35 results on '"Rodriguez OL"'
Search Results
2. Digital core repository coupled with machine learning as a tool to classify and assess petrophysical rock properties
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Hébert Vanessa, Porcher Thierry, Planes Valentin, Léger Marie, Alperovich Anna, Goldluecke Bastian, Rodriguez Olivier, and Youssef Souhail
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Environmental sciences ,GE1-350 - Abstract
To make efficient use of image-based rock physics workflow, it is necessary to optimize different criteria, among which: quantity, representativeness, size and resolution. Advances in artificial intelligence give insights of databases potential. Deep learning methods not only enable to classify rock images, but could also help to estimate their petrophysical properties. In this study we prepare a set of thousands high-resolution 3D images captured in a set of four reservoir rock samples as a base for learning and training. The Voxilon software computes numerical petrophysical analysis. We identify different descriptors directly from 3D images used as inputs. We use convolutional neural network modelling with supervised training using TensorFlow framework. Using approximately fifteen thousand 2D images to drive the classification network, the test on thousand unseen images shows any error of rock type misclassification. The porosity trend provides good fit between digital benchmark datasets and machine learning tests. In a few minutes, database screening classifies carbonates and sandstones images and associates the porosity values and distribution. This work aims at conveying the potential of deep learning method in reservoir characterization to petroleum research, to illustrate how a smart image-based rock physics database at industrial scale can swiftly give access to rock properties.
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- 2020
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3. Inducción de organogénesis indirecta en Abarco(Cariniana pyriformis Miers.)
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Yaya Mary Luz, Rodríguez Olga Lucía, Usaquén William, and Chaparro Alejandro
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Plant ecology ,QK900-989 - Abstract
Se indujeron procesos primarios de morfogénesis de novo vía organogénesis indirecta en segmentos de hipocótilo de abarco, provenientes de plántulas in vitro de dos semanas de edad. El material fuente se obtuvo por germinación de embriones en Woody Plant Médium (WPM) diluido a la mitad y sin reguladores de crecimiento. La formación de callo organogénico se estimuló mediante la adición de ácido indolacético (AIA) conjuntamente con 6-bencilaminopurina (BAP). Después de cuatro semanas el mayor porcentaje de formación de callo (75%) se observó con la combinación AIA 1,21 μM y BAP 7,6 μM.
- Published
- 2005
4. Addressing Technical Pitfalls in Pursuit of Molecular Factors That Mediate Immunoglobulin Gene Regulation.
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Engelbrecht E, Rodriguez OL, and Watson CT
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- Humans, Immunoglobulin Heavy Chains genetics, Haplotypes, V(D)J Recombination genetics, Genes, Immunoglobulin, Gene Expression Regulation
- Abstract
The expressed Ab repertoire is a critical determinant of immune-related phenotypes. Ab-encoding transcripts are distinct from other expressed genes because they are transcribed from somatically rearranged gene segments. Human Abs are composed of two identical H and L chain polypeptides derived from genes in IGH locus and one of two L chain loci. The combinatorial diversity that results from Ab gene rearrangement and the pairing of different H and L chains contributes to the immense diversity of the baseline Ab repertoire. During rearrangement, Ab gene selection is mediated by factors that influence chromatin architecture, promoter/enhancer activity, and V(D)J recombination. Interindividual variation in the composition of the Ab repertoire associates with germline variation in IGH, implicating polymorphism in Ab gene regulation. Determining how IGH variants directly mediate gene regulation will require integration of these variants with other functional genomic datasets. In this study, we argue that standard approaches using short reads have limited utility for characterizing regulatory regions in IGH at haplotype resolution. Using simulated and chromatin immunoprecipitation sequencing reads, we define features of IGH that limit use of short reads and a single reference genome, namely 1) the highly duplicated nature of the DNA sequence in IGH and 2) structural polymorphisms that are frequent in the population. We demonstrate that personalized diploid references enhance performance of short-read data for characterizing mappable portions of the locus, while also showing that long-read profiling tools will ultimately be needed to fully resolve functional impacts of IGH germline variation on expressed Ab repertoires., (Copyright © 2024 by The American Association of Immunologists, Inc.)
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- 2024
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5. Resolving haplotype variation and complex genetic architecture in the human immunoglobulin kappa chain locus in individuals of diverse ancestry.
- Author
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Engelbrecht E, Rodriguez OL, Shields K, Schultze S, Tieri D, Jana U, Yaari G, Lees WD, Smith ML, and Watson CT
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- Humans, Gene Frequency, Alleles, Haplotypes, Immunoglobulin kappa-Chains genetics, Polymorphism, Single Nucleotide
- Abstract
Immunoglobulins (IGs), critical components of the human immune system, are composed of heavy and light protein chains encoded at three genomic loci. The IG Kappa (IGK) chain locus consists of two large, inverted segmental duplications. The complexity of the IG loci has hindered use of standard high-throughput methods for characterizing genetic variation within these regions. To overcome these limitations, we use long-read sequencing to create haplotype-resolved IGK assemblies in an ancestrally diverse cohort (n = 36), representing the first comprehensive description of IGK haplotype variation. We identify extensive locus polymorphism, including novel single nucleotide variants (SNVs) and novel structural variants harboring functional IGKV genes. Among 47 functional IGKV genes, we identify 145 alleles, 67 of which were not previously curated. We report inter-population differences in allele frequencies for 10 IGKV genes, including alleles unique to specific populations within this dataset. We identify haplotypes carrying signatures of gene conversion that associate with SNV enrichment in the IGK distal region, and a haplotype with an inversion spanning the proximal and distal regions. These data provide a critical resource of curated genomic reference information from diverse ancestries, laying a foundation for advancing our understanding of population-level genetic variation in the IGK locus., (© 2024. The Author(s).)
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- 2024
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6. Author Correction: Vaccination induces broadly neutralizing antibody precursors to HIV gp41.
