Skip to main content
eScholarship
Open Access Publications from the University of California

Scholarly Works (15 results)

  • Article
  • Peer Reviewed
Lawrence Berkeley National Laboratory (2008)

The VISTA portal for comparative genomics is designed to give biomedical scientists a unified set of tools to lead them from the raw DNA sequences through the alignment and annotation to the visualization of the results. The VISTA portal also hosts alignments of a number of genomes computed by our group, allowing users to study regions of their interest without having to manually download the individual sequences. Here we describe various algorithmic and functional improvements implemented in the VISTA portal over the last two years. The VISTA Portal is accessible at http://genome.lbl.gov/vista.

    Cover page: Multiple Whole Genome Alignments and Novel Biomedical Applications at the VISTA Portal
    • Article
    LBL Publications (2004)
    We present an analysis of rates and patterns of microevolutionary phenomena that have shaped the human, mouse, and rat genomes since their last common ancestor. We find evidence for a shift in the mutational spectrum between the mouse and rat lineages, with the net effect being a relative increase in GC content in the rat genome. Our estimate for the neutral point substitution rate separating the two rodents is 0.196 substitutions per site, and 0.65 substitutions per site for the tree relating all three mammals. Small insertions and deletions of 1-10 bp in length ("microindels") occur at approximately 5% of the point substitution rate. Inferred regional correlations in evolutionary rates between lineages and between types of sites support the idea that rates of evolution are influenced by local genomic or cell biological context. No substantial correlations between rates of point substitutions and rates of microindels are found, however, implying that the influences that affect these processes are distinct. Finally, we have identified those regions in the human genome that are evolving slowly, which are likely to include functional elements important to human biology. At least 5% of the human genome is under substantial constraint, most of which is noncoding.
      Cover page: Characterization of evolutionary rates and constraints in three mammalian genomes
      • Article
      Lawrence Berkeley National Laboratory (2004)

      We have developed Phylo-VISTA (Shah et al., 2003), an interactive software tool for analyzing multiple alignments by visualizing a similarity measure for DNA sequences of multiple species. The complexity of visual presentation is effectively organized using a framework based upon inter-species phylogenetic relationships. The phylogenetic organization supports rapid, user-guided inter-species comparison. To aid in navigation through large sequence datasets, Phylo-VISTA provides a user with the ability to select and view data at varying resolutions. The combination of multi-resolution data visualization and analysis, combined with the phylogenetic framework for inter-species comparison, produces a highly flexible and powerful tool for visual data analysis of multiple sequence alignments.

        Cover page: Phylo-VISTA: An Interactive Visualization Tool for Multiple DNA Sequence Alignments
        • Article
        Lawrence Berkeley National Laboratory (2003)

        Motivation. The power of multi-sequence comparison for biological discovery is well established and sequence data from a growing list of organisms is becoming available. Thus, a need exists for computational strategies to visually compare multiple aligned sequences to support conservation analysis across various species. To be efficient these visualization algorithms require the ability to universally handle a wide range of evolutionary distances while taking into account phylogeny Results. We have developed Phylo-VISTA, an interactive tool for analyzing multiple alignments by visualizing the similarity of DNA sequences among multiple species while considering their phylogenic relationships. Features include a broad spectrum of resolution parameters for examining the alignment and the ability to easily compare any subtree of sequences within a complete alignment dataset. Phylo-VISTA uses VISTA concepts that have been successfully applied previously to a wide range of comparative genomics data analysis problems. Availability Phylo-VISTA is an interactive java applet available for downloading at http://graphics.cs.ucdavis.edu/~;nyshah/Phylo-VISTA. It is also available on-line at http://www-gsd.lbl.gov/phylovista and is integrated with the global alignment program LAGAN at http://lagan.stanford.edu.Contactphylovista@lbl.gov

