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Open Access Publications from the University of California

Scholarly Works (32 results)

  • Thesis
  • Peer Reviewed
UC Santa Cruz Electronic Theses and Dissertations (2015)

Although sea level has fluctuated repeatedly over the Pleistocene by up to 120 meters, how (or whether) this cyclic base level forcing impacts the development of bedrock river profiles in tectonically active settings is poorly understood. A major reason for this uncertainty is that bedrock river channels in unglaciated locations are typically buried at their mouths under sediment resulting from the Holocene marine transgression, making direct observations impossible. Here I present a novel approach to constraining the influence of cyclical sea-level forcing on the development of bedrock river profiles in the Oregon Coast Range.

Using a 1 m LiDAR DEM, I estimate the depth to the buried bedrock longitudinal profile using measurements of valley width, elevation, wall slope, and present day river width for the Smith River and its tributaries where the river is currently buried by Holocene fluvial and marine sediments. Assuming the current river width is spatially and temporally constant, I calculate the depth to bedrock based on a trapezoidal geometry. In an effort to reduce the noise in our signal, I calculate linear regressions for valley and river width and hold the valley wall slope constant at its average value (~ 30 degrees) for all our calculations.

Several important observations stem from this analysis. First, the bedrock profile of the Smith River projects to the same elevation (~ -110 m) as the bench cut into the continental shelf by the sea-level low stand of the last glacial maximum, suggesting the bedrock river is currently graded to the low-stand elevation. Second, almost all of the tributary bedrock profiles plot tens of meters above the mainstem bedrock profile. One key exception is the significantly larger North Fork of the Smith River, which falls directly on the projected bedrock curve for the Smith. These observations suggest that sea-level low stands force incision of the entire bedrock river network, but that smaller tributaries, which are buried and/or flooded during highstands, cannot keep pace with the mainstem during these periods of brief down-cutting. Our results imply that difference in erosion rates between tributaries and the mainstem results in the formation of fluvial hanging valleys that are buried during marine transgressions.

    Cover page: Transient response of bedrock channel networks to Pleistocene sea-level forcing in the Oregon Coast Range
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2015)
    iCTNet (integrated Complex Traits Networks) version 2 is a Cytoscape app and database that allows researchers to build heterogeneous networks by integrating a variety of biological interactions, thus offering a systems-level view of human complex traits. i
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2020)
      Animal models are widely employed in basic research to test mechanistic hypotheses in a complex biological environment as well as to evaluate the therapeutic potential of candidate compounds in preclinical settings. Rodents, and in particular mice, represent the most common in vivo models for their small size, short lifespan and possibility to manipulate their genome. Over time, a typical laboratory will develop a substantial number of inbred strains and transgenic mouse lines, requiring a substantial effort, in both logistic and economic terms, to maintain an animal colony for research purposes and to safeguard the integrity of results. To meet this need, here we present TopoDB, a robust and extensible web-based platform for the rational management of laboratory animals. TopoDB allows an easy tracking of individual animals within the colony and breeding protocols as well as the convenient storage of both genetic and phenotypic data generated in the different experiments. Altogether, these features facilitate and enhance the design of in vivo research, thus reducing the number of necessary animals and the housing costs. In summary, TopoDB represents a novel valuable tool in modern biomedical research. Database URL: https://github.com/UCSF-MS-DCC/TopoDB.
        Cover page: TopoDB: a novel multifunctional management system for laboratory animal colonies
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2015)
        Objective: To assess the influence of common mitochondrial DNA (mtDNA) sequence variation on multiple sclerosis (MS) risk in cases and controls part of an international consortium. Methods: We analyzed 115 high-quality mtDNA variants and common haplogroups from a previously published genome-wide association study among 7,391 cases from the International Multiple Sclerosis Genetics Consortium and 14,568 controls from the Wellcome Trust Case Control Consortium 2 project from 7 countries. Significant single nucleotide polymorphism and haplogroup associations were replicated in 3,720 cases and 879 controls from the University of California, San Francisco. Results: An elevated risk of MS was detected among haplogroup JT carriers from 7 pooled clinic sites (odds ratio [OR] = 1.15, 95% confidence interval [CI] = 1.07-1.24, p = 0.0002) included in the discovery study. The increased risk of MS was observed for both haplogroup T (OR = 1.17, 95% CI = 1.06-1.29, p = 0.002) and haplogroup J carriers (OR = 1.11, 95% CI = 1.01-1.22, p = 0.03). These haplogroup associations with MS were not replicated in the independent sample set. An elevated risk of primary progressive (PP) MS was detected for haplogroup J participants from 3 European discovery populations (OR = 1.49, 95% CI = 1.10-2.01, p = 0.009). This elevated risk was borderline significant in the US replication population (OR = 1.43, 95% CI = 0.99-2.08, p = 0.058) and remained significant in pooled analysis of discovery and replication studies (OR = 1.43, 95% CI = 1.14-1.81, p = 0.002). No common individual mtDNA variants were associated with MS risk. Conclusions: Identification and validation of mitochondrial genetic variants associated with MS and PPMS may lead to new targets for treatment and diagnostic tests for identifying potential responders to interventions that target mitochondria.
          • Article
          • Peer Reviewed
          Proceedings of the Annual Meeting of the Cognitive Science Society, Volume 37 (2015)
          Despite an extensive literature on the brain substrates of response inhibition, it still remains to be determined which is the best functional comparison to tease apart neural activity underlying this cognitive process. Here we aimed to shed light on this issue be recording event-related potentials while participants performed a modified stop-signal task that allowed us to compare the following conditions: successful versus unsuccessful response inhibitions, successful response inhibitions versus successful response executions, and easy versus difficult response inhibitions. Electrophysiological activity related to response inhibition was best isolated by comparing easy and difficult inhibitions. This activity was observed at fronto-central scalp electrodes between 260 and 300 milliseconds after stop-stimulus presentation. Notably, the stop-signal reaction time (an estimate of the time required to inhibit the motor response) fell within this window interval.
            Cover page: Searching for the best functional comparison to isolate neural processes related to response inhibtion
            • Article
            • Peer Reviewed
            UC San Francisco Previously Published Works (2010)
            Abstract Background When selecting mates, many vertebrate species seek partners with major histocompatibility complex (MHC) genes different from their own, presumably in response to selective pressure against inbreeding and towards MHC diversity. Attempts at replication of these genetic results in human studies, however, have reached conflicting conclusions. Results Using a multi-analytical strategy, we report validated genome-wide relationships between genetic identity and human mate choice in 930 couples of European ancestry. We found significant similarity between spouses in the MHC at class I region in chromosome 6p21, and at the odorant receptor family 13 locus in chromosome 9. Conversely, there was significant dissimilarity in the MHC class II region, near the HLA-DQA1 and -DQB1 genes. We also found that genomic regions with significant similarity between spouses show excessive homozygosity in the general population (assessed in the HapMap CEU dataset). Conversely, loci that were significantly dissimilar among spouses were more likely to show excessive heterozygosity in the general population. Conclusions This study highlights complex patterns of genomic identity among partners in unrelated couples, consistent with a multi-faceted role for genetic factors in mate choice behavior in human populations.
            • 9 supplemental files
            Cover page: Genetic variation in the odorant receptors family 13 and the MHC loci influence mate selection in a Multiple Sclerosis dataset
            • Article
            • Peer Reviewed
            UC San Francisco Previously Published Works (2015)

