathogenesis. The analyses presented in Chapter 2 try to determine whether NGS approaches can identify known and potentially novel ALS genetic risk loci in individual FALS patients. Next, efforts to better understand the importance of known ALS risk loci in SALS pathogenesis will be covered in Chapter 3. Chapter 4 will focus on attempts to find novel ALS risk genes in a cohort of SALS patients. Chapter 5 will focus on the results of functional studies aimed at validating TP73 as an ALS candidate risk gene. Lastly, Chapter 6 will be focused on determining whether SALS can be caused by deleterious genetic variation shared between distantly related patients. The

Published
2019
Full Text
View/download PDF

14. Loss ofTP73function contributes to amyotrophic lateral sclerosis pathogenesis

Author

Downie, Jonathan M., primary, Gibson, Summer B., additional, Tsetsou, Spyridoula, additional, Russell, Kristi L., additional, Keefe, Matthew D., additional, Figueroa, Karla P., additional, Bromberg, Mark B., additional, Murtaugh, L. Charles, additional, Bonkowsky, Joshua L., additional, Pulst, Stefan M., additional, and Jorde, Lynn B., additional

Published
2018
Full Text
View/download PDF

16. The evolving genetic risk for sporadic ALS

Author

Gibson, Summer B., primary, Downie, Jonathan M., additional, Tsetsou, Spyridoula, additional, Feusier, Julie E., additional, Figueroa, Karla P., additional, Bromberg, Mark B., additional, Jorde, Lynn B., additional, and Pulst, Stefan M., additional

Published
2017
Full Text
View/download PDF

17. Evolutionary history of Tibetans inferred from whole-genome sequencing

Author

Hu, Hao, primary, Petousi, Nayia, additional, Glusman, Gustavo, additional, Yu, Yao, additional, Bohlender, Ryan, additional, Tashi, Tsewang, additional, Downie, Jonathan M., additional, Roach, Jared C., additional, Cole, Amy M., additional, Lorenzo, Felipe R., additional, Rogers, Alan R., additional, Brunkow, Mary E., additional, Cavalleri, Gianpiero, additional, Hood, Leroy, additional, Alpatty, Sama M., additional, Prchal, Josef T., additional, Jorde, Lynn B., additional, Robbins, Peter A., additional, Simonson, Tatum S., additional, and Huff, Chad D., additional

Published
2017
Full Text
View/download PDF

18. Genomic characterization of pediatric B-lymphoblastic lymphoma and B-lymphoblastic leukemia using formalin-fixed tissues

Author

Meyer, Julia A., primary, Zhou, Delu, additional, Mason, Clinton C., additional, Downie, Jonathan M., additional, Rodic, Vladimir, additional, Abromowitch, Minnie, additional, Wistinghausen, Birte, additional, Termuhlen, Amanda M., additional, Angiolillo, Anne L., additional, Perkins, Sherrie L., additional, Lones, Mark A., additional, Barnette, Phillip, additional, Schiffman, Joshua D., additional, and Miles, Rodney R., additional

Published
2016
Full Text
View/download PDF

21. Human Spermatogenic Failure Purges Deleterious Mutation Load from the Autosomes and Both Sex Chromosomes, including the Gene DMRT1

Author

Lopes, Alexandra M., primary, Aston, Kenneth I., additional, Thompson, Emma, additional, Carvalho, Filipa, additional, Gonçalves, João, additional, Huang, Ni, additional, Matthiesen, Rune, additional, Noordam, Michiel J., additional, Quintela, Inés, additional, Ramu, Avinash, additional, Seabra, Catarina, additional, Wilfert, Amy B., additional, Dai, Juncheng, additional, Downie, Jonathan M., additional, Fernandes, Susana, additional, Guo, Xuejiang, additional, Sha, Jiahao, additional, Amorim, António, additional, Barros, Alberto, additional, Carracedo, Angel, additional, Hu, Zhibin, additional, Hurles, Matthew E., additional, Moskovtsev, Sergey, additional, Ober, Carole, additional, Paduch, Darius A., additional, Schiffman, Joshua D., additional, Schlegel, Peter N., additional, Sousa, Mário, additional, Carrell, Douglas T., additional, and Conrad, Donald F., additional

