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2. Mitochondrial genome sequence analysis: A custom bioinformatics pipeline substantially improves Affymetrix MitoChip v2.0 call rate and accuracy

Author

Xie Hongbo M, Perin Juan C, Schurr Theodore G, Dulik Matthew C, Zhadanov Sergey I, Baur Joseph A, King Michael P, Place Emily, Clarke Colleen, Grauer Michael, Schug Jonathan, Santani Avni, Albano Anthony, Kim Cecilia, Procaccio Vincent, Hakonarson Hakon, Gai Xiaowu, and Falk Marni J

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background Mitochondrial genome sequence analysis is critical to the diagnostic evaluation of mitochondrial disease. Existing methodologies differ widely in throughput, complexity, cost efficiency, and sensitivity of heteroplasmy detection. Affymetrix MitoChip v2.0, which uses a sequencing-by-genotyping technology, allows potentially accurate and high-throughput sequencing of the entire human mitochondrial genome to be completed in a cost-effective fashion. However, the relatively low call rate achieved using existing software tools has limited the wide adoption of this platform for either clinical or research applications. Here, we report the design and development of a custom bioinformatics software pipeline that achieves a much improved call rate and accuracy for the Affymetrix MitoChip v2.0 platform. We used this custom pipeline to analyze MitoChip v2.0 data from 24 DNA samples representing a broad range of tissue types (18 whole blood, 3 skeletal muscle, 3 cell lines), mutations (a 5.8 kilobase pair deletion and 6 known heteroplasmic mutations), and haplogroup origins. All results were compared to those obtained by at least one other mitochondrial DNA sequence analysis method, including Sanger sequencing, denaturing HPLC-based heteroduplex analysis, and/or the Illumina Genome Analyzer II next generation sequencing platform. Results An average call rate of 99.75% was achieved across all samples with our custom pipeline. Comparison of calls for 15 samples characterized previously by Sanger sequencing revealed a total of 29 discordant calls, which translates to an estimated 0.012% for the base call error rate. We successfully identified 4 known heteroplasmic mutations and 24 other potential heteroplasmic mutations across 20 samples that passed quality control. Conclusions Affymetrix MitoChip v2.0 analysis using our optimized MitoChip Filtering Protocol (MFP) bioinformatics pipeline now offers the high sensitivity and accuracy needed for reliable, high-throughput and cost-efficient whole mitochondrial genome sequencing. This approach provides a viable alternative of potential utility for both clinical diagnostic and research applications to traditional Sanger and other emerging sequencing technologies for whole mitochondrial genome analysis.

Published
2011
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3. CNV Workshop: an integrated platform for high-throughput copy number variation discovery and clinical diagnostics

Author

Rappaport Eric F, Xie Hongbo M, Wenocur Adam, D'arcy Monica, O'Hara Ryan, Murphy Kevin, Perin Juan C, Gai Xiaowu, Shaikh Tamim H, and White Peter S

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background Recent studies have shown that copy number variations (CNVs) are frequent in higher eukaryotes and associated with a substantial portion of inherited and acquired risk for various human diseases. The increasing availability of high-resolution genome surveillance platforms provides opportunity for rapidly assessing research and clinical samples for CNV content, as well as for determining the potential pathogenicity of identified variants. However, few informatics tools for accurate and efficient CNV detection and assessment currently exist. Results We developed a suite of software tools and resources (CNV Workshop) for automated, genome-wide CNV detection from a variety of SNP array platforms. CNV Workshop includes three major components: detection, annotation, and presentation of structural variants from genome array data. CNV detection utilizes a robust and genotype-specific extension of the Circular Binary Segmentation algorithm, and the use of additional detection algorithms is supported. Predicted CNVs are captured in a MySQL database that supports cohort-based projects and incorporates a secure user authentication layer and user/admin roles. To assist with determination of pathogenicity, detected CNVs are also annotated automatically for gene content, known disease loci, and gene-based literature references. Results are easily queried, sorted, filtered, and visualized via a web-based presentation layer that includes a GBrowse-based graphical representation of CNV content and relevant public data, integration with the UCSC Genome Browser, and tabular displays of genomic attributes for each CNV. Conclusions To our knowledge, CNV Workshop represents the first cohesive and convenient platform for detection, annotation, and assessment of the biological and clinical significance of structural variants. CNV Workshop has been successfully utilized for assessment of genomic variation in healthy individuals and disease cohorts and is an ideal platform for coordinating multiple associated projects. Availability and Implementation Available on the web at: http://sourceforge.net/projects/cnv

