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Open Access Publications from the University of California

Scholarly Works (12 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2019)

Neurodevelopmental and neuropsychiatric diseases, such as autism spectrum disorder (ASD) and schizophrenia (SCZ), are highly heritable, with hundreds of risk loci contributing to disease risk identified through large-scale genomic studies. The ability to interpret these susceptibility variants and their contributions to disease has been difficult due to the fact that many of these variants fall in non-coding regions of the genome, or in regions of high linkage disequilibrium. Given the non-coding nature of the majority of these variants, as well as their enrichment in known enhancers, many of these variants are predicted to regulate gene expression, which is known to be dependent on tissue, cell type and developmental stage.

Here, I have characterized functional genetic variation controlling transcriptional regulation in developing human brain to dissect common variation contributing to neurodevelopmental and early onset neuropsychiatric diseases, characterized by phenotypes originating in utero or early postnatal life. I have comprehensively profiled expression and splicing levels by RNA sequencing and high-density genotyping in 201 mid-gestational human brains and have performed expression and splicing quantitative trait loci analysis, which is currently the largest eQTL study in the developing brain. I identified 7962 expression QTL (eQTL) and 4635 splice QTL (sQTL), including several thousand fetal-specific regulatory regions when compared to published QTL studies of the adult brain. I leveraged these eQTL and sQTL to identify splicing and transcriptional drivers affected by human genetic variation, by significant enrichment in experimentally determined transcription factor, DNA binding proteins, and RNA bringing proteins binding sides. Further integration with experimental transcription factor knockdown data provide evidence that the regulatory regions identified through the eQTL and sQTL analysis are functional and validate that the changes seen in gene expression levels and/or splicing are likely due to the transcription factor’s role in regulating that gene.

By integration with GWAS, I characterized the genes and isoforms contributing to specific neuropsychiatric disorders, including SCZ and ASD, as well as other cognitive or behavioral-related phenotypes. Specifically showing prenatal brain regulatory regions are significantly enriched for SCZ GWAS risk in a complimentary and additive manner to adult brain regulatory regions. I then perform gene co-expression network analysis and identify co-expressed modules of genes representing distinct biological processes in the developing brain. By integrating the QTL identified gene regulatory regions with co-expression modules and GWAS risk loci, I find SCZ and ASD impact distinct developmental gene co-expression modules. Yet, in both disorders, common and rare genetic variation converge. In ASD this convergence also implicates a specific cell type as well, superficial cortical neurons.

Additionally, integration of eQTL and sQTL with GWAS via transcriptome wide association identified dozens of novel candidate risk genes, highlighting shared and stage-specific mechanisms in SCZ. These analyses demonstrate the highly distinctive effects of transcriptional control, as well as divergent age-related contributions to disease. More broadly, these findings demonstrate the genetic mechanisms by which early developmental events have a striking and widespread influence on adult anatomical and behavioral phenotypes.