Published
2013
Full Text
View/download PDF

22. Focal 22q11.22 Loss Combined with IKZF1 Alterations Predict Very Poor Outcome in Childhood Acute Lymphoblastic Leukemia

Author

Mangum, D. Spencer, primary, Shams, Soheil, additional, Downie, Jonathan M., additional, von Schwedler, Uta, additional, Rodic, Vladimir, additional, Engel, Michael, additional, Barnette, Phillip, additional, Frazer, J. Kimble, additional, Trede, Nikolaus, additional, Pei, Dequing, additional, Cheng, Cheng, additional, Pui, Ching-Hon, additional, Hunger, Stephen P, additional, Yang, Jun J., additional, Miles, Rodney R., additional, Mullighan, Charles G, additional, and Schiffman, Joshua D., additional

Published
2011
Full Text
View/download PDF

25. Focal 22q11.22 Loss Combined with IKZF1Alterations Predict Very Poor Outcome in Childhood Acute Lymphoblastic Leukemia

Author

Mangum, D. Spencer, Shams, Soheil, Downie, Jonathan M., von Schwedler, Uta, Rodic, Vladimir, Engel, Michael, Barnette, Phillip, Frazer, J. Kimble, Trede, Nikolaus, Pei, Dequing, Cheng, Cheng, Pui, Ching-Hon, Hunger, Stephen P, Yang, Jun J., Miles, Rodney R., Mullighan, Charles G, and Schiffman, Joshua D.

Abstract

Abstract 741

Published
2011
Full Text
View/download PDF

26. Novel metabolomic predictors of incident colorectal cancer in men and women.

Author

Downie JM, Joshi AD, Geraghty CM, Guercio BJ, Zeleznik OA, Song M, Bever AM, Drew DA, Tabung FK, Zhang X, Jin L, Eliassen AH, Willett WC, Wu K, Kraft P, Tamimi R, Clish C, Fuchs CS, Giovannucci E, Meyerhardt JA, and Chan AT

Abstract

Background: Metabolomic profiles may influence colorectal cancer (CRC) development. Few studies have performed pre-diagnostic metabolome-wide analyses with CRC risk., Methods: We conducted a nested case-control study among women (Nurses' Health Study (NHS)) and men (Health Professionals Follow-up Study (HPFS)) who provided blood between 1989 and 1995. Over 22.9 years, 684 (409 NHS, 275 HPFS) incident CRC cases occurred and were matched 1:1 to controls. Liquid chromatography-mass spectrometry (LC-MS) identified 255 plasma metabolites after quality control. Cohort-specific and combined metabolite association analyses were performed using conditional logistic regression. Metabolite set enrichment analysis (MSEA) was used to identify differential abundance in metabolite classes. Weighted Correlation Network Analysis (WGCNA) provided modules of covarying metabolites, which were tested for CRC association., Results: MSEA identified specific acylcarnitines associated with higher CRC risk and triacylglycerols with lower CRC risk among women and men. Further, phosphatidylcholines were associated with a higher risk of CRC among men. In an analysis restricted to CRC cases diagnosed two years after blood draw, myristoleic acid (OR = 1.37; 95%CI = 1.15-1.62; FDR = 0.072) and C60:12 triacylglycerol (OR = 0.75; 95%CI = 0.64-0.88; FDR = 0.072 were associated with CRC risk in women. WGCNA identified amino acids associated with CRC in men, fatty acid esters (carnitines) with distal CRC in men, and triradylcglycerols inversely associated with CRC in women., Conclusions: We identified pre-diagnostic CRC-associated metabolites with distinct sex-specific profiles. These results provide insight into CRC etiopathogenesis and have implications for risk prediction strategies., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Published
2024
Full Text
View/download PDF