Published
2010
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4. OpenPBTA: The Open Pediatric Brain Tumor Atlas

Author

Shapiro, Joshua A., Gaonkar, Krutika S., Spielman, Stephanie J., Savonen, Candace L., Bethell, Chante J., Jin, Run, Rathi, Komal S., Zhu, Yuankun, Egolf, Laura E., Farrow, Bailey K., Miller, Daniel P., Yang, Yang, Koganti, Tejaswi, Noureen, Nighat, Koptyra, Mateusz P., Duong, Nhat, Santi, Mariarita, Kim, Jung, Robins, Shannon, Storm, Phillip B., Mack, Stephen C., Lilly, Jena V., Xie, Hongbo M., Jain, Payal, Raman, Pichai, Rood, Brian R., Lulla, Rishi R., Nazarian, Javad, Kraya, Adam A., Vaksman, Zalman, Heath, Allison P., Kline, Cassie, Scolaro, Laura, Viaene, Angela N., Huang, Xiaoyan, Way, Gregory P., Foltz, Steven M., Zhang, Bo, Poetsch, Anna R., Mueller, Sabine, Ennis, Brian M., Prados, Michael, Diskin, Sharon J., Zheng, Siyuan, Guo, Yiran, Kannan, Shrivats, Waanders, Angela J., Margol, Ashley S., Kim, Meen Chul, Hanson, Derek, Van Kuren, Nicholas, Wong, Jessica, Kaufman, Rebecca S., Coleman, Noel, Blackden, Christopher, Cole, Kristina A., Mason, Jennifer L., Madsen, Peter J., Koschmann, Carl J., Stewart, Douglas R., Wafula, Eric, Brown, Miguel A., Resnick, Adam C., Greene, Casey S., Rokita, Jo Lynne, and Taroni, Jaclyn N.

Published
2023
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5. Patient-derived Colonoids From Disease-spared Tissue Retain Inflammatory Bowel Disease-specific Transcriptomic Signatures

Author

Karakasheva, Tatiana A., Zhou, Yusen, Xie, Hongbo M., Soto, Gloria E., Johnson, Tiana D., Stoltz, Madison A., Roach, Daana M., Nema, Noor, Umeweni, Chizoba N., Naughton, Kaitlyn, Dolinsky, Lauren, Pippin, James A., Wells, Andrew D., Grant, Struan F.A., Ghanem, Louis, Terry, Natalie, Muir, Amanda B., and Hamilton, Kathryn E.

Published
2023
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9. Clonal evolution mediates Menin-inhibitor resistance in KMT2A-rearranged leukemias.

Author

Mahdavi, Leila, primary, Lenard, Alexandra, additional, Xie, Hongbo M, additional, Alikarami, Fatemeh, additional, Riedel, Simone S, additional, Libbrecht, Clara, additional, Falkenstein, Catherine, additional, Tasian, Sarah K, additional, Manning, Bryan, additional, Skuli, Sarah, additional, Carroll, Martin P, additional, Wertheim, Gerald, additional, McGeehan, Gerard, additional, and Bernt, Kathrin Maria, additional

Published
2023
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10. OpenPBTA: The Open Pediatric Brain Tumor Atlas

