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

Scholarly Works (11 results)

  • Thesis
  • Peer Reviewed
UC Santa Cruz Electronic Theses and Dissertations (2014)

Advancements in technologies have resulted in an explosion of data, the volume of which continues to increase at an exponential rate. The accumulating wealth of data is enabling numerous new research possibilities and is transforming the world profoundly. In genomics, new genomes are being regularly sequenced, with a growing number of individual genomes becoming available for many species. As the ability to have complete genomic information becomes the norm, the need for a reference genome that better represents the particular species population intensifies: It becomes important to utilize the newly emerged sequences to improve current references and ensure better quality for future assemblies and experiments. Additionally, the proliferation of data has necessitated the decentralization of computational resources together with the empowerment of users to a do-it-yourself system, in which users create their own assemblies, alignments, visualizations and analyses. This is because with the accelerating amount of data, it is impossible and undesirable to maintain the infrastructure model in which only a number of specialized institutions handle most if not all of the data and analyses.

Joining many other on-going efforts, the works in this dissertation attempt to address some of these rising demands. First, I describe the problem of constructing a pan-genome reference for a population and demonstrate that the resulting pan-genome reference is more representative of the population than is any individual genome, using both simulated and real data. Second, I describe a comparative genomic framework that allows for easy generation of collections of web accessible UCSC genome browsers interrelated by an alignment. The pipeline, named the comparative assembly hub (CAH) pipeline, is intended to democratize UCSC comparative genomic resources and facilitate public sharing via the internet. As a demonstration, I create comparative assembly hubs for 66 Escherichia coli/Shigella genomes and highlight comparative analyses on their pan-genomic, core genomic and phylogenetic relationships. Last, I report on comprehensive assessments of the T cell receptor (TCR) repertoires of the autoimmune disease Ankylosing Spondylitis and show example comparative analyses for finding evidence of antigen selection and identifying potential disease-associated clones. In addition, I describe an open-source software package for profiling and comparing TCR sequencing data, called the “Adaptive IMmunoSequencing ToolKit”, or the aimseqtk package. The aimseqtk package is comprised of four main components addressing common analyses of this type of data: clone tracking, repertoire profiling, public clone identification and publication mining.

    Cover page: Addressing the Omics Data Explosion: a Comprehensive Reference Genome Representation and the Democratization of Comparative Genomics and Immunogenomics
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2023)
    BACKGROUND: Local area immigrant fraction is strongly and positively correlated with local life expectancy in the United States. The aim of the study was to determine the relationship between local area immigrant fraction and local prevalence of coronary heart disease (CHD) and stroke. METHODS: Cross-sectional study design, with ZIP code as the unit of observation. Demographic data was obtained from the American Community Survey, and linked to indicators of health access (e.g., insurance, annual check-ups, cholesterol screening), obesity, behavior (smoking, exercise), and cardiovascular outcomes data from the 2020 Population Level Analysis and Community Estimates. Multivariable regression and path analyses were used to assess both direct and indirect relationships among variables. FINDINGS: CHD prevalence was lower in the second (3.9% relative difference, 95% CI: 3.1-4.5%), third (6.5%, 95% CI: 5.8-7.1%), and fourth (14.8%, 95% CI: 14.1-15.8%) quartiles of immigrant fraction compared to the lowest (p-trend <0.001). These effects remained robust in multivariable analysis following adjustment for indicators of access, obesity, and behavioral variables (p-trend <0.0001). For stroke, only the highest quartile demonstrated a significant difference in prevalence (2.1%, 95% CI: 1.2-3.0% with full adjustment). In CHD path analysis, ∼45% of the association of immigrant fraction was direct, and ∼55% was mediated through lower prevalence of deleterious behaviors (e.g., smoking). In stroke path analysis, the effect was entirely mediated through indirect effects. INTERPRETATION: In the United States, ZIP codes with higher immigrant fractions have lower prevalence of cardiovascular diseases. These associations are partially mediated through differences in health behaviors at the community level. FUNDING: NIH (K08CA252635, P30AG0059304, K24HL150476), Stanford University, Rutgers University.
      Cover page: The association between local area immigrant fraction and prevalence of cardiovascular diseases in the United States: an observational study.
      • Article
      • Peer Reviewed
      UC Santa Cruz Previously Published Works (2015)
      A reference genome is a high quality individual genome that is used as a coordinate system for the genomes of a population, or genomes of closely related subspecies. Given a set of genomes partitioned by homology into alignment blocks we formalize the problem of ordering and orienting the blocks such that the resulting ordering maximally agrees with the underlying genomes' ordering and orientation, creating a pan-genome reference ordering. We show this problem is NP-hard, but also demonstrate, empirically and within simulations, the performance of heuristic algorithms based upon a cactus graph decomposition to find locally maximal solutions. We describe an extension of our Cactus software to create a pan-genome reference for whole genome alignments, and demonstrate how it can be used to create novel genome browser visualizations using human variation data as a test. In addition, we test the use of a pan-genome for describing variations and as a reference for read mapping.
        Cover page: Building a Pan-Genome Reference for a Population
        • Article
        • Peer Reviewed
        UC Santa Cruz Previously Published Works (2014)
        Throughout evolution primate genomes have been modified by waves of retrotransposon insertions. For each wave, the host eventually finds a way to repress retrotransposon transcription and prevent further insertions. In mouse embryonic stem cells, transcriptional silencing of retrotransposons requires KAP1 (also known as TRIM28) and its repressive complex, which can be recruited to target sites by KRAB zinc-finger (KZNF) proteins such as murine-specific ZFP809 which binds to integrated murine leukaemia virus DNA elements and recruits KAP1 to repress them. KZNF genes are one of the fastest growing gene families in primates and this expansion is hypothesized to enable primates to respond to newly emerged retrotransposons. However, the identity of KZNF genes battling retrotransposons currently active in the human genome, such as SINE-VNTR-Alu (SVA) and long interspersed nuclear element 1 (L1), is unknown. Here we show that two primate-specific KZNF genes rapidly evolved to repress these two distinct retrotransposon families shortly after they began to spread in our ancestral genome. ZNF91 underwent a series of structural changes 8-12 million years ago that enabled it to repress SVA elements. ZNF93 evolved earlier to repress the primate L1 lineage until ∼12.5 million years ago when the L1PA3-subfamily of retrotransposons escaped ZNF93's restriction through the removal of the ZNF93-binding site. Our data support a model where KZNF gene expansion limits the activity of newly emerged retrotransposon classes, and this is followed by mutations in these retrotransposons to evade repression, a cycle of events that could explain the rapid expansion of lineage-specific KZNF genes.
          Cover page: An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons
          • Article
          • Peer Reviewed
          UC San Francisco Previously Published Works (2011)