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Schiffner T, Phung I, Ray R, Irimia A, Tian M, Swanson O, Lee JH, Lee CD, Marina-Zárate E, Cho SY, Huang J, Ozorowski G, Skog PD, Serra AM, Rantalainen K, Allen JD, Baboo S, Rodriguez OL, Himansu S, Zhou J, Hurtado J, Flynn CT, McKenney K, Havenar-Daughton C, Saha S, Shields K, Schultze S, Smith ML, Liang CH, Toy L, Pecetta S, Lin YC, Willis JR, Sesterhenn F, Kulp DW, Hu X, Cottrell CA, Zhou X, Ruiz J, Wang X, Nair U, Kirsch KH, Cheng HL, Davis J, Kalyuzhniy O, Liguori A, Diedrich JK, Ngo JT, Lewis V, Phelps N, Tingle RD, Spencer S, Georgeson E, Adachi Y, Kubitz M, Eskandarzadeh S, Elsliger MA, Amara RR, Landais E, Briney B, Burton DR, Carnathan DG, Silvestri G, Watson CT, Yates JR 3rd, Paulson JC, Crispin M, Grigoryan G, Ward AB, Sok D, Alt FW, Wilson IA, Batista FD, Crotty S, and Schief WR
- Published
- 2024
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7. Vaccination induces broadly neutralizing antibody precursors to HIV gp41.
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Schiffner T, Phung I, Ray R, Irimia A, Tian M, Swanson O, Lee JH, Lee CD, Marina-Zárate E, Cho SY, Huang J, Ozorowski G, Skog PD, Serra AM, Rantalainen K, Allen JD, Baboo S, Rodriguez OL, Himansu S, Zhou J, Hurtado J, Flynn CT, McKenney K, Havenar-Daughton C, Saha S, Shields K, Schultze S, Smith ML, Liang CH, Toy L, Pecetta S, Lin YC, Willis JR, Sesterhenn F, Kulp DW, Hu X, Cottrell CA, Zhou X, Ruiz J, Wang X, Nair U, Kirsch KH, Cheng HL, Davis J, Kalyuzhniy O, Liguori A, Diedrich JK, Ngo JT, Lewis V, Phelps N, Tingle RD, Spencer S, Georgeson E, Adachi Y, Kubitz M, Eskandarzadeh S, Elsliger MA, Amara RR, Landais E, Briney B, Burton DR, Carnathan DG, Silvestri G, Watson CT, Yates JR 3rd, Paulson JC, Crispin M, Grigoryan G, Ward AB, Sok D, Alt FW, Wilson IA, Batista FD, Crotty S, and Schief WR
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- Animals, Humans, Mice, Vaccination, Broadly Neutralizing Antibodies immunology, B-Lymphocytes immunology, Nanoparticles chemistry, Female, Complementarity Determining Regions immunology, Epitopes immunology, HIV Envelope Protein gp41 immunology, HIV Antibodies immunology, AIDS Vaccines immunology, Macaca mulatta, Antibodies, Neutralizing immunology, HIV-1 immunology, HIV Infections immunology, HIV Infections prevention & control, HIV Infections virology
- Abstract
A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display. Scaffolds exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens, protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. Thus, germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features., (© 2024. The Author(s).)
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- 2024
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8. Vaccine priming of rare HIV broadly neutralizing antibody precursors in nonhuman primates.
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Steichen JM, Phung I, Salcedo E, Ozorowski G, Willis JR, Baboo S, Liguori A, Cottrell CA, Torres JL, Madden PJ, Ma KM, Sutton HJ, Lee JH, Kalyuzhniy O, Allen JD, Rodriguez OL, Adachi Y, Mullen TM, Georgeson E, Kubitz M, Burns A, Barman S, Mopuri R, Metz A, Altheide TK, Diedrich JK, Saha S, Shields K, Schultze SE, Smith ML, Schiffner T, Burton DR, Watson CT, Bosinger SE, Crispin M, Yates JR 3rd, Paulson JC, Ward AB, Sok D, Crotty S, and Schief WR
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- Animals, Humans, B-Lymphocytes immunology, Cryoelectron Microscopy, env Gene Products, Human Immunodeficiency Virus immunology, HIV Infections immunology, HIV Infections prevention & control, HIV-1 immunology, Immunoglobulin Heavy Chains immunology, Immunoglobulin Heavy Chains genetics, Macaca mulatta, Memory B Cells immunology, AIDS Vaccines immunology, Broadly Neutralizing Antibodies immunology, Complementarity Determining Regions immunology, Germinal Center immunology, HIV Antibodies immunology
- Abstract
Germline-targeting immunogens hold promise for initiating the induction of broadly neutralizing antibodies (bnAbs) to HIV and other pathogens. However, antibody-antigen recognition is typically dominated by heavy chain complementarity determining region 3 (HCDR3) interactions, and vaccine priming of HCDR3-dominant bnAbs by germline-targeting immunogens has not been demonstrated in humans or outbred animals. In this work, immunization with N332-GT5, an HIV envelope trimer designed to target precursors of the HCDR3-dominant bnAb BG18, primed bnAb-precursor B cells in eight of eight rhesus macaques to substantial frequencies and with diverse lineages in germinal center and memory B cells. We confirmed bnAb-mimicking, HCDR3-dominant, trimer-binding interactions with cryo-electron microscopy. Our results demonstrate proof of principle for HCDR3-dominant bnAb-precursor priming in outbred animals and suggest that N332-GT5 holds promise for the induction of similar responses in humans.
- Published
- 2024
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9. AIRR-C IG Reference Sets: curated sets of immunoglobulin heavy and light chain germline genes.
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Collins AM, Ohlin M, Corcoran M, Heather JM, Ralph D, Law M, Martínez-Barnetche J, Ye J, Richardson E, Gibson WS, Rodriguez OL, Peres A, Yaari G, Watson CT, and Lees WD
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- Humans, Alleles, V(D)J Recombination genetics, Germ Cells, Immunoglobulins genetics, Genes, Immunoglobulin
- Abstract
Introduction: Analysis of an individual's immunoglobulin (IG) gene repertoire requires the use of high-quality germline gene reference sets. When sets only contain alleles supported by strong evidence, AIRR sequencing (AIRR-seq) data analysis is more accurate and studies of the evolution of IG genes, their allelic variants and the expressed immune repertoire is therefore facilitated., Methods: The Adaptive Immune Receptor Repertoire Community (AIRR-C) IG Reference Sets have been developed by including only human IG heavy and light chain alleles that have been confirmed by evidence from multiple high-quality sources. To further improve AIRR-seq analysis, some alleles have been extended to deal with short 3' or 5' truncations that can lead them to be overlooked by alignment utilities. To avoid other challenges for analysis programs, exact paralogs (e.g. IGHV1-69*01 and IGHV1-69D*01) are only represented once in each set, though alternative sequence names are noted in accompanying metadata., Results and Discussion: The Reference Sets include less than half the previously recognised IG alleles (e.g. just 198 IGHV sequences), and also include a number of novel alleles: 8 IGHV alleles, 2 IGKV alleles and 5 IGLV alleles. Despite their smaller sizes, erroneous calls were eliminated, and excellent coverage was achieved when a set of repertoires comprising over 4 million V(D)J rearrangements from 99 individuals were analyzed using the Sets. The version-tracked AIRR-C IG Reference Sets are freely available at the OGRDB website (https://ogrdb.airr-community.org/germline_sets/Human) and will be regularly updated to include newly observed and previously reported sequences that can be confirmed by new high-quality data., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Collins, Ohlin, Corcoran, Heather, Ralph, Law, Martínez-Barnetche, Ye, Richardson, Gibson, Rodriguez, Peres, Yaari, Watson and Lees.)