Author

Shapiro, Joshua A, Gaonkar, Krutika S; https://orcid.org/0000-0003-0838-2405, Spielman, Stephanie J, Savonen, Candace L, Bethell, Chante J, Jin, Run, Rathi, Komal S, Zhu, Yuankun, Egolf, Laura E, Farrow, Bailey K, Miller, Daniel P, Yang, Yang; https://orcid.org/0000-0001-6645-2454, Koganti, Tejaswi, Noureen, Nighat, Koptyra, Mateusz P, Duong, Nhat, Santi, Mariarita, Kim, Jung, Robins, Shannon, Storm, Phillip B, Mack, Stephen C, Lilly, Jena V, Xie, Hongbo M, Jain, Payal; https://orcid.org/0000-0002-5914-9083, Raman, Pichai, Rood, Brian R, Lulla, Rishi R, Nazarian, Javad; https://orcid.org/0000-0002-1951-9828, Kraya, Adam A, Vaksman, Zalman, et al, Shapiro, Joshua A, Gaonkar, Krutika S; https://orcid.org/0000-0003-0838-2405, Spielman, Stephanie J, Savonen, Candace L, Bethell, Chante J, Jin, Run, Rathi, Komal S, Zhu, Yuankun, Egolf, Laura E, Farrow, Bailey K, Miller, Daniel P, Yang, Yang; https://orcid.org/0000-0001-6645-2454, Koganti, Tejaswi, Noureen, Nighat, Koptyra, Mateusz P, Duong, Nhat, Santi, Mariarita, Kim, Jung, Robins, Shannon, Storm, Phillip B, Mack, Stephen C, Lilly, Jena V, Xie, Hongbo M, Jain, Payal; https://orcid.org/0000-0002-5914-9083, Raman, Pichai, Rood, Brian R, Lulla, Rishi R, Nazarian, Javad; https://orcid.org/0000-0002-1951-9828, Kraya, Adam A, Vaksman, Zalman, and et al

Abstract

Pediatric brain and spinal cancers are collectively the leading disease-related cause of death in children; thus, we urgently need curative therapeutic strategies for these tumors. To accelerate such discoveries, the Children's Brain Tumor Network (CBTN) and Pacific Pediatric Neuro-Oncology Consortium (PNOC) created a systematic process for tumor biobanking, model generation, and sequencing with immediate access to harmonized data. We leverage these data to establish OpenPBTA, an open collaborative project with over 40 scalable analysis modules that genomically characterize 1,074 pediatric brain tumors. Transcriptomic classification reveals universal TP53 dysregulation in mismatch repair-deficient hypermutant high-grade gliomas and TP53 loss as a significant marker for poor overall survival in ependymomas and H3 K28-mutant diffuse midline gliomas. Already being actively applied to other pediatric cancers and PNOC molecular tumor board decision-making, OpenPBTA is an invaluable resource to the pediatric oncology community.

Published
2023

12. A recurrent de novo splice site variant involving DNM1 exon 10a causes developmental and epileptic encephalopathy through a dominant-negative mechanism

Author

Parthasarathy, Shridhar, primary, Ruggiero, Sarah McKeown, additional, Gelot, Antoinette, additional, Soardi, Fernanda C, additional, Ribeiro, Bethânia F R, additional, Pires, Douglas E V, additional, Ascher, David B, additional, Schmitt, Alain, additional, Rambaud, Caroline, additional, Represa, Alfonso, additional, Xie, Hongbo M, additional, Lusk, Laina, additional, Wilmarth, Olivia, additional, McDonnell, Pamela Pojomovsky, additional, Juarez, Olivia A, additional, Grace, Alexandra N, additional, Buratti, Julien, additional, Mignot, Cyril, additional, Gras, Domitille, additional, Nava, Caroline, additional, Pierce, Samuel R, additional, Keren, Boris, additional, Kennedy, Benjamin C, additional, Pena, Sergio D J, additional, Helbig, Ingo, additional, and Cuddapah, Vishnu Anand, additional

Published
2022
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13. Pathogenicity and impact of HLA class I alleles in aplastic anemia patients of different ethnicities