            Objective

            To assess the influence of common mitochondrial DNA (mtDNA) sequence variation on multiple sclerosis (MS) risk in cases and controls part of an international consortium.

            Methods

            We analyzed 115 high-quality mtDNA variants and common haplogroups from a previously published genome-wide association study among 7,391 cases from the International Multiple Sclerosis Genetics Consortium and 14,568 controls from the Wellcome Trust Case Control Consortium 2 project from 7 countries. Significant single nucleotide polymorphism and haplogroup associations were replicated in 3,720 cases and 879 controls from the University of California, San Francisco.

            Results

            An elevated risk of MS was detected among haplogroup JT carriers from 7 pooled clinic sites (odds ratio [OR] = 1.15, 95% confidence interval [CI] = 1.07-1.24, p = 0.0002) included in the discovery study. The increased risk of MS was observed for both haplogroup T (OR = 1.17, 95% CI = 1.06-1.29, p = 0.002) and haplogroup J carriers (OR = 1.11, 95% CI = 1.01-1.22, p = 0.03). These haplogroup associations with MS were not replicated in the independent sample set. An elevated risk of primary progressive (PP) MS was detected for haplogroup J participants from 3 European discovery populations (OR = 1.49, 95% CI = 1.10-2.01, p = 0.009). This elevated risk was borderline significant in the US replication population (OR = 1.43, 95% CI = 0.99-2.08, p = 0.058) and remained significant in pooled analysis of discovery and replication studies (OR = 1.43, 95% CI = 1.14-1.81, p = 0.002). No common individual mtDNA variants were associated with MS risk.