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- 2024
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10. Looking to the future of antibody genetics: resolving the roles of immunoglobulin diversity in gene regulation, function, and immunity.
- Author
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Watson CT, Rodriguez OL, Engelbrecht E, Safonova Y, Marasco WA, and Smith ML
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- Genes, Immunoglobulin, Antibodies, Antibody Diversity
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- 2024
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11. Ultrasensitive allele inference from immune repertoire sequencing data with MiXCR.
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Mikelov A, Nefediev G, Tashkeev A, Rodriguez OL, Ortmans DA, Skatova V, Izraelson M, Davydov A, Poslavsky S, Rahmouni S, Watson CT, Chudakov D, Boyd SD, and Bolotin D
- Abstract
Allelic variability in the adaptive immune receptor loci, which harbor the gene segments that encode B cell and T cell receptors (BCR/TCR), has been shown to be of critical importance for immune responses to pathogens and vaccines. In recent years, B cell and T cell receptor repertoire sequencing (Rep-Seq) has become widespread in immunology research making it the most readily available source of information about allelic diversity in immunoglobulin (IG) and T cell receptor (TR) loci in different populations. Here we present a novel algorithm for extra-sensitive and specific variable (V) and joining (J) gene allele inference and genotyping allowing reconstruction of individual high-quality gene segment libraries. The approach can be applied for inferring allelic variants from peripheral blood lymphocyte BCR and TCR repertoire sequencing data, including hypermutated isotype-switched BCR sequences, thus allowing high-throughput genotyping and novel allele discovery from a wide variety of existing datasets. The developed algorithm is a part of the MiXCR software ( https://mixcr.com ) and can be incorporated into any pipeline utilizing upstream processing with MiXCR. We demonstrate the accuracy of this approach using Rep-Seq paired with long-read genomic sequencing data, comparing it to a widely used algorithm, TIgGER. We applied the algorithm to a large set of IG heavy chain (IGH) Rep-Seq data from 450 donors of ancestrally diverse population groups, and to the largest reported full-length TCR alpha and beta chain (TRA; TRB) Rep-Seq dataset, representing 134 individuals. This allowed us to assess the genetic diversity of genes within the IGH, TRA and TRB loci in different populations and demonstrate the connection between antibody repertoire gene usage and the number of allelic variants present in the population. Finally we established a database of allelic variants of V and J genes inferred from Rep-Seq data and their population frequencies with free public access at https://vdj.online .
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- 2023
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12. IGHV allele similarity clustering improves genotype inference from adaptive immune receptor repertoire sequencing data.
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Peres A, Lees WD, Rodriguez OL, Lee NY, Polak P, Hope R, Kedmi M, Collins AM, Ohlin M, Kleinstein SH, Watson CT, and Yaari G
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- Alleles, Genotype, Genomics, Receptors, Antigen, B-Cell genetics, Immunoglobulin Heavy Chains genetics
- Abstract
In adaptive immune receptor repertoire analysis, determining the germline variable (V) allele associated with each T- and B-cell receptor sequence is a crucial step. This process is highly impacted by allele annotations. Aligning sequences, assigning them to specific germline alleles, and inferring individual genotypes are challenging when the repertoire is highly mutated, or sequence reads do not cover the whole V region. Here, we propose an alternative naming scheme for the V alleles, as well as a novel method to infer individual genotypes. We demonstrate the strengths of the two by comparing their outcomes to other genotype inference methods. We validate the genotype approach with independent genomic long-read data. The naming scheme is compatible with current annotation tools and pipelines. Analysis results can be converted from the proposed naming scheme to the nomenclature determined by the International Union of Immunological Societies (IUIS). Both the naming scheme and the genotype procedure are implemented in a freely available R package (PIgLET https://bitbucket.org/yaarilab/piglet). To allow researchers to further explore the approach on real data and to adapt it for their uses, we also created an interactive website (https://yaarilab.github.io/IGHV_reference_book)., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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- 2023
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13. Genetic variation in the immunoglobulin heavy chain locus shapes the human antibody repertoire.
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Rodriguez OL, Safonova Y, Silver CA, Shields K, Gibson WS, Kos JT, Tieri D, Ke H, Jackson KJL, Boyd SD, Smith ML, Marasco WA, and Watson CT
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- Humans, Alleles, Germ-Line Mutation, Immunoglobulin Heavy Chains genetics, Genes, Immunoglobulin Heavy Chain genetics, Genes, Immunoglobulin
- Abstract
Variation in the antibody response has been linked to differential outcomes in disease, and suboptimal vaccine and therapeutic responsiveness, the determinants of which have not been fully elucidated. Countering models that presume antibodies are generated largely by stochastic processes, we demonstrate that polymorphisms within the immunoglobulin heavy chain locus (IGH) impact the naive and antigen-experienced antibody repertoire, indicating that genetics predisposes individuals to mount qualitatively and quantitatively different antibody responses. We pair recently developed long-read genomic sequencing methods with antibody repertoire profiling to comprehensively resolve IGH genetic variation, including novel structural variants, single nucleotide variants, and genes and alleles. We show that IGH germline variants determine the presence and frequency of antibody genes in the expressed repertoire, including those enriched in functional elements linked to V(D)J recombination, and overlapping disease-associated variants. These results illuminate the power of leveraging IGH genetics to better understand the regulation, function, and dynamics of the antibody response in disease., (© 2023. The Author(s).)
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- 2023
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14. FLAIRR-Seq: A Method for Single-Molecule Resolution of Near Full-Length Antibody H Chain Repertoires.