Author

Olson, Timothy S., primary, Frost, Benjamin F., additional, Duke, Jamie L., additional, Dribus, Marian, additional, Xie, Hongbo M., additional, Prudowsky, Zachary D., additional, Furutani, Elissa, additional, Gudera, Jonas, additional, Shah, Yash B., additional, Ferriola, Deborah, additional, Dinou, Amalia, additional, Pagkrati, Ioanna, additional, Kim, Soyoung, additional, Xu, Yixi, additional, He, Meilun, additional, Zheng, Shannon, additional, Nijim, Sally, additional, Lin, Ping, additional, Xu, Chong, additional, Nakano, Taizo A., additional, Oved, Joseph H., additional, Carreno, Beatriz M., additional, Bolon, Yung-Tsi, additional, Gadalla, Shahinaz M., additional, Marsh, Steven G.E., additional, Paczesny, Sophie, additional, Lee, Stephanie J., additional, Monos, Dimitrios S., additional, Shimamura, Akiko, additional, Bertuch, Alison A., additional, Gragert, Loren, additional, Spellman, Stephen R., additional, and Babushok, Daria V., additional

Published
2022
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15. Pathogenicity and Impact of HLA Class I Alleles in Aplastic Anemia Patients of Different Ethnicities

Author

Olson, Timothy S, Frost, Benjamin F, Duke, Jamie L, Dribus, Marian, Xie, Hongbo M, Prudowsky, Zachary D, Furutani, Elissa, Gudera, Jonas, Shah, Yash B, Ferriola, Deborah, Dinou, Amalia, Pagkrati, Ioanna, Kim, Soyoung, Xu, Yixi, He, Meilun, Zheng, Shannon, Nijim, Sally, Lin, Ping, Xu, Chong, Nakano, Taizo A, Oved, Joseph H, Carreno, Beatriz M, Bolon, Yung-Tsi, Gadalla, Shahinaz M, Marsh, Steven Ge, Paczesny, Sophie, Lee, Stephanie J, Monos, Dimitrios S, Shimamura, Akiko, Bertuch, Alison A, Gragert, Loren, Spellman, Stephen R, Babushok, Daria V, Olson, Timothy S, Frost, Benjamin F, Duke, Jamie L, Dribus, Marian, Xie, Hongbo M, Prudowsky, Zachary D, Furutani, Elissa, Gudera, Jonas, Shah, Yash B, Ferriola, Deborah, Dinou, Amalia, Pagkrati, Ioanna, Kim, Soyoung, Xu, Yixi, He, Meilun, Zheng, Shannon, Nijim, Sally, Lin, Ping, Xu, Chong, Nakano, Taizo A, Oved, Joseph H, Carreno, Beatriz M, Bolon, Yung-Tsi, Gadalla, Shahinaz M, Marsh, Steven Ge, Paczesny, Sophie, Lee, Stephanie J, Monos, Dimitrios S, Shimamura, Akiko, Bertuch, Alison A, Gragert, Loren, Spellman, Stephen R, and Babushok, Daria V

Abstract

Acquired aplastic anemia (AA) is caused by autoreactive T cell-mediated destruction of early hematopoietic cells. Somatic loss of human leukocyte antigen (HLA) class I alleles was identified as a mechanism of immune escape in surviving hematopoietic cells of some patients with AA. However, pathogenicity, structural characteristics, and clinical impact of specific HLA alleles in AA remain poorly understood. Here, we evaluated somatic HLA loss in 505 patients with AA from 2 multi-institutional cohorts. Using a combination of HLA mutation frequencies, peptide-binding structures, and association with AA in an independent cohort of 6,323 patients from the National Marrow Donor Program, we identified 19 AA risk alleles and 12 non-risk alleles and established a potentially novel AA HLA pathogenicity stratification. Our results define pathogenicity for the majority of common HLA-A/B alleles across diverse populations. Our study demonstrates that HLA alleles confer different risks of developing AA, but once AA develops, specific alleles are not associated with response to immunosuppression or transplant outcomes. However, higher pathogenicity alleles, particularly HLA-B*14:02, are associated with higher rates of clonal evolution in adult patients with AA. Our study provides insights into the immune pathogenesis of AA, opening the door to future autoantigen identification and improved understanding of clonal evolution in AA.

