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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2023)

Specialization on fruit, or frugivory, is a dietary adaptation that has evolved multiple times in primates and bats. While there are some genes that have been linked to this dietary specialization, the genetic factors, particularly gene regulatory factors, underlying mammalian frugivory are largely unknown. In this work, I utilized a combination of comparative and functional genomics to identify and functionally examine genetic factors for frugivorous adaptation in mammals. First, I used accelerated regions analysis to identify regions of the genome that are highly conserved across mammals but have significantly changed in fruit-eating bats and primates, termed frugivorous accelerated regions (FARs), and tested selected FARs in vitro and in vivo. I found that FARs drive transcriptional activity in luciferase reporter assays and mouse transgenic reporter assays, and we are now examining FAR phenotypes from mouse genomic sequence swapping. Next, I conducted the first combined single-cell RNA- and ATAC-seq on fasted and fed frugivorous and insectivorous bat kidneys and pancreases. We characterized cell composition, gene expression, and gene regulation in these heterogeneous tissues and revealed many novel cellular and molecular traits in frugivorous bats. Importantly, we found frugivorous bats share many traits with human diabetes and demonstrate how our integrative single-cell profilings can be used for therapeutic purposes.

  • 2 supplemental ZIPs
Cover page: Investigating the genetic factors underlying the evolution of frugivory using comparative and functional genomics
  • Article
  • Peer Reviewed
UC San Diego Previously Published Works (2019)
Ionocytes are specialized cells in the epidermis of embryonic zebrafish (Danio rerio) that play important roles in ion homeostasis and have functional similarities to mammalian renal cells. Here, we examined whether these cells might also share another functional similarity with renal cells, which is the presence of efflux transporter activities useful for elimination of toxic small molecules. Xenobiotic transporters (XTs), including the ATP-Binding Cassette (ABC) family, are a major defense mechanism against diffusible toxic molecules in aquatic embryos, including zebrafish, but their activity in the ionocytes has not previously been studied. Using fluorescent small molecule substrates of XT, we observed that specific populations of ionocytes uptake and efflux fluorescent small molecules in a manner consistent with active transport. We specifically identified a P-gp/ABCB1 inhibitor-sensitive efflux activity in the H+-ATPase-rich (HR) ionocytes, and show that these cells exhibit enriched expression of the ABCB gene, abcb5. The results extend our understanding of the functional significance of zebrafish ionocytes and indicate that these cells could play an important role in protection of the fish embryo from harmful small molecules.
    Cover page: Xenobiotic transporter activity in zebrafish embryo ionocytes
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2024)
    Frugivory evolved multiple times in mammals, including bats. However, the cellular and molecular components driving it remain largely unknown. Here, we use integrative single-cell sequencing (scRNA-seq and scATAC-seq) on insectivorous (Eptesicus fuscus; big brown bat) and frugivorous (Artibeus jamaicensis; Jamaican fruit bat) bat kidneys and pancreases and identify key cell population, gene expression and regulatory differences associated with the Jamaican fruit bat that also relate to human disease, particularly diabetes. We find a decrease in loop of Henle and an increase in collecting duct cells, and differentially active genes and regulatory elements involved in fluid and electrolyte balance in the Jamaican fruit bat kidney. The Jamaican fruit bat pancreas shows an increase in endocrine and a decrease in exocrine cells, and differences in genes and regulatory elements involved in insulin regulation. We also find that these frugivorous bats share several molecular characteristics with human diabetes. Combined, our work provides insights from a frugivorous mammal that could be leveraged for therapeutic purposes.
      Cover page: Integrative single-cell characterization of a frugivorous and an insectivorous bat kidney and pancreas
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2021)
      Gene regulatory divergence is thought to play a central role in determining human-specific traits. However, our ability to link divergent regulation to divergent phenotypes is limited. Here, we utilized human-chimpanzee hybrid induced pluripotent stem cells to study gene expression separating these species. The tetraploid hybrid cells allowed us to separate cis- from trans-regulatory effects, and to control for nongenetic confounding factors. We differentiated these cells into cranial neural crest cells, the primary cell type giving rise to the face. We discovered evidence of lineage-specific selection on the hedgehog signaling pathway, including a human-specific sixfold down-regulation of EVC2 (LIMBIN), a key hedgehog gene. Inducing a similar down-regulation of EVC2 substantially reduced hedgehog signaling output. Mice and humans lacking functional EVC2 show striking phenotypic parallels to human-chimpanzee craniofacial differences, suggesting that the regulatory divergence of hedgehog signaling may have contributed to the unique craniofacial morphology of humans.
        Cover page: Human–chimpanzee fused cells reveal cis-regulatory divergence underlying skeletal evolution
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