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Ford EE, Tieri D, Rodriguez OL, Francoeur NJ, Soto J, Kos JT, Peres A, Gibson WS, Silver CA, Deikus G, Hudson E, Woolley CR, Beckmann N, Charney A, Mitchell TC, Yaari G, Sebra RP, Watson CT, and Smith ML
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- Humans, Base Sequence, Complementarity Determining Regions genetics
- Abstract
Current Adaptive Immune Receptor Repertoire sequencing (AIRR-seq) using short-read sequencing strategies resolve expressed Ab transcripts with limited resolution of the C region. In this article, we present the near-full-length AIRR-seq (FLAIRR-seq) method that uses targeted amplification by 5' RACE, combined with single-molecule, real-time sequencing to generate highly accurate (99.99%) human Ab H chain transcripts. FLAIRR-seq was benchmarked by comparing H chain V (IGHV), D (IGHD), and J (IGHJ) gene usage, complementarity-determining region 3 length, and somatic hypermutation to matched datasets generated with standard 5' RACE AIRR-seq using short-read sequencing and full-length isoform sequencing. Together, these data demonstrate robust FLAIRR-seq performance using RNA samples derived from PBMCs, purified B cells, and whole blood, which recapitulated results generated by commonly used methods, while additionally resolving H chain gene features not documented in IMGT at the time of submission. FLAIRR-seq data provide, for the first time, to our knowledge, simultaneous single-molecule characterization of IGHV, IGHD, IGHJ, and IGHC region genes and alleles, allele-resolved subisotype definition, and high-resolution identification of class switch recombination within a clonal lineage. In conjunction with genomic sequencing and genotyping of IGHC genes, FLAIRR-seq of the IgM and IgG repertoires from 10 individuals resulted in the identification of 32 unique IGHC alleles, 28 (87%) of which were previously uncharacterized. Together, these data demonstrate the capabilities of FLAIRR-seq to characterize IGHV, IGHD, IGHJ, and IGHC gene diversity for the most comprehensive view of bulk-expressed Ab repertoires to date., (Copyright © 2023 by The American Association of Immunologists, Inc.)
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- 2023
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15. Characterization of the immunoglobulin lambda chain locus from diverse populations reveals extensive genetic variation.
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Gibson WS, Rodriguez OL, Shields K, Silver CA, Dorgham A, Emery M, Deikus G, Sebra R, Eichler EE, Bashir A, Smith ML, and Watson CT
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- Humans, Genomics, Genetic Variation, Nucleotides, Immunoglobulin lambda-Chains genetics, Genes, Immunoglobulin
- Abstract
Immunoglobulins (IGs), crucial components of the adaptive immune system, are encoded by three genomic loci. However, the complexity of the IG loci severely limits the effective use of short read sequencing, limiting our knowledge of population diversity in these loci. We leveraged existing long read whole-genome sequencing (WGS) data, fosmid technology, and IG targeted single-molecule, real-time (SMRT) long-read sequencing (IG-Cap) to create haplotype-resolved assemblies of the IG Lambda (IGL) locus from 6 ethnically diverse individuals. In addition, we generated 10 diploid assemblies of IGL from a diverse cohort of individuals utilizing IG-Cap. From these 16 individuals, we identified significant allelic diversity, including 36 novel IGLV alleles. In addition, we observed highly elevated single nucleotide variation (SNV) in IGLV genes relative to IGL intergenic and genomic background SNV density. By comparing SNV calls between our high quality assemblies and existing short read datasets from the same individuals, we show a high propensity for false-positives in the short read datasets. Finally, for the first time, we nucleotide-resolved common 5-10 Kb duplications in the IGLC region that contain functional IGLJ and IGLC genes. Together these data represent a significant advancement in our understanding of genetic variation and population diversity in the IGL locus., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2023
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16. The evolutionary and functional significance of germline immunoglobulin gene variation.
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Pennell M, Rodriguez OL, Watson CT, and Greiff V
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- Animals, Humans, Immunity, Humoral genetics, Biological Evolution, Germ Cells, Mammals, Genes, Immunoglobulin genetics, Germ-Line Mutation
- Abstract
The recombination between immunoglobulin (IG) gene segments determines an individual's naïve antibody repertoire and, consequently, (auto)antigen recognition. Emerging evidence suggests that mammalian IG germline variation impacts humoral immune responses associated with vaccination, infection, and autoimmunity - from the molecular level of epitope specificity, up to profound changes in the architecture of antibody repertoires. These links between IG germline variants and immunophenotype raise the question on the evolutionary causes and consequences of diversity within IG loci. We discuss why the extreme diversity in IG loci remains a mystery, why resolving this is important for the design of more effective vaccines and therapeutics, and how recent evidence from multiple lines of inquiry may help us do so., Competing Interests: Declaration of interests V.G. declares advisory board positions in aiNET GmbH, Enpicom B.V, Specifica Inc, Adaptyv Biosystems, EVQLV, Omniscope, Diagonal Therapeutics, and Absci. V.G. is a consultant for Roche/Genentech, immunai, and Proteinea., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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17. Targeted long-read sequencing facilitates phased diploid assembly and genotyping of the human T cell receptor alpha, delta, and beta loci.
- Author
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Rodriguez OL, Silver CA, Shields K, Smith ML, and Watson CT
- Abstract
T cell receptors (TCRs) recognize peptide fragments presented by the major histocompatibility complex (MHC) and are critical to T cell-mediated immunity. Recent data have indicated that genetic diversity within TCR-encoding gene regions is underexplored, limiting understanding of the impact of TCR loci polymorphisms on TCR function in disease, even though TCR repertoire signatures (1) are heritable and (2) associate with disease phenotypes. To address this, we developed a targeted long-read sequencing approach to generate highly accurate haplotype resolved assemblies of the TCR beta (TRB) and alpha/delta (TRA/D) loci, facilitating the genotyping of all variant types, including structural variants. We validate our approach using two mother-father-child trios and 5 unrelated donors representing multiple populations. This resulted in improved genotyping accuracy and the discovery of 84 undocumented V, D, J, and C alleles, demonstrating the utility of this framework for improving our understanding of TCR diversity and function in disease., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)
- Published
- 2022
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18. A phenome-wide association study identifies effects of copy-number variation of VNTRs and multicopy genes on multiple human traits.