Published
2022

19. Genome-Wide Association Studies of Conotruncal Heart Defects with Normally Related Great Vessels in the United States

Author

Oluwafemi, Omobola O., primary, Musfee, Fadi I., additional, Mitchell, Laura E., additional, Goldmuntz, Elizabeth, additional, Xie, Hongbo M., additional, Hakonarson, Hakon, additional, Morrow, Bernice E., additional, Guo, Tingwei, additional, Taylor, Deanne M., additional, McDonald-McGinn, Donna M., additional, Emanuel, Beverly S., additional, and Agopian, A. J., additional

Published
2021
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20. Intrinsically disordered Meningioma-1 stabilizes the BAF complex to cause AML

Author

Riedel, Simone S., primary, Lu, Congcong, additional, Xie, Hongbo M., additional, Nestler, Kevin, additional, Vermunt, Marit W., additional, Lenard, Alexandra, additional, Bennett, Laura, additional, Speck, Nancy A., additional, Hanamura, Ichiro, additional, Lessard, Julie A., additional, Blobel, Gerd A., additional, Garcia, Benjamin A., additional, and Bernt, Kathrin M., additional

Published
2021
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23. Prevalence of rare mitochondrial DNA mutations in mitochondrial disorders

Author

Bannwarth, Sylvie, Procaccio, Vincent, Lebre, Anne Sophie, Jardel, Claude, Chaussenot, Annabelle, Hoarau, Claire, Maoulida, Hassani, Charrier, Nathanaël, Gai, Xiaowu, Xie, Hongbo M, Ferre, Marc, Fragaki, Konstantina, Hardy, Gaëlle, Mousson de Camaret, Bénédicte, Marlin, Sandrine, Dhaenens, Claire Marie, Slama, Abdelhamid, Rocher, Christophe, Paul Bonnefont, Jean, Rötig, Agnès, Aoutil, Nadia, Gilleron, Mylène, Desquiret-Dumas, Valérie, Reynier, Pascal, Ceresuela, Jennifer, Jonard, Laurence, Devos, Aurore, Espil-Taris, Caroline, Martinez, Delphine, Gaignard, Pauline, Le Quan Sang, Kim-Hanh, Amati-Bonneau, Patrizia, Falk, Marni J, Florentz, Catherine, Chabrol, Brigitte, Durand-Zaleski, Isabelle, and Paquis-Flucklinger, Véronique

Published
2013
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24. Copy number variations in individuals with conotruncal heart defects reveal some shared developmental pathways irrespective of 22q11.2 deletion status

Author

Xie, Hongbo M., primary, Taylor, Deanne M., additional, Zhang, Zhe, additional, McDonald‐McGinn, Donna M., additional, Zackai, Elaine H., additional, Stambolian, Dwight, additional, Hakonarson, Hakon, additional, Morrow, Bernice E., additional, Emanuel, Beverly S., additional, and Goldmuntz, Elizabeth, additional

Published
2019
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25. Inducible Sbdsdeletion impairs bone marrow niche capacity to engraft donor bone marrow after transplantation

Author

Zha, Ji, Kunselman, Lori K., Xie, Hongbo M., Ennis, Brian, Shah, Yash B., Qin, Xia, Fan, Jian-Meng, Babushok, Daria V., and Olson, Timothy S.