          Objectives

          Longitudinal studies examining the baseline predictors of fatigue in SSc have not been reported. Our objectives were to examine the course of fatigue severity over time and to identify baseline clinical, demographic, and psychosocial predictors of sequentially obtained fatigue scores in early SSc. We also examined baseline predictors of change in fatigue severity over time.

          Methods

          We analyzed 1090 longitudinal Fatigue Severity Scale (FSS) scores belonging to 256 patients who were enrolled in the Genetics versus Environment in Scleroderma Outcomes Study (GENISOS). Predictive significance of baseline variables for sequentially obtained FSS scores was examined with generalized linear mixed models. Predictors of change in FSS over time were examined by adding an interaction term between the baseline variable and time-in-study to the model.

          Results

          The patients' mean age was 48.6 years, 47% were Caucasians, and 59% had diffuse cutaneous involvement. The mean disease duration at enrollment was 2.5 years. The FSS was obtained at enrollment and follow-up visits (mean follow-up time = 3.8 years). Average baseline FSS score was 4.7(±0.96). The FSS was relatively stable and did not show a consistent trend for change over time (p = 0.221). In a multivariable model of objective clinical variables, higher Medsger Gastrointestinal (p = 0.006) and Joint (p = 0.024) Severity Indices, and anti-U1-RNP antibodies (p = 0.024) were independent predictors of higher FSS. In the final model, ineffective coping skills captured by higher Illness Behavior Questionnaire scores (p<0.001), higher self-reported pain (p = 0.006), and higher Medsger Gastrointestinal Severity Index (p = 0.009) at enrollment were independent predictors of higher longitudinal FSS scores. Baseline DLco % predicted was the only independent variable that significantly predicted a change in FSS scores over time (p = 0.013), with lower DLco levels predicting an increase in FSS over time.