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Garg P, Jadhav B, Lee W, Rodriguez OL, Martin-Trujillo A, and Sharp AJ
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- Genome, Human, Genome-Wide Association Study, Humans, Phenotype, DNA Copy Number Variations genetics, Minisatellite Repeats genetics
- Abstract
The human genome contains tens of thousands of large tandem repeats and hundreds of genes that show common and highly variable copy-number changes. Due to their large size and repetitive nature, these variable number tandem repeats (VNTRs) and multicopy genes are generally recalcitrant to standard genotyping approaches and, as a result, this class of variation is poorly characterized. However, several recent studies have demonstrated that copy-number variation of VNTRs can modify local gene expression, epigenetics, and human traits, indicating that many have a functional role. Here, using read depth from whole-genome sequencing to profile copy number, we report results of a phenome-wide association study (PheWAS) of VNTRs and multicopy genes in a discovery cohort of ∼35,000 samples, identifying 32 traits associated with copy number of 38 VNTRs and multicopy genes at 1% FDR. We replicated many of these signals in an independent cohort and observed that VNTRs showing trait associations were significantly enriched for expression QTLs with nearby genes, providing strong support for our results. Fine-mapping studies indicated that in the majority (∼90%) of cases, the VNTRs and multicopy genes we identified represent the causal variants underlying the observed associations. Furthermore, several lie in regions where prior SNV-based GWASs have failed to identify any significant associations with these traits. Our study indicates that copy number of VNTRs and multicopy genes contributes to diverse human traits and suggests that complex structural variants potentially explain some of the so-called "missing heritability" of SNV-based GWASs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
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- 2022
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19. T cell receptor beta germline variability is revealed by inference from repertoire data.
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Omer A, Peres A, Rodriguez OL, Watson CT, Lees W, Polak P, Collins AM, and Yaari G
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- Alleles, Germ Cells, Humans, Receptors, Antigen, T-Cell genetics, High-Throughput Nucleotide Sequencing methods, Receptors, Antigen, T-Cell, alpha-beta genetics
- Abstract
Background: T and B cell receptor (TCR, BCR) repertoires constitute the foundation of adaptive immunity. Adaptive immune receptor repertoire sequencing (AIRR-seq) is a common approach to study immune system dynamics. Understanding the genetic factors influencing the composition and dynamics of these repertoires is of major scientific and clinical importance. The chromosomal loci encoding for the variable regions of TCRs and BCRs are challenging to decipher due to repetitive elements and undocumented structural variants., Methods: To confront this challenge, AIRR-seq-based methods have recently been developed for B cells, enabling genotype and haplotype inference and discovery of undocumented alleles. However, this approach relies on complete coverage of the receptors' variable regions, whereas most T cell studies sequence a small fraction of that region. Here, we adapted a B cell pipeline for undocumented alleles, genotype, and haplotype inference for full and partial AIRR-seq TCR data sets. The pipeline also deals with gene assignment ambiguities, which is especially important in the analysis of data sets of partial sequences., Results: From the full and partial AIRR-seq TCR data sets, we identified 39 undocumented polymorphisms in T cell receptor Beta V (TRBV) and 31 undocumented 5
' UTR sequences. A subset of these inferences was also observed using independent genomic approaches. We found that a single nucleotide polymorphism differentiating between the two documented T cell receptor Beta D2 (TRBD2) alleles is strongly associated with dramatic changes in the expressed repertoire., Conclusions: We reveal a rich picture of germline variability and demonstrate how a single nucleotide polymorphism dramatically affects the composition of the whole repertoire. Our findings provide a basis for annotation of TCR repertoires for future basic and clinical studies., (© 2021. The Author(s).)- Published
- 2022
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20. Limitations of lymphoblastoid cell lines for establishing genetic reference datasets in the immunoglobulin loci.
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Rodriguez OL, Sharp AJ, and Watson CT
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- Alleles, B-Lymphocytes immunology, Cell Line, Tumor immunology, Cell Line, Tumor metabolism, Databases, Genetic, Gene Frequency genetics, Genes, Immunoglobulin genetics, High-Throughput Nucleotide Sequencing methods, Humans, Immunoglobulin Variable Region genetics, Immunoglobulins genetics, Immunoglobulins immunology, Sequence Analysis, DNA methods, V(D)J Recombination immunology, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, V(D)J Recombination genetics
- Abstract
Lymphoblastoid cell lines (LCLs) have been critical to establishing genetic resources for biomedical science. They have been used extensively to study human genetic diversity, genome function, and inform the development of tools and methodologies for augmenting disease genetics research. While the validity of variant callsets from LCLs has been demonstrated for most of the genome, previous work has shown that DNA extracted from LCLs is modified by V(D)J recombination within the immunoglobulin (IG) loci, regions that harbor antibody genes critical to immune system function. However, the impacts of V(D)J on short read sequencing data generated from LCLs has not been extensively investigated. In this study, we used LCL-derived short read sequencing data from the 1000 Genomes Project (n = 2,504) to identify signatures of V(D)J recombination. Our analyses revealed sample-level impacts of V(D)J recombination that varied depending on the degree of inferred monoclonality. We showed that V(D)J associated somatic deletions impacted genotyping accuracy, leading to adulterated population-level estimates of allele frequency and linkage disequilibrium. These findings illuminate limitations of using LCLs and short read data for building genetic resources in the IG loci, with implications for interpreting previous disease association studies in these regions., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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21. Diversity in immunogenomics: the value and the challenge.
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Peng K, Safonova Y, Shugay M, Popejoy AB, Rodriguez OL, Breden F, Brodin P, Burkhardt AM, Bustamante C, Cao-Lormeau VM, Corcoran MM, Duffy D, Fuentes-Guajardo M, Fujita R, Greiff V, Jönsson VD, Liu X, Quintana-Murci L, Rossetti M, Xie J, Yaari G, Zhang W, Abedalthagafi MS, Adekoya KO, Ahmed RA, Chang WC, Gray C, Nakamura Y, Lees WD, Khatri P, Alachkar H, Scheepers C, Watson CT, Karlsson Hedestam GB, and Mangul S
- Subjects
- B-Lymphocytes immunology, Databases, Genetic, Germ Cells, Humans, Receptors, Antigen, B-Cell genetics, Receptors, Antigen, B-Cell immunology, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell immunology, T-Lymphocytes immunology, Whole Genome Sequencing, Genomics, Immunogenetics
- Published
- 2021
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22. Pervasive cis effects of variation in copy number of large tandem repeats on local DNA methylation and gene expression.