Abstract

Bone marrow (BM) niche-derived signals are critical for facilitating engraftment after hematopoietic stem cell (HSC) transplantation (HSCT). HSCT is required for restoration of hematopoiesis in patients with inherited BM failure syndromes (iBMFSs). Shwachman-Diamond syndrome (SDS) is a rare iBMFS associated with mutations in SBDS. Previous studies have demonstrated that SBDS deficiency in osteolineage niche cells causes BM dysfunction that promotes leukemia development. However, it is unknown whether BM niche defects caused by SBDS deficiency also impair efficient engraftment of healthy donor HSC after HSCT, a hypothesis that could explain morbidity noted after clinical HSCT for patients with SDS. Here, we report a mouse model with inducible Sbdsdeletion in hematopoietic and osteolineage cells. Primary and secondary BM transplantation (BMT) studies demonstrated that SBDS deficiency within BM niches caused poor donor hematopoietic recovery and specifically poor HSC engraftment after myeloablative BMT. We have also identified multiple molecular and cellular defects within niche populations that are driven by SBDS deficiency and are accentuated by or develop specifically after myeloablative conditioning. These abnormalities include altered frequencies of multiple niche cell subsets, including mesenchymal lineage cells, macrophages, and endothelial cells; disruption of growth factor signaling, chemokine pathway activation, and adhesion molecule expression; and p53 pathway activation and signals involved in cell cycle arrest. Taken together, this study demonstrates that SBDS deficiency profoundly impacts recipient hematopoietic niche function in the setting of HSCT, suggesting that novel therapeutic strategies targeting host niches could improve clinical HSCT outcomes for patients with SDS.

Published
2022
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26. Rare Copy Number Variants in Patients with Congenital Conotruncal Heart Defects

Author

Xie, Hongbo M., Werner, Petra, Stambolian, Dwight, Bailey-Wilson, Joan E., Hakonarson, Hakon, White, Peter S., Taylor, Deanne M., and Goldmuntz, Elizabeth

Subjects
Adult, Heart Defects, Congenital, Male, Adolescent, DNA Copy Number Variations, Genotype, Gene Expression Profiling, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, Article, Cohort Studies, Genetic Heterogeneity, Gene Ontology, Phenotype, Case-Control Studies, Child, Preschool, Humans, Female, Gene Regulatory Networks, Genetic Predisposition to Disease, Child
Abstract

Previous studies using different cardiac phenotypes, technologies and designs suggest a burden of large, rare or de novo copy number variants (CNVs) in subjects with congenital heart defects. We sought to identify disease-related CNVs, candidate genes, and functional pathways in a large number of cases with conotruncal and related defects that carried no known genetic syndrome.Cases and control samples were divided into two cohorts and genotyped to assess each subject's CNV content. Analyses were performed to ascertain differences in overall CNV prevalence and to identify enrichment of specific genes and functional pathways in conotruncal cases relative to healthy controls.Only findings present in both cohorts are presented. From 973 total conotruncal cases, a burden of rare CNVs was detected in both cohorts. Candidate genes from rare CNVs found in both cohorts were identified based on their association with cardiac development or disease, and/or their reported disruption in published studies. Functional and pathway analyses revealed significant enrichment of terms involved in either heart or early embryonic development.Our study tested one of the largest cohorts specifically with cardiac conotruncal and related defects. These results confirm and extend previous findings that CNVs contribute to disease risk for congenital heart defects in general and conotruncal defects in particular. As disease heterogeneity renders identification of single recurrent genes or loci difficult, functional pathway and gene regulation network analyses appear to be more informative. Birth Defects Research 109:271-295, 2017. © 2017 Wiley Periodicals, Inc.

Published
2017

27. Somatic HLA mutations expose the role of class I–mediated autoimmunity in aplastic anemia and its clonal complications

Author

Babushok, Daria V., primary, Duke, Jamie L., additional, Xie, Hongbo M., additional, Stanley, Natasha, additional, Atienza, Jamie, additional, Perdigones, Nieves, additional, Nicholas, Peter, additional, Ferriola, Deborah, additional, Li, Yimei, additional, Huang, Hugh, additional, Ye, Wenda, additional, Morrissette, Jennifer J. D., additional, Kearns, Jane, additional, Porter, David L., additional, Podsakoff, Gregory M., additional, Eisenlohr, Laurence C., additional, Biegel, Jaclyn A., additional, Chou, Stella T., additional, Monos, Dimitrios S., additional, Bessler, Monica, additional, and Olson, Timothy S., additional

