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Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2020)

The “replication crisis” has highlighted the apparent lack of replication across scientific fields. Assessing the true effect size of a genetic variant and designing an adequately powered study remain difficult when replicating genome-wide association studies (GWAS) results. Functional replication studies that validate the identified loci have also been scarce. Given the importance of replication, my thesis focuses on the computational and the functional aspects of replication. In chapter 1, I explored replication in a mouse model using an advanced intercross line (AIL), which is a multigenerational intercross between two inbred strains. I used genotyped and re-genotyped data from two cohorts of the LG/J x SM/J AIL mice (F34, n=428; F39-43, n=600). For the subset of traits that were measured in both cohorts (locomotor activity, body weight, and coat color), I attempted to replicate loci identified in either F34 or F39-43 in the other cohort. Coat color was robustly replicated; locomotor activity and body weight were only partially replicated, which was inconsistent with our power simulations. We used a random effects model to show that the partial replications could not be explained by Winner’s Curse but could be explained by study-specific heterogeneity. Despite this heterogeneity, I performed a mega-analysis by combining F34 and F39-43 cohorts (n=1,028). In chapter 2, I followed up on a candidate gene, Azi2, which had previously been identified in a GWAS for locomotor response to methamphetamine using an outbred Carworth Farms White (CFW) population. To validate Azi2 as a putative causal gene for methamphetamine sensitivity, I created an Azi2 knockout mouse line using CRISPR/Cas9 and established the mutant phenotype of locomotor response to methamphetamine. In addition, I investigated a published hypothesis that an independent transcript that matches to the second half of the 3’UTR sequence of Azi2 is a downregulator of Slc6a3, which encodes the dopamine transporter (DAT), in the ventral tegmental area (VTA) region of midbrain. To test this hypothesis, I examined the possible correlations among Azi2, Azi2 3’UTR, and Slc6a3 expression in the Azi2 KO line and in naïve CFW mice.

  • 2 supplemental ZIPs
Cover page: Genome-wide Association Discovery, Replication, and Validation in Mouse Models
  • Article
  • Peer Reviewed
UC San Diego Previously Published Works (2020)
There has been extensive discussion of the "Replication Crisis" in many fields, including genome-wide association studies (GWAS). We explored replication in a mouse model using an advanced intercross line (AIL), which is a multigenerational intercross between two inbred strains. We re-genotyped a previously published cohort of LG/J x SM/J AIL mice (F34; n = 428) using a denser marker set and genotyped a new cohort of AIL mice (F39-43; n = 600) for the first time. We identified 36 novel genome-wide significant loci in the F34 and 25 novel loci in the F39-43 cohort. The subset of traits that were measured in both cohorts (locomotor activity, body weight, and coat color) showed high genetic correlations, although the SNP heritabilities were slightly lower in the F39-43 cohort. For this subset of traits, we attempted to replicate loci identified in either F34 or F39-43 in the other cohort. Coat color was robustly replicated; locomotor activity and body weight were only partially replicated, which was inconsistent with our power simulations. We used a random effects model to show that the partial replications could not be explained by Winner's Curse but could be explained by study-specific heterogeneity. Despite this heterogeneity, we performed a mega-analysis by combining F34 and F39-43 cohorts (n = 1,028), which identified four novel loci associated with locomotor activity and body weight. These results illustrate that even with the high degree of genetic and environmental control possible in our experimental system, replication was hindered by study-specific heterogeneity, which has broad implications for ongoing concerns about reproducibility.
    Cover page: Genome-Wide Association Study in Two Cohorts from a Multi-generational Mouse Advanced Intercross Line Highlights the Difficulty of Replication
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2021)
    Identification of the cis-regulatory elements controlling cell-type specific gene expression patterns is essential for understanding the origin of cellular diversity. Conventional assays to map regulatory elements via open chromatin analysis of primary tissues is hindered by sample heterogeneity. Single cell analysis of accessible chromatin (scATAC-seq) can overcome this limitation. However, the high-level noise of each single cell profile and the large volume of data pose unique computational challenges. Here, we introduce SnapATAC, a software package for analyzing scATAC-seq datasets. SnapATAC dissects cellular heterogeneity in an unbiased manner and map the trajectories of cellular states. Using the Nyström method, SnapATAC can process data from up to a million cells. Furthermore, SnapATAC incorporates existing tools into a comprehensive package for analyzing single cell ATAC-seq dataset. As demonstration of its utility, SnapATAC is applied to 55,592 single-nucleus ATAC-seq profiles from the mouse secondary motor cortex. The analysis reveals ~370,000 candidate regulatory elements in 31 distinct cell populations in this brain region and inferred candidate cell-type specific transcriptional regulators.
      Creative Commons 'BY' version 4.0 license
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