          Conclusions

          This study identified potentially modifiable clinical and psychological factors that predict longitudinal fatigue severity in early SSc.
            Cover page: Predictors of Fatigue Severity in Early Systemic Sclerosis: A Prospective Longitudinal Study of the GENISOS Cohort
            • Article
            • Peer Reviewed
            UC Santa Cruz Previously Published Works (2014)
            Throughout evolution primate genomes have been modified by waves of retrotransposon insertions. For each wave, the host eventually finds a way to repress retrotransposon transcription and prevent further insertions. In mouse embryonic stem cells, transcriptional silencing of retrotransposons requires KAP1 (also known as TRIM28) and its repressive complex, which can be recruited to target sites by KRAB zinc-finger (KZNF) proteins such as murine-specific ZFP809 which binds to integrated murine leukaemia virus DNA elements and recruits KAP1 to repress them. KZNF genes are one of the fastest growing gene families in primates and this expansion is hypothesized to enable primates to respond to newly emerged retrotransposons. However, the identity of KZNF genes battling retrotransposons currently active in the human genome, such as SINE-VNTR-Alu (SVA) and long interspersed nuclear element 1 (L1), is unknown. Here we show that two primate-specific KZNF genes rapidly evolved to repress these two distinct retrotransposon families shortly after they began to spread in our ancestral genome. ZNF91 underwent a series of structural changes 8-12 million years ago that enabled it to repress SVA elements. ZNF93 evolved earlier to repress the primate L1 lineage until ∼12.5 million years ago when the L1PA3-subfamily of retrotransposons escaped ZNF93's restriction through the removal of the ZNF93-binding site. Our data support a model where KZNF gene expansion limits the activity of newly emerged retrotransposon classes, and this is followed by mutations in these retrotransposons to evade repression, a cycle of events that could explain the rapid expansion of lineage-specific KZNF genes.
              Cover page: An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons.
              • Article
              • Peer Reviewed
              UC Santa Cruz Previously Published Works (2014)

              Motivation

              Researchers now have access to large volumes of genome sequences for comparative analysis, some generated by the plethora of public sequencing projects and, increasingly, from individual efforts. It is not possible, or necessarily desirable, that the public genome browsers attempt to curate all these data. Instead, a wealth of powerful tools is emerging to empower users to create their own visualizations and browsers.

              Results

              We introduce a pipeline to easily generate collections of Web-accessible UCSC Genome Browsers interrelated by an alignment. It is intended to democratize our comparative genomic browser resources, serving the broad and growing community of evolutionary genomicists and facilitating easy public sharing via the Internet. Using the alignment, all annotations and the alignment itself can be efficiently viewed with reference to any genome in the collection, symmetrically. A new, intelligently scaled alignment display makes it simple to view all changes between the genomes at all levels of resolution, from substitutions to complex structural rearrangements, including duplications. To demonstrate this work, we create a comparative assembly hub containing 57 Escherichia coli and 9 Shigella genomes and show examples that highlight their unique biology.

              Availability and implementation

              The source code is available as open source at: https://github.com/glennhickey/progressiveCactus The E.coli and Shigella genome hub is now a public hub listed on the UCSC browser public hubs Web page.
                Cover page: Comparative assembly hubs: Web-accessible browsers for comparative genomics
                • 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
                  UC Santa Cruz Previously Published Works (2015)
                  Launched in 2001 to showcase the draft human genome assembly, the UCSC Genome Browser database (http://genome.ucsc.edu) and associated tools continue to grow, providing a comprehensive resource of genome assemblies and annotations to scientists and students worldwide. Highlights of the past year include the release of a browser for the first new human genome reference assembly in 4 years in December 2013 (GRCh38, UCSC hg38), a watershed comparative genomics annotation (100-species multiple alignment and conservation) and a novel distribution mechanism for the browser (GBiB: Genome Browser in a Box). We created browsers for new species (Chinese hamster, elephant shark, minke whale), 'mined the web' for DNA sequences and expanded the browser display with stacked color graphs and region highlighting. As our user community increasingly adopts the UCSC track hub and assembly hub representations for sharing large-scale genomic annotation data sets and genome sequencing projects, our menu of public data hubs has tripled.
                    Cover page: The UCSC Genome Browser database: 2015 update
                    • Article
                    • Peer Reviewed
                    UC Santa Cruz Previously Published Works (2015)
                    Launched in 2001 to showcase the draft human genome assembly, the UCSC Genome Browser database (http://genome.ucsc.edu) and associated tools continue to grow, providing a comprehensive resource of genome assemblies and annotations to scientists and students worldwide. Highlights of the past year include the release of a browser for the first new human genome reference assembly in 4 years in December 2013 (GRCh38, UCSC hg38), a watershed comparative genomics annotation (100-species multiple alignment and conservation) and a novel distribution mechanism for the browser (GBiB: Genome Browser in a Box). We created browsers for new species (Chinese hamster, elephant shark, minke whale), 'mined the web' for DNA sequences and expanded the browser display with stacked color graphs and region highlighting. As our user community increasingly adopts the UCSC track hub and assembly hub representations for sharing large-scale genomic annotation data sets and genome sequencing projects, our menu of public data hubs has tripled.
                      Cover page: The UCSC Genome Browser database: 2015 update
                      Top