Published
2017
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28. Copy-number variation is an important contributor to the genetic causality of inherited retinal degenerations

Author

Bujakowska, Kinga M., primary, Fernandez-Godino, Rosario, additional, Place, Emily, additional, Consugar, Mark, additional, Navarro-Gomez, Daniel, additional, White, Joseph, additional, Bedoukian, Emma C., additional, Zhu, Xiaosong, additional, Xie, Hongbo M., additional, Gai, Xiaowu, additional, Leroy, Bart P., additional, and Pierce, Eric A., additional

Published
2017
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30. Somatic Loss of HLA Class I Alleles Is a Common Genetic Alteration in Acquired Aplastic Anemia and Reveals Aplastic Anemia Risk Alleles

Author

Babushok, Daria V., primary, Duke, Jamie, additional, Xie, Hongbo M., additional, Ferriola, Deborah, additional, Stanley, Natasha, additional, Atienza, Jamie, additional, Huang, Hugh, additional, Biegel, Jaclyn A, additional, Bessler, Monica, additional, Monos, Dimitri S., additional, and Olson, Timothy S., additional

Published
2016
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33. Abstract 2977: Most patients with acquired aplastic anemia develop clonal hematopoiesis early in disease

Author

Babushok, Daria V., primary, Perdigones, Nieves, additional, Perin, Juan C., additional, Olson, Timothy S., additional, Ye, Wenda, additional, Roth, Jacquelyn J., additional, Lind, Curt, additional, Cattier, Carine, additional, Li, Yimei, additional, Hartung, Helge, additional, Paessler, Michele E., additional, Frank, Dale M., additional, Xie, Hongbo M., additional, Busse, Tracy M., additional, Cross, Shanna, additional, Podsakoff, Gregory M., additional, Monos, Dimitrios, additional, Biegel, Jaclyn A., additional, Mason, Philip J., additional, and Bessler, Monica, additional

Published
2015
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35. Mitochondrial genome sequence analysis: a custom bioinformatics pipeline substantially improves Affymetrix MitoChip v2.0 call rate and accuracy.

Author

Xie, Hongbo M, Perin, Juan C, Schurr, Theodore G, Dulik, Matthew C, Zhadanov, Sergey I, Baur, Joseph A, King, Michael P, Place, Emily, Clarke, Colleen, Grauer, Michael, Schug, Jonathan, Santani, Avni, Albano, Anthony, Kim, Cecilia, Procaccio, Vincent, Hakonarson, Hakon, Gai, Xiaowu, Falk, Marni J, Xie, Hongbo M, Perin, Juan C, Schurr, Theodore G, Dulik, Matthew C, Zhadanov, Sergey I, Baur, Joseph A, King, Michael P, Place, Emily, Clarke, Colleen, Grauer, Michael, Schug, Jonathan, Santani, Avni, Albano, Anthony, Kim, Cecilia, Procaccio, Vincent, Hakonarson, Hakon, Gai, Xiaowu, and Falk, Marni J

