ACAR, OMER
(2023)
UNDERSTANDING CELLULAR INNOVATION AND COMPLEXITY WITH A NETWORK PERSPECTIVE.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Biological systems are composed of numerous interconnected elements that form intricate networks, facilitating the proper functioning of living organisms. By examining these networks, we can uncover the mechanisms through which genotypes give rise to diverse phenotypes. As these networks evolve, new genes and proteins emerge, while existing ones are repurposed, duplicated, or lost, leading to the continuous reshaping of genotype-phenotype landscapes. While certain properties of genetic networks remain conserved across species, the integration of clade- or species-specific genes is critical for understanding unique phenotypes and adaptations to diverse environments and stressors. Furthermore, thousands of noncanonical open reading frames (nORFs), which have been omitted from genome annotations have been shown to be transcribed and translated, potentially impacting cellular network structures and phenotypes. However, nORFs have been less studied compared to canonical ORFs, leaving a significant knowledge gap in our understanding of their biological roles.
In this dissertation, we first delve deeper into the complex relationships and conserved properties of genetic interaction profile similarity networks, which represent functional similarities based on gene deletion phenotypes in similar biological backgrounds. We pinpoint modules that are vital for information transfer and the indirect relationships between these modules, demonstrating a preserved hierarchical structure of cellular networks enabling efficient signal propagation. Next, to study the transcription of nORFs, we construct an extended coexpression network in yeast and investigate the mechanisms by which nORFs get integrated into coexpression networks, as well as the genomic context influencing their emergence and cellular functions. Finally, we investigate a specific evolutionarily novel ORF, YBR196C-A, dissecting its transcriptional and structural evolution to study YBR196C-A’s potential cellular roles. This thorough examination illuminates the ORF’s origin, its transcriptional regulation, and the folding process resulting in stable tertiary structures, while also providing insights into its possible roles within cellular membranes.
Our findings significantly enhance our understanding of communication within cellular networks, the incorporation of new genetic components into these networks, and the interplay between gene transcription, protein folding, and cellular functionality. This knowledge offers valuable insights into the mechanisms of adaptation and evolution, laying the foundation for future research in evolutionary systems biology.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
4 October 2023 |
| Date Type: |
Publication |
| Defense Date: |
11 May 2023 |
| Approval Date: |
4 October 2023 |
| Submission Date: |
2 June 2023 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
167 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Computational Biology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
network biology, de novo gene birth, noncanonical translatome |
| Date Deposited: |
04 Oct 2023 19:11 |
| Last Modified: |
04 Oct 2023 19:11 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/44853 |
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