            Conclusions

            Identification and validation of mitochondrial genetic variants associated with MS and PPMS may lead to new targets for treatment and diagnostic tests for identifying potential responders to interventions that target mitochondria.
              • Article
              • Peer Reviewed
              UC San Francisco Previously Published Works (2019)
              The human leukocyte antigen (HLA) genes are extremely polymorphic and are useful molecular markers to make inferences about human population history. However, the accuracy of the estimation of genetic diversity at HLA loci very much depends on the technology used to characterize HLA alleles; high-resolution genotyping of long-range HLA gene products improves the assessment of HLA population diversity as well as other population parameters compared to lower resolution typing methods. In this study we examined allelic and haplotype HLA diversity in a large healthy European American population sourced from the UCSF-DNA bank. A high-resolution next-generation sequencing method was applied to define non-ambiguous 3- and 4-field alleles at the HLA-A, HLA-C, HLA-B, HLA-DRB1, HLA-DRB3/4/5, HLA-DQA1, HLA-DQB1, HLA-DPA1, and HLA-DPB1 loci in samples provided by 2248 unrelated individuals. A number of population parameters were examined including balancing selection and various measurements of linkage disequilibrium were calculated. There were no detectable deviations from Hardy-Weinberg proportions at HLA-A, HLA-DRB1, HLA-DQA1 and HLA-DQB1. For the remaining loci moderate and significant deviations were detected at HLA-C, HLA-B, HLA-DRB3/4/5, HLA-DPA1 and HLA-DPB1 loci mostly from population substructures. Unique 4-field associations were observed among alleles at 2 loci and haplotypes extending large intervals that were not apparent in results obtained using testing methodologies with limited sequence coverage and phasing. The high diversity at HLA-DPA1 results from detection of intron variants of otherwise well conserved protein sequences. It may be speculated that divergence in exon sequences may be negatively selected. Our data provides a valuable reference source for future population studies that may allow for precise fine mapping of coding and non-coding sequences determining disease susceptibility and allo-immunogenicity.
                Cover page: Next-generation sequencing reveals new information about HLA allele and haplotype diversity in a large European American population
                • Article
                • Peer Reviewed
                UC San Francisco Previously Published Works (2018)

                Objective

                Primary progressive multiple sclerosis (PPMS) causes accumulation of neurological disability from disease onset without clinical attacks typical of relapsing multiple sclerosis (RMS). However, whether genetic variation influences the disease course remains unclear. We aimed to determine whether mutations causative of neurological disorders that share features with multiple sclerosis (MS) contribute to risk for developing PPMS.

                Methods

                We examined whole-genome sequencing (WGS) data from 38 PPMS and 81 healthy subjects of European ancestry. We selected pathogenic variants exclusively found in PPMS patients that cause monogenic neurological disorders and performed two rounds of replication genotyping in 746 PPMS, 3,049 RMS, and 1,000 healthy subjects. To refine our findings, we examined the burden of rare, potentially pathogenic mutations in 41 genes that cause hereditary spastic paraplegias (HSPs) in PPMS (n = 314), secondary progressive multiple sclerosis (SPMS; n = 587), RMS (n = 2,248), and healthy subjects (n = 987) genotyped using the MS replication chip.

                Results

                WGS and replication studies identified three pathogenic variants in PPMS patients that cause neurological disorders sharing features with MS: KIF5A p.Ala361Val in spastic paraplegia 10; MLC1 p.Pro92Ser in megalencephalic leukodystrophy with subcortical cysts, and REEP1 c.606 + 43G>T in Spastic Paraplegia 31. Moreover, we detected a significant enrichment of HSP-related mutations in PPMS patients compared to controls (risk ratio [RR] = 1.95; 95% confidence interval [CI], 1.27-2.98; p = 0.002), as well as in SPMS patients compared to controls (RR = 1.57; 95% CI, 1.18-2.10; p = 0.002). Importantly, this enrichment was not detected in RMS.

                Interpretation

                This study provides evidence to support the hypothesis that rare Mendelian genetic variants contribute to the risk for developing progressive forms of MS. Ann Neurol 2018;83:51-63.
                  Cover page: Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis.
                  • Article
                  • Peer Reviewed
                  UC San Francisco Previously Published Works (2020)

                  Background

                  Substantial progress has been made toward unraveling the genetic architecture of multiple sclerosis (MS) within populations of European ancestry, but few genetic studies have focused on Hispanic and African American populations within the United States.

                  Objective

                  We sought to test the relevance of common European MS risk variants outside of the major histocompatibility complex (n = 200) within these populations.

                  Methods

                  Genotype data were available on 2652 Hispanics (1298 with MS, 1354 controls) and 2435 African Americans (1298 with MS, 1137 controls). We conducted single variant, pathway, and cumulative genetic risk score analyses.

                  Results

                  We found less replication than statistical power suggested, particularly among African Americans. This could be due to limited correlation between the tested and causal variants within the sample or alternatively could indicate allelic and locus heterogeneity. Differences were observed between pathways enriched among the replicating versus all 200 variants. Although these differences should be examined in larger samples, a potential role exists for gene-environment or gene-gene interactions which alter phenotype differentially across racial and ethnic groups. Cumulative genetic risk scores were associated with MS within each study sample but showed limited diagnostic capability.

                  Conclusion

                  These findings provide a framework for fine-mapping efforts in multi-ethnic populations of MS.
                    Cover page: The genetic diversity of multiple sclerosis risk among Hispanic and African American populations living in the United States.
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