Abstract

BACKGROUND: Mitochondrial genome sequence analysis is critical to the diagnostic evaluation of mitochondrial disease. Existing methodologies differ widely in throughput, complexity, cost efficiency, and sensitivity of heteroplasmy detection. Affymetrix MitoChip v2.0, which uses a sequencing-by-genotyping technology, allows potentially accurate and high-throughput sequencing of the entire human mitochondrial genome to be completed in a cost-effective fashion. However, the relatively low call rate achieved using existing software tools has limited the wide adoption of this platform for either clinical or research applications. Here, we report the design and development of a custom bioinformatics software pipeline that achieves a much improved call rate and accuracy for the Affymetrix MitoChip v2.0 platform. We used this custom pipeline to analyze MitoChip v2.0 data from 24 DNA samples representing a broad range of tissue types (18 whole blood, 3 skeletal muscle, 3 cell lines), mutations (a 5.8 kilobase pair deletion and 6 known heteroplasmic mutations), and haplogroup origins. All results were compared to those obtained by at least one other mitochondrial DNA sequence analysis method, including Sanger sequencing, denaturing HPLC-based heteroduplex analysis, and/or the Illumina Genome Analyzer II next generation sequencing platform. RESULTS: An average call rate of 99.75% was achieved across all samples with our custom pipeline. Comparison of calls for 15 samples characterized previously by Sanger sequencing revealed a total of 29 discordant calls, which translates to an estimated 0.012% for the base call error rate. We successfully identified 4 known heteroplasmic mutations and 24 other potential heteroplasmic mutations across 20 samples that passed quality control. CONCLUSIONS: Affymetrix MitoChip v2.0 analysis using our optimized MitoChip Filtering Protocol (MFP) bioinformatics pipeline now offers the high sensitivity and accuracy needed for reliable, high-throughpu

Published
2011

36. Single Nucleotide Polymorphism Array Analysis Of Bone Marrow Failure Patients Reveals Characteristic Patterns Of Genetic Changes

Author

Babushok, Daria V., primary, Xie, Hongbo M., additional, Roth, Jacquelyn J., additional, Perdigones, Nieves, additional, Olson, Timothy S., additional, Cockroft, Joshua D., additional, Gai, Xiaowu, additional, Perin, Juan C., additional, Li, Yimei, additional, Paessler, Michele E., additional, Hakonarson, Hakon, additional, Podsakoff, Gregory M., additional, Mason, Philip J., additional, Biegel, Jaclyn A., additional, and Bessler, Monica, additional

Published
2013
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40. CNV Workshop: an integrated platform for high-throughput copy number variation discovery and clinical diagnostics.

Author

Xiaowu Gai, Perin, Juan C., Murphy, Kevin, O'Hara, Ryan, D'arcy, Monica, Wenocur, Adam, Xie, Hongbo M., Rappaport, Eric F., Shaikh, Tamim H., and White, Peter S.

Subjects
GENOMES, GENETICS, PATHOGENICITY of enteroviruses, ALGORITHMS, GENETIC mutation
Abstract

Background: Recent studies have shown that copy number variations (CNVs) are frequent in higher eukaryotes and associated with a substantial portion of inherited and acquired risk for various human diseases. The increasing availability of high-resolution genome surveillance platforms provides opportunity for rapidly assessing research and clinical samples for CNV content, as well as for determining the potential pathogenicity of identified variants. However, few informatics tools for accurate and efficient CNV detection and assessment currently exist. Results: We developed a suite of software tools and resources (CNV Workshop) for automated, genome-wide CNV detection from a variety of SNP array platforms. CNV Workshop includes three major components: detection, annotation, and presentation of structural variants from genome array data. CNV detection utilizes a robust and genotype-specific extension of the Circular Binary Segmentation algorithm, and the use of additional detection algorithms is supported. Predicted CNVs are captured in a MySQL database that supports cohort-based projects and incorporates a secure user authentication layer and user/admin roles. To assist with determination of pathogenicity, detected CNVs are also annotated automatically for gene content, known disease loci, and genebased literature references. Results are easily queried, sorted, filtered, and visualized via a web-based presentation layer that includes a GBrowse-based graphical representation of CNV content and relevant public data, integration with the UCSC Genome Browser, and tabular displays of genomic attributes for each CNV. Conclusions: To our knowledge, CNV Workshop represents the first cohesive and convenient platform for detection, annotation, and assessment of the biological and clinical significance of structural variants. CNV Workshop has been successfully utilized for assessment of genomic variation in healthy individuals and disease cohorts and is an ideal platform for coordinating multiple associated projects. [ABSTRACT FROM AUTHOR]

Published
2010
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