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Open Access Publications from the University of California

Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UC Berkeley Electronic Theses and Dissertations (2021)

Alternative splicing is a post-transcriptional gene regulatory process that increases transcriptomic diversity through the differential selection of exons. Over the past decade, single cell RNA sequencing (scRNA-seq) experiments have allowed the study of the complex heterogeneity of tissues, and the gene expression regulation mechanisms that determine the identity of individual cells. However the study of alternative splicing has largely lagged behind in single-cell approaches. This is in part due to a number of technical limitations that make this study particularly difficult. In this dissertation, I first demonstrate that the technical distortion of splicing observations in single cells produces the appearance of bimodality in single cell splicing. I discuss how this limitation has affected our understanding of single cell splicing, and what computational approaches can be used to extract meaningful biological information from this exceptionally noisy data. I then present Psix: a computational tool that implements an updated model for single cell splicing observations that takes into account this distortion. Using Psix, I identify alternative splicing that changes across a phenotypic landscape, as well as groups of potentially co-spliced exons. Finally, I explore potential regulatory roles for these poison exons in the production of Serine/Arginine-rich (SR) splicing factor proteins.

    • Article
    • Peer Reviewed
    UC Santa Cruz Previously Published Works (2015)

    Background

    Determining whether two DNA samples originate from the same individual is difficult when the amount of retrievable DNA is limited. This is often the case for ancient, historic, and forensic samples. The most widely used approaches rely on amplification of a defined panel of multi-allelic markers and comparison to similar data from other samples. When the amount retrievable DNA is low these approaches fail.

    Results

    We describe a new method for assessing whether shotgun DNA sequence data from two samples are consistent with originating from the same or different individuals. Our approach makes use of the large catalogs of single nucleotide polymorphism (SNP) markers to maximize the chances of observing potentially discriminating alleles. We further reduce the amount of data required by taking advantage of patterns of linkage disequilibrium modeled by a reference panel of haplotypes to indirectly compare observations at pairs of linked SNPs. Using both coalescent simulations and real sequencing data from modern and ancient sources, we show that this approach is robust with respect to the reference panel and has power to detect positive identity from DNA libraries with less than 1 % random and non-overlapping genome coverage in each sample.

    Conclusion

    We present a powerful new approach that can determine whether DNA from two samples originated from the same individual even when only minute quantities of DNA are recoverable from each.
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