          Cover page: Phylo-VISTA: An interactive visualization tool for multiple DNA sequence alignments
          • Article
          • Peer Reviewed
          Lawrence Berkeley National Laboratory (2004)
            Cover page: Automated whole-genome multiple alignment of rat, mouse, and human
            • Article
            • Peer Reviewed
            Environ Genomics & Systems Bio (2016)
            The National Institutes of Health Undiagnosed Diseases Program (NIH UDP) applies translational research systematically to diagnose patients with undiagnosed diseases. The challenge is to implement an information system enabling scalable translational research. The authors hypothesized that similar complex problems are resolvable through process management and the distributed cognition of communities. The team, therefore, built the NIH UDP integrated collaboration system (UDPICS) to form virtual collaborative multidisciplinary research networks or communities. UDPICS supports these communities through integrated process management, ontology-based phenotyping, biospecimen management, cloud-based genomic analysis, and an electronic laboratory notebook. UDPICS provided a mechanism for efficient, transparent, and scalable translational research and thereby addressed many of the complex and diverse research and logistical problems of the NIH UDP. Full definition of the strengths and deficiencies of UDPICS will require formal qualitative and quantitative usability and process improvement measurement.
              • Article
              • Peer Reviewed
              UC Santa Cruz Previously Published Works (2014)
              Multiple sequence alignments (MSAs) are a prerequisite for a wide variety of evolutionary analyses. Published assessments and benchmark data sets for protein and, to a lesser extent, global nucleotide MSAs are available, but less effort has been made to establish benchmarks in the more general problem of whole-genome alignment (WGA). Using the same model as the successful Assemblathon competitions, we organized a competitive evaluation in which teams submitted their alignments and then assessments were performed collectively after all the submissions were received. Three data sets were used: Two were simulated and based on primate and mammalian phylogenies, and one was comprised of 20 real fly genomes. In total, 35 submissions were assessed, submitted by 10 teams using 12 different alignment pipelines. We found agreement between independent simulation-based and statistical assessments, indicating that there are substantial accuracy differences between contemporary alignment tools. We saw considerable differences in the alignment quality of differently annotated regions and found that few tools aligned the duplications analyzed. We found that many tools worked well at shorter evolutionary distances, but fewer performed competitively at longer distances. We provide all data sets, submissions, and assessment programs for further study and provide, as a resource for future benchmarking, a convenient repository of code and data for reproducing the simulation assessments.
                Cover page: Alignathon: a competitive assessment of whole-genome alignment methods
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2021)

                Background

                Cisplatin, a chemotherapy used to treat solid tumors, causes acute kidney injury (AKI), a known risk factor for chronic kidney disease and mortality. AKI diagnosis relies on biomarkers which are only measurable after kidney damage has occurred and functional impairment is apparent; this prevents timely AKI diagnosis and treatment. Metabolomics seeks to identify metabolite patterns involved in cell tissue metabolism related to disease or patient factors. The A Canadian study of Cisplatin mEtabolomics and NephroToxicity (ACCENT) team was established to harness the power of metabolomics to identify novel biomarkers that predict risk and discriminate for presence of cisplatin nephrotoxicity, so that early intervention strategies to mitigate onset and severity of AKI can be implemented.

                Objective

                Describe the design and methods of the ACCENT study which aims to identify and validate metabolomic profiles in urine and serum associated with risk for cisplatin-mediated nephrotoxicity in children and adults.

                Design

                Observational prospective cohort study.

                Setting

                Six Canadian oncology centers (3 pediatric, 1 adult and 2 both).

                Patients

                Three hundred adults and 300 children planned to receive cisplatin therapy.

                Measurements

                During two cisplatin infusion cycles, serum and urine will be measured for creatinine and electrolytes to ascertain AKI. Many patient and disease variables will be collected prospectively at baseline and throughout therapy. Metabolomic analyses of serum and urine will be done using mass spectrometry. An untargeted metabolomics approach will be used to analyze serum and urine samples before and after cisplatin infusions to identify candidate biomarkers of cisplatin AKI. Candidate metabolites will be validated using an independent cohort.

                Methods

                Patients will be recruited before their first cycle of cisplatin. Blood and urine will be collected at specified time points before and after cisplatin during the first infusion and an infusion later during cancer treatment. The primary outcome is AKI, defined using a traditional serum creatinine-based definition and an electrolyte abnormality-based definition. Chart review 3 months after cisplatin therapy end will be conducted to document kidney health and survival.

                Limitations

                It may not be possible to adjust for all measured and unmeasured confounders when evaluating prediction of AKI using metabolite profiles. Collection of data across multiple sites will be a challenge.

                Conclusions

                ACCENT is the largest study of children and adults treated with cisplatin and aims to reimagine the current model for AKI diagnoses using metabolomics. The identification of biomarkers predicting and detecting AKI in children and adults treated with cisplatin can greatly inform future clinical investigations and practices.
                  Cover page: A Canadian Study of Cisplatin Metabolomics and Nephrotoxicity (ACCENT): A Clinical Research Protocol
                  • Article
                  • Peer Reviewed
                  UC Santa Cruz Previously Published Works (2018)
                  The Global Alliance for Genomics and Health (GA4GH) proposes a data access policy model-"registered access"-to increase and improve access to data requiring an agreement to basic terms and conditions, such as the use of DNA sequence and health data in research. A registered access policy would enable a range of categories of users to gain access, starting with researchers and clinical care professionals. It would also facilitate general use and reuse of data but within the bounds of consent restrictions and other ethical obligations. In piloting registered access with the Scientific Demonstration data sharing projects of GA4GH, we provide additional ethics, policy and technical guidance to facilitate the implementation of this access model in an international setting.
                    Cover page: Registered access: authorizing data access
                    • Article
                    • Peer Reviewed
                    UC San Diego Previously Published Works (2020)
                    Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.
                      Cover page: DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes
                      Top