- Author
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Garg P, Martin-Trujillo A, Rodriguez OL, Gies SJ, Hadelia E, Jadhav B, Jain M, Paten B, and Sharp AJ
- Subjects
- Adolescent, Adult, Algorithms, Child, Child, Preschool, Chromosomes, Human, X genetics, Cohort Studies, CpG Islands genetics, Enhancer Elements, Genetic genetics, Female, Genome-Wide Association Study, Genotype, Humans, Infant, Infant, Newborn, Male, Middle Aged, Phenotype, Promoter Regions, Genetic genetics, Young Adult, DNA Copy Number Variations genetics, DNA Methylation, Gene Expression Regulation, Minisatellite Repeats genetics, Quantitative Trait Loci genetics
- Abstract
Variable number tandem repeats (VNTRs) are composed of large tandemly repeated motifs, many of which are highly polymorphic in copy number. However, because of their large size and repetitive nature, they remain poorly studied. To investigate the regulatory potential of VNTRs, we used read-depth data from Illumina whole-genome sequencing to perform association analysis between copy number of ∼70,000 VNTRs (motif size ≥ 10 bp) with both gene expression (404 samples in 48 tissues) and DNA methylation (235 samples in peripheral blood), identifying thousands of VNTRs that are associated with local gene expression (eVNTRs) and DNA methylation levels (mVNTRs). Using an independent cohort, we validated 73%-80% of signals observed in the two discovery cohorts, while allelic analysis of VNTR length and CpG methylation in 30 Oxford Nanopore genomes gave additional support for mVNTR loci, thus providing robust evidence to support that these represent genuine associations. Further, conditional analysis indicated that many eVNTRs and mVNTRs act as QTLs independently of other local variation. We also observed strong enrichments of eVNTRs and mVNTRs for regulatory features such as enhancers and promoters. Using the Human Genome Diversity Panel, we define sets of VNTRs that show highly divergent copy numbers among human populations and show that these are enriched for regulatory effects and preferentially associate with genes that have been linked with human phenotypes through GWASs. Our study provides strong evidence supporting functional variation at thousands of VNTRs and defines candidate sets of VNTRs, copy number variation of which potentially plays a role in numerous human phenotypes., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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23. A robust benchmark for detection of germline large deletions and insertions.
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Zook JM, Hansen NF, Olson ND, Chapman L, Mullikin JC, Xiao C, Sherry S, Koren S, Phillippy AM, Boutros PC, Sahraeian SME, Huang V, Rouette A, Alexander N, Mason CE, Hajirasouliha I, Ricketts C, Lee J, Tearle R, Fiddes IT, Barrio AM, Wala J, Carroll A, Ghaffari N, Rodriguez OL, Bashir A, Jackman S, Farrell JJ, Wenger AM, Alkan C, Soylev A, Schatz MC, Garg S, Church G, Marschall T, Chen K, Fan X, English AC, Rosenfeld JA, Zhou W, Mills RE, Sage JM, Davis JR, Kaiser MD, Oliver JS, Catalano AP, Chaisson MJP, Spies N, Sedlazeck FJ, and Salit M
- Subjects
- Diploidy, Genomic Structural Variation, Humans, Molecular Sequence Annotation, Sequence Analysis, DNA, Germ-Line Mutation genetics, INDEL Mutation genetics
- 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
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24. Author Correction: A robust benchmark for detection of germline large deletions and insertions.
- Author
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Zook JM, Hansen NF, Olson ND, Chapman L, Mullikin JC, Xiao C, Sherry S, Koren S, Phillippy AM, Boutros PC, Sahraeian SME, Huang V, Rouette A, Alexander N, Mason CE, Hajirasouliha I, Ricketts C, Lee J, Tearle R, Fiddes IT, Barrio AM, Wala J, Carroll A, Ghaffari N, Rodriguez OL, Bashir A, Jackman S, Farrell JJ, Wenger AM, Alkan C, Soylev A, Schatz MC, Garg S, Church G, Marschall T, Chen K, Fan X, English AC, Rosenfeld JA, Zhou W, Mills RE, Sage JM, Davis JR, Kaiser MD, Oliver JS, Catalano AP, Chaisson MJP, Spies N, Sedlazeck FJ, and Salit M
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
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25. A Survey of Rare Epigenetic Variation in 23,116 Human Genomes Identifies Disease-Relevant Epivariations and CGG Expansions.
- Author
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Garg P, Jadhav B, Rodriguez OL, Patel N, Martin-Trujillo A, Jain M, Metsu S, Olsen H, Paten B, Ritz B, Kooy RF, Gecz J, and Sharp AJ
- Subjects
- BRCA1 Protein metabolism, DNA Methylation, Female, Folic Acid metabolism, Gene Silencing, Genetic Diseases, Inborn diagnosis, Genetic Diseases, Inborn pathology, Genetic Loci, Genetic Variation, High-Throughput Nucleotide Sequencing, Humans, Male, Promoter Regions, Genetic, Receptors, LDL metabolism, Twins, Monozygotic, BRCA1 Protein genetics, Epigenesis, Genetic, Genetic Diseases, Inborn genetics, Genome, Human, Receptors, LDL genetics, Trinucleotide Repeat Expansion
- Abstract
There is growing recognition that epivariations, most often recognized as promoter hypermethylation events that lead to gene silencing, are associated with a number of human diseases. However, little information exists on the prevalence and distribution of rare epigenetic variation in the human population. In order to address this, we performed a survey of methylation profiles from 23,116 individuals using the Illumina 450k array. Using a robust outlier approach, we identified 4,452 unique autosomal epivariations, including potentially inactivating promoter methylation events at 384 genes linked to human disease. For example, we observed promoter hypermethylation of BRCA1 and LDLR at population frequencies of ∼1 in 3,000 and ∼1 in 6,000, respectively, suggesting that epivariations may underlie a fraction of human disease which would be missed by purely sequence-based approaches. Using expression data, we confirmed that many epivariations are associated with outlier gene expression. Analysis of variation data and monozygous twin pairs suggests that approximately two-thirds of epivariations segregate in the population secondary to underlying sequence mutations, while one-third are likely sporadic events that occur post-zygotically. We identified 25 loci where rare hypermethylation coincided with the presence of an unstable CGG tandem repeat, validated the presence of CGG expansions at several loci, and identified the putative molecular defect underlying most of the known folate-sensitive fragile sites in the genome. Our study provides a catalog of rare epigenetic changes in the human genome, gives insight into the underlying origins and consequences of epivariations, and identifies many hypermethylated CGG repeat expansions., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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26. A Novel Framework for Characterizing Genomic Haplotype Diversity in the Human Immunoglobulin Heavy Chain Locus.