27. Optimizing single-cell RNA sequencing methods for human colon biopsies: droplet-based vs. picowell-based platforms.

Author

Downie JM, Musich RJ, Geraghty CM, Caraballo A, He S, Khawaled S, Lachut K, Long T, Zhou JY, Yilmaz OH, Stappenbeck T, Chan AT, and Drew DA

Abstract

Background & Aims: Single-cell RNA sequencing (scRNA) has empowered many insights into gastrointestinal microenvironments. However, profiling human biopsies using droplet-based scRNA (D-scRNA) is challenging since it requires immediate processing to minimize epithelial cell damage. In contrast, picowell-based (P-scRNA) platforms permit short-term frozen storage before sequencing. We compared P- and D-scRNA platforms on cells derived from human colon biopsies., Methods: Endoscopic rectosigmoid mucosal biopsies were obtained from two adults and conducted D-scRNA (10X Chromium) and P-scRNA (Honeycomb HIVE) in parallel using an individual's pool of single cells (> 10,000 cells/participant). Three experiments were performed to evaluate 1) P-scRNA with cells under specific storage conditions (immediately processed [fresh], vs. frozen at -20C vs. -80C [2 weeks]); 2) fresh P-scRNA versus fresh D-scRNA; and 3) P-scRNA stored at -80C with fresh D-scRNA., Results: Significant recovery of loaded cells was achieved for fresh (80.9%) and -80C (48.5%) P-scRNA and D-scRNA (76.6%), but not -20C P-scRNA (3.7%). However, D-scRNA captures more typeable cells among recovered cells (71.5% vs. 15.8% Fresh and 18.4% -80C P-scRNA), and these cells exhibit higher gene coverage at the expense of higher mitochondrial read fractions across most cell types. Cells profiled using D-scRNA demonstrated more consistent gene expression profiles among the same cell type than those profiled using P-scRNA. Significant intra-cell-type differences were observed in profiled gene classes across platforms., Conclusions: Our results highlight non-overlapping advantages of P-scRNA and D-scRNA and underscore the need for innovation to enable high-fidelity capture of colonic epithelial cells. The platform-specific variation highlights the challenges of maintaining rigor and reproducibility across studies that use different platforms.

Published
2024
Full Text
View/download PDF

28. Pathogenic Effect of TP73 Gene Variants in People With Amyotrophic Lateral Sclerosis.

Author

Russell KL, Downie JM, Gibson SB, Tsetsou S, Keefe MD, Duran JA, Figueroa KP, Bromberg MB, Murtaugh LC, Bonkowsky JL, Pulst SM, and Jorde LB

Abstract

Objective: To identify novel disease associated loci for amyotrophic lateral sclerosis (ALS), we used sequencing data and performed in vitro and in vivo experiments to demonstrate pathogenicity of mutations identified in TP73 ., Methods: We analyzed exome sequences of 87 patients with sporadic ALS and 324 controls, with confirmatory sequencing in independent ALS cohorts of >2,800 patients. For the top hit, TP73 , a regulator of apoptosis and differentiation and a binding partner and homolog of the tumor suppressor gene TP53 , we assayed mutation effects using in vitro and in vivo experiments. C2C12 myoblast differentiation assays, characterization of myotube appearance, and immunoprecipitation of p53-p73 complexes were performed in vitro. In vivo, we used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 targeting of zebrafish tp73 to assay motor neuron number and axon morphology., Results: Four heterozygous rare, nonsynonymous mutations in TP73 were identified in our sporadic ALS cohort. In independent ALS cohorts, we identified an additional 19 rare, deleterious variants in TP73 . Patient TP73 mutations caused abnormal differentiation and increased apoptosis in the myoblast differentiation assay, with abnormal myotube appearance. Immunoprecipitation of mutant ΔN-p73 demonstrated that patient mutations hinder the ability of ΔN-p73 to bind p53. CRISPR/Cas9 knockout of tp73 in zebrafish led to impaired motor neuron development and abnormal axonal morphology, concordant with ALS pathology., Conclusion: Together, these results strongly suggest that variants in TP73 correlate with risk for ALS and indicate a role for apoptosis in ALS disease pathology., (© 2021 American Academy of Neurology.)

Published
2021
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results