Systematic discovery of human gene function and principles of modular organization through phylogenetic profiling
Abstract/Contents
- Abstract
- A significant fraction of human genes remain functionally uncharacterized despite major advances in perturbation and mapping techniques. The correlated gain and loss of orthologous genes across species, reflecting a shared evolutionary history, can be used to infer novel functional interactions in a technique known as phylogenetic profiling. Advances in sequencing technology and plummeting costs have enabled the sequencing of hundreds of eukaryotic genomes, hugely increasing the potential utility of phylogenetic profiling in providing systematic functional predictions for the human genome. However, genome-wide profiling has been hindered by challenges in orthology assignment caused by the large number of human genes related to each other through duplication events and the lack of robust scalable methods to assess the degree of coevolution. I overcame these challenges in automatically profiling over 30,000 groups of homologous human genes (orthogroups) representing the entire protein-coding genome across 177 eukaryotic species. By generating a full pairwise orthogroup phylogenetic co-occurrence matrix, I derived unbiased genome-wide predictions of functional modules and identified topological constraints on evolutionary modularity, with metabolic genes and physical protein complexes more likely to coevolve than signaling and transcriptional networks. Importantly, the algorithm predicts functions for hundreds of poorly characterized genes. To demonstrate its utility in guiding experimental gene function discovery, I validated two subsets of candidates experimentally for their predicted link to the actin-nucleating WASH complex and cilia/basal body function.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2015 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Dey, Gautam |
|---|---|
| Associated with | Stanford University, Department of Chemical and Systems Biology. |
| Primary advisor | Meyer, Tobias |
| Thesis advisor | Meyer, Tobias |
| Thesis advisor | Ferrell, James Ellsworth |
| Thesis advisor | Skotheim, Jan, 1977- |
| Thesis advisor | Wandless, Thomas |
| Advisor | Ferrell, James Ellsworth |
| Advisor | Skotheim, Jan, 1977- |
| Advisor | Wandless, Thomas |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Gautam Dey. |
|---|---|
| Note | Submitted to the Department of Chemical and Systems Biology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2015. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2015 by Gautam Dey
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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