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Rodriguez OL, Gibson WS, Parks T, Emery M, Powell J, Strahl M, Deikus G, Auckland K, Eichler EE, Marasco WA, Sebra R, Sharp AJ, Smith ML, Bashir A, and Watson CT
- Subjects
- Cell Line, Data Display, Datasets as Topic, Family, Gene Library, Genomic Structural Variation, Humans, Molecular Sequence Annotation, Sequence Alignment, Sequence Analysis, DNA, Sequence Homology, Nucleic Acid, User-Computer Interface, Workflow, Computational Biology methods, Genes, Immunoglobulin, Genetic Variation, Genotyping Techniques, Haplotypes genetics, Immunoglobulin Heavy Chains genetics, Polymorphism, Genetic
- Abstract
An incomplete ascertainment of genetic variation within the highly polymorphic immunoglobulin heavy chain locus (IGH) has hindered our ability to define genetic factors that influence antibody-mediated processes. Due to locus complexity, standard high-throughput approaches have failed to accurately and comprehensively capture IGH polymorphism. As a result, the locus has only been fully characterized two times, severely limiting our knowledge of human IGH diversity. Here, we combine targeted long-read sequencing with a novel bioinformatics tool, IGenotyper, to fully characterize IGH variation in a haplotype-specific manner. We apply this approach to eight human samples, including a haploid cell line and two mother-father-child trios, and demonstrate the ability to generate high-quality assemblies (>98% complete and >99% accurate), genotypes, and gene annotations, identifying 2 novel structural variants and 15 novel IGH alleles. We show multiplexing allows for scaling of the approach without impacting data quality, and that our genotype call sets are more accurate than short-read (>35% increase in true positives and >97% decrease in false-positives) and array/imputation-based datasets. This framework establishes a desperately needed foundation for leveraging IG genomic data to study population-level variation in antibody-mediated immunity, critical for bettering our understanding of disease risk, and responses to vaccines and therapeutics., (Copyright © 2020 Rodriguez, Gibson, Parks, Emery, Powell, Strahl, Deikus, Auckland, Eichler, Marasco, Sebra, Sharp, Smith, Bashir and Watson.)
- Published
- 2020
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27. Elucidation of de novo small insertion/deletion biology with parent-of-origin phasing.
- Author
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Seiden AH, Richter F, Patel N, Rodriguez OL, Deikus G, Shah H, Smith M, Roberts A, King EC, Sebra RP, Sharp AJ, and Gelb BD
- Subjects
- High-Throughput Nucleotide Sequencing, Humans, Polymorphism, Single Nucleotide, Computational Biology methods, Genome, Human, Genomics methods, INDEL Mutation, Software
- Abstract
The mechanisms underlying de novo insertion/deletion (indel) genesis, such as polymerase slippage, have been hypothesized but not well characterized in the human genome. We implemented two methodological improvements, which were leveraged to dissect indel mutagenesis. We assigned de novo variants to parent-of-origin (i.e., phasing) with low-coverage long-read whole-genome sequencing, achieving better phasing compared to short-read sequencing (medians of 84% and 23%, respectively). We then wrote an application programming interface to classify indels into three subtypes according to sequence context. Across three cohorts with different phasing methods (N
trios = 540, all cohorts), we observed that one de novo indel subtype, change in copy count (CCC), was significantly correlated with father's (p = 7.1 × 10-4 ) but not mother's (p = .45) age at conception. We replicated this effect in three cohorts without de novo phasing (ppaternal = 1.9 × 10-9 , pmaternal = .61; Ntrios = 3,391, all cohorts). Although this is consistent with polymerase slippage during spermatogenesis, the percentage of variance explained by paternal age was low, and we did not observe an association with replication timing. These results suggest that spermatogenesis-specific events have a minor role in CCC indel mutagenesis, one not observed for other indel subtypes nor for maternal age in general. These results have implications for indel modeling in evolution and disease., (© 2020 Wiley Periodicals, Inc.)- Published
- 2020
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28. MsPAC: a tool for haplotype-phased structural variant detection.
- Author
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Rodriguez OL, Ritz A, Sharp AJ, and Bashir A
- Subjects
- Genome, Haplotypes, Sequence Analysis, DNA, Software, Genomics, High-Throughput Nucleotide Sequencing
- Abstract
Summary: While next-generation sequencing (NGS) has dramatically increased the availability of genomic data, phased genome assembly and structural variant (SV) analyses are limited by NGS read lengths. Long-read sequencing from Pacific Biosciences and NGS barcoding from 10x Genomics hold the potential for far more comprehensive views of individual genomes. Here, we present MsPAC, a tool that combines both technologies to partition reads, assemble haplotypes (via existing software) and convert assemblies into high-quality, phased SV predictions. MsPAC represents a framework for haplotype-resolved SV calls that moves one step closer to fully resolved, diploid genomes., Availability and Implementation: https://github.com/oscarlr/MsPAC., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2020
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29. Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance.
- Author
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Cirelli KM, Carnathan DG, Nogal B, Martin JT, Rodriguez OL, Upadhyay AA, Enemuo CA, Gebru EH, Choe Y, Viviano F, Nakao C, Pauthner MG, Reiss S, Cottrell CA, Smith ML, Bastidas R, Gibson W, Wolabaugh AN, Melo MB, Cossette B, Kumar V, Patel NB, Tokatlian T, Menis S, Kulp DW, Burton DR, Murrell B, Schief WR, Bosinger SE, Ward AB, Watson CT, Silvestri G, Irvine DJ, and Crotty S
- Published
- 2020
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30. A unified encyclopedia of human functional DNA elements through fully automated annotation of 164 human cell types.
- Author
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Libbrecht MW, Rodriguez OL, Weng Z, Bilmes JA, Hoffman MM, and Noble WS
- Subjects
- Algorithms, Automation, Cell Line, Humans, Machine Learning, Phenotype, Transcription, Genetic, DNA genetics, Databases, Genetic, Molecular Sequence Annotation
- Abstract
Semi-automated genome annotation methods such as Segway take as input a set of genome-wide measurements such as of histone modification or DNA accessibility and output an annotation of genomic activity in the target cell type. Here we present annotations of 164 human cell types using 1615 data sets. To produce these annotations, we automated the label interpretation step to produce a fully automated annotation strategy. Using these annotations, we developed a measure of the importance of each genomic position called the "conservation-associated activity score." We further combined all annotations into a single, cell type-agnostic encyclopedia that catalogs all human regulatory elements.
