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  4. The functional evolution of human microRNA families
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The functional evolution of human microRNA families

Full metadata

Description

MicroRNAs (miRNAs) are short non-coding RNAs that play key roles during metazoan development, and are frequently misregulated in human disease. MiRNAs regulate gene output by targeting degenerate elements primarily in the 3´ untranslated regions of mRNAs. MiRNAs are often deeply conserved, but have undergone drastic expansions in higher metazoans, leading to families of miRNAs with highly similar sequences. The evolutionary advantage of maintaining multiple copies of duplicated miRNAs is not well understood, nor has the distinct functions of miRNA family members been systematically studied. Furthermore, the unbiased and high-throughput discovery of targets remains a major challenge, yet is required to understand the biological function of a given miRNA.

I hypothesize that duplication events grant miRNA families with enhanced regulatory capabilities, specifically through distinct targeting preferences by family members. This has relevance for our understanding of vertebrate evolution, as well disease detection and personalized medicine. To test this hypothesis, I apply a conjunction of bioinformatic and experimental approaches, and design a novel high-throughput screening platform to identify human miRNA targets. Combined with conventional approaches, this tool allows systematic testing for functional targets of human miRNAs, and the identification of novel target genes on an unprecedented scale.

In this dissertation, I explore evolutionary signatures of 62 deeply conserved metazoan miRNA families, as well as the targeting preferences for several human miRNAs. I find that constraints on miRNA processing impact sequence evolution, creating evolutionary hotspots within families that guide distinct target preferences. I apply our novel screening platform to two cancer-relevant miRNAs, and identify hundreds of previously undescribed targets. I also analyze critical features of functional miRNA target sites, finding that each miRNA recognizes surprisingly distinct features of targets. To further explore the functional distinction between family members, I analyze miRNA expression patterns in multiple contexts, including mouse embryogenesis, RNA-seq data from human tissues, and cancer cell lines. Together, my results inform a model that describes the evolution of metazoan miRNAs, and suggests that highly similar miRNA family members possess distinct functions. These findings broaden our understanding of miRNA function in vertebrate evolution and development, and how their misexpression contributes to human disease.

Date Created
2016
Contributors
  • Wolter, Justin M (Author)
  • Mangone, Marco (Thesis advisor)
  • LaBaer, Joshua (Committee member)
  • Kusumi, Kenro (Committee member)
  • Anderson, Karen (Committee member)
  • Arizona State University (Publisher)
Topical Subject
  • Molecular Biology
  • Evolution & development
  • Genetics
  • 3'LIFE
  • 3'UTR
  • developmental evolution
  • microRNA
  • miRNA
  • miRNA targets
  • RNA--Evolution.
  • RNA
Resource Type
Text
Genre
Doctoral Dissertation
Academic theses
Extent
xiv, 226 pages : illustrations (some color)
Language
eng
Copyright Statement
In Copyright
Reuse Permissions
All Rights Reserved
Primary Member of
ASU Electronic Theses and Dissertations
Peer-reviewed
No
Open Access
No
Handle
https://hdl.handle.net/2286/R.I.41220
Statement of Responsibility
by Justin M. Wolter
Description Source
Retrieved on June 8, 2017
Level of coding
full
Note
Partial requirement for: Ph.D., Arizona State University, 2016
Note type
thesis
Includes bibliographical references (pages 179-214)
Note type
bibliography
Field of study: Molecular and cellular biology
System Created
  • 2017-02-01 07:00:21
System Modified
  • 2021-08-30 01:20:11
  •     
  • 1 year 9 months ago
Additional Formats
  • OAI Dublin Core
  • MODS XML

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