    Cover page: Genetic Control of Expression and Splicing in the Developing Human Brain
    • Article
    • Peer Reviewed
    LBL Publications (2021)
    Achiral mesogenic molecules are shown to be able to spontaneously assemble into liquid crystalline smectic phases having either simple or double-helical structures. At the transition between these phases, the double-helical structure unwinds. As a consequence, in some temperature range, the pitch of the helix becomes comparable to the wavelength of visible light and the selective reflection of light in the visible range is observed. The photonic bandgap phenomenon is reported for achiral liquid crystals.
      Cover page: Photonic Bandgap in Achiral Liquid Crystals—A Twist on a Twist
      • Article
      • Peer Reviewed
      LBL Publications (2019)
      Complex materials often exhibit a hierarchical structure with an intriguing mechanism responsible for the 'propagation' of order from the molecular to the nano- or micro-scale level. In particular, the chirality of biological molecules such as nucleic acids and amino acids is responsible for the helical structure of DNA and proteins, which in turn leads to the lack of mirror symmetry of macro-bio-objects. To fully understand mechanisms of cross-level order transfer there is an intensive search for simpler artificial structures exhibiting hierarchical arrangement. Here we present complex systems built of achiral molecules that show four levels of structural chirality: layer chirality, helicity of a basic repeating unit, mesoscopic helix and helical filaments. The structures are identified by a combination of hard and soft x-ray diffraction measurements, optical studies and theoretical modelling. Similarly to many biological systems, the studied materials exhibit a coupling between chirality at different levels.
        Cover page: Multi-level chirality in liquid crystals formed by achiral molecules
        • Article
        • Peer Reviewed
        LBL Publications (2023)
        We report two new series of compounds that show the ferroelectric nematic, NF, phase in which the terminal chain length is varied. The longer the terminal chain, the weaker the dipole-dipole interactions of the molecules are along the director and thus the lower the temperature at which the axially polar NF phase is formed. For homologues of intermediate chain lengths, between the non-polar and ferroelectric nematic phases, a wide temperature range nematic phase emerges with antiferroelectric character. The size of the antiparallel ferroelectric domains critically increases upon transition to the NF phase. In dielectric studies, both collective ("ferroelectric") and non-collective fluctuations are present, and the "ferroelectric" mode softens weakly at the N-NX phase transition because the polar order in this phase is weak. The transition to the NF phase is characterized by a much stronger lowering of the mode relaxation frequency and an increase in its strength, and a typical critical behavior is observed.
          Cover page: To Be or Not To Be Polar: The Ferroelectric and Antiferroelectric Nematic Phases
          • Article
          • Peer Reviewed
          UC San Francisco Previously Published Works (2021)
            • Article
            • Peer Reviewed
            LBL Publications (2018)
            Chiral symmetry breaking in soft matter is a hot topic of current research. Recently, such a phenomenon was found in a fluidic phase showing orientational order of molecules-the nematic phase; although built of achiral molecules, the phase can exhibit structural chirality-average molecular direction follows a short-pitch helix. Here, we report a series of achiral asymmetric dimers with an odd number of atoms in the spacer, which form twisted structures in nematic as well as in lamellar phases. The tight pitch heliconical nematic (NTB) phase and heliconical tilted smectic C (SmCTB) phase are formed. The formation of a variety of helical structures is accompanied by a gradual freezing of molecular rotation. In the lowest temperature smectic phase, HexI, the twist is expressed through the formation of hierarchical structure: nanoscale helices and mesoscopic helical filaments. The short-pitch helical structure in the smectic phases is confirmed by resonant X-ray measurements.
              Cover page: Heliconical smectic phases formed by achiral molecules
              • Article
              • Peer Reviewed
              LBL Publications (2018)
                Cover page: Addendum: Heliconical smectic phases formed by achiral molecules
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2019)
                Tissue-specific regulatory regions harbor substantial genetic risk for disease. Because brain development is a critical epoch for neuropsychiatric disease susceptibility, we characterized the genetic control of the transcriptome in 201 mid-gestational human brains, identifying 7,962 expression quantitative trait loci (eQTL) and 4,635 spliceQTL (sQTL), including several thousand prenatal-specific regulatory regions. We show that significant genetic liability for neuropsychiatric disease lies within prenatal eQTL and sQTL. Integration of eQTL and sQTL with genome-wide association studies (GWAS) via transcriptome-wide association identified dozens of novel candidate risk genes, highlighting shared and stage-specific mechanisms in schizophrenia (SCZ). Gene network analysis revealed that SCZ and autism spectrum disorder (ASD) affect distinct developmental gene co-expression modules. Yet, in each disorder, common and rare genetic variation converges within modules, which in ASD implicates superficial cortical neurons. More broadly, these data, available as a web browser and our analyses, demonstrate the genetic mechanisms by which developmental events have a widespread influence on adult anatomical and behavioral phenotypes.
                  Cover page: Genetic Control of Expression and Splicing in Developing Human Brain Informs Disease Mechanisms
                  • Article
                  • Peer Reviewed
                  UC San Diego Previously Published Works (2014)
                  The database of genotypes and phenotypes (dbGaP) developed by the National Center for Biotechnology Information (NCBI) is a resource that contains information on various genome-wide association studies (GWAS) and is currently available via NCBI's dbGaP Entrez interface. The database is an important resource, providing GWAS data that can be used for new exploratory research or cross-study validation by authorized users. However, finding studies relevant to a particular phenotype of interest is challenging, as phenotype information is presented in a non-standardized way. To address this issue, we developed PhenDisco (phenotype discoverer), a new information retrieval system for dbGaP. PhenDisco consists of two main components: (1) text processing tools that standardize phenotype variables and study metadata, and (2) information retrieval tools that support queries from users and return ranked results. In a preliminary comparison involving 18 search scenarios, PhenDisco showed promising performance for both unranked and ranked search comparisons with dbGaP's search engine Entrez. The system can be accessed at http://pfindr.net.
                    Cover page: PhenDisco: phenotype discovery system for the database of genotypes and phenotypes
                    • Article
                    • Peer Reviewed
                    UC San Diego Previously Published Works (2024)
                    Attention deficit hyperactivity disorder (ADHD) is a complex disorder that manifests variability in long-term outcomes and clinical presentations. The genetic contributions to such heterogeneity are not well understood. Here we show several genetic links to clinical heterogeneity in ADHD in a case-only study of 14,084 diagnosed individuals. First, we identify one genome-wide significant locus by comparing cases with ADHD and autism spectrum disorder (ASD) to cases with ADHD but not ASD. Second, we show that cases with ASD and ADHD, substance use disorder and ADHD, or first diagnosed with ADHD in adulthood have unique polygenic score (PGS) profiles that distinguish them from complementary case subgroups and controls. Finally, a PGS for an ASD diagnosis in ADHD cases predicted cognitive performance in an independent developmental cohort. Our approach uncovered evidence of genetic heterogeneity in ADHD, helping us to understand its etiology and providing a model for studies of other disorders.
                      Cover page: Polygenic profiles define aspects of clinical heterogeneity in attention deficit hyperactivity disorder
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