- Published
- 2019
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- View/download PDF
31. Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance.
- Author
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Cirelli KM, Carnathan DG, Nogal B, Martin JT, Rodriguez OL, Upadhyay AA, Enemuo CA, Gebru EH, Choe Y, Viviano F, Nakao C, Pauthner MG, Reiss S, Cottrell CA, Smith ML, Bastidas R, Gibson W, Wolabaugh AN, Melo MB, Cossette B, Kumar V, Patel NB, Tokatlian T, Menis S, Kulp DW, Burton DR, Murrell B, Schief WR, Bosinger SE, Ward AB, Watson CT, Silvestri G, Irvine DJ, and Crotty S
- Subjects
- Animals, B-Lymphocytes pathology, Female, Germinal Center pathology, Germinal Center virology, Macaca mulatta, Male, T-Lymphocytes, Helper-Inducer pathology, env Gene Products, Human Immunodeficiency Virus immunology, Antibodies, Neutralizing immunology, B-Lymphocytes immunology, Germinal Center immunology, HIV Antibodies immunology, HIV-1 immunology, Immunization, Passive, T-Lymphocytes, Helper-Inducer immunology
- Abstract
Conventional immunization strategies will likely be insufficient for the development of a broadly neutralizing antibody (bnAb) vaccine for HIV or other difficult pathogens because of the immunological hurdles posed, including B cell immunodominance and germinal center (GC) quantity and quality. We found that two independent methods of slow delivery immunization of rhesus monkeys (RMs) resulted in more robust T follicular helper (T
FH ) cell responses and GC B cells with improved Env-binding, tracked by longitudinal fine needle aspirates. Improved GCs correlated with the development of >20-fold higher titers of autologous nAbs. Using a new RM genomic immunoglobulin locus reference, we identified differential IgV gene use between immunization modalities. Ab mapping demonstrated targeting of immunodominant non-neutralizing epitopes by conventional bolus-immunized animals, whereas slow delivery-immunized animals targeted a more diverse set of epitopes. Thus, alternative immunization strategies can enhance nAb development by altering GCs and modulating the immunodominance of non-neutralizing epitopes., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2019
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32. Multi-platform discovery of haplotype-resolved structural variation in human genomes.
- Author
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Chaisson MJP, Sanders AD, Zhao X, Malhotra A, Porubsky D, Rausch T, Gardner EJ, Rodriguez OL, Guo L, Collins RL, Fan X, Wen J, Handsaker RE, Fairley S, Kronenberg ZN, Kong X, Hormozdiari F, Lee D, Wenger AM, Hastie AR, Antaki D, Anantharaman T, Audano PA, Brand H, Cantsilieris S, Cao H, Cerveira E, Chen C, Chen X, Chin CS, Chong Z, Chuang NT, Lambert CC, Church DM, Clarke L, Farrell A, Flores J, Galeev T, Gorkin DU, Gujral M, Guryev V, Heaton WH, Korlach J, Kumar S, Kwon JY, Lam ET, Lee JE, Lee J, Lee WP, Lee SP, Li S, Marks P, Viaud-Martinez K, Meiers S, Munson KM, Navarro FCP, Nelson BJ, Nodzak C, Noor A, Kyriazopoulou-Panagiotopoulou S, Pang AWC, Qiu Y, Rosanio G, Ryan M, Stütz A, Spierings DCJ, Ward A, Welch AE, Xiao M, Xu W, Zhang C, Zhu Q, Zheng-Bradley X, Lowy E, Yakneen S, McCarroll S, Jun G, Ding L, Koh CL, Ren B, Flicek P, Chen K, Gerstein MB, Kwok PY, Lansdorp PM, Marth GT, Sebat J, Shi X, Bashir A, Ye K, Devine SE, Talkowski ME, Mills RE, Marschall T, Korbel JO, Eichler EE, and Lee C
- Subjects
- Algorithms, Chromosome Mapping methods, Databases, Genetic, High-Throughput Nucleotide Sequencing methods, Humans, INDEL Mutation, Whole Genome Sequencing methods, Genome, Human genetics, Genomic Structural Variation, Genomics methods, Haplotypes genetics
- 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 (<50 bp) and 27,622 SVs (≥50 bp) per genome. We also discover 156 inversions per genome and 58 of the inversions intersect with the critical regions of recurrent microdeletion and microduplication syndromes. Taken together, our SV callsets represent a three to sevenfold increase in SV detection compared to most standard high-throughput sequencing studies, including those from the 1000 Genomes Project. The methods and the dataset presented serve as a gold standard for the scientific community allowing us to make recommendations for maximizing structural variation sensitivity for future genome sequencing studies.
- Published
- 2019
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33. Revision of a home safety assessment curriculum improves medical student reporting of safety problems.
- Author
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van Zuilen MH, Tunuguntla R, Rodriguez OL, and Mintzer MJ
- Subjects
- Cohort Studies, Curriculum, Housing, Humans, Accidental Falls prevention & control, Accidents, Home prevention & control, Geriatrics education, Safety
- Published
- 2010
- Full Text
- View/download PDF
34. Effect of rates of freezing, thawing and level of glycerol on the survival of bovine spermatozoa in straws.
- Author
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Rodriguez OL, Berndtson WE, Ennen BD, and Pickett BW
- Subjects
- Animals, Cell Survival, Fertility, Male, Preservation, Biological instrumentation, Sperm Motility, Spermatozoa drug effects, Cattle physiology, Freezing, Glycerol pharmacology, Preservation, Biological methods, Spermatozoa physiology
- Published
- 1975
- Full Text
- View/download PDF
35. Perforated hepatic artery aneurysm and multiple aneurysms in incomplete Marfan syndrome.
- Author
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Santiago-Delpin EA, Marquez E, Rodriguez OL, Oliveras FE, Baldizon C, and Martínez-Cabruja R
- Subjects
- Aneurysm surgery, Aortic Aneurysm surgery, Aortography, Common Bile Duct, Gastrointestinal Hemorrhage etiology, Humans, Male, Middle Aged, Necrosis, Aneurysm complications, Aortic Aneurysm complications, Hepatic Artery surgery, Marfan Syndrome complications
- Published
- 1972
- Full Text
- View/download PDF
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