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Found in Translation: Characterizing...

Johnstone, Timothy George.

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Found in Translation: Characterizing the Prevalence, Translation, and Regulatory Potential of Small Open Reading Frames in Vertebrates.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Found in Translation: Characterizing the Prevalence, Translation, and Regulatory Potential of Small Open Reading Frames in Vertebrates./
Author:	Johnstone, Timothy George.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2016,
Description:	130 p.
Notes:	Source: Dissertation Abstracts International, Volume: 77-12(E), Section: B.
Contained By:	Dissertation Abstracts International77-12B(E).
Subject:	Genetics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10154983
ISBN:	9781369100686

Found in Translation: Characterizing the Prevalence, Translation, and Regulatory Potential of Small Open Reading Frames in Vertebrates.
Johnstone, Timothy George.

Found in Translation: Characterizing the Prevalence, Translation, and Regulatory Potential of Small Open Reading Frames in Vertebrates. - Ann Arbor : ProQuest Dissertations & Theses, 2016 - 130 p.

Source: Dissertation Abstracts International, Volume: 77-12(E), Section: B.

Thesis (Ph.D.)--Yale University, 2016.

Identification of the coding elements in the genome is a fundamental step toward understanding the building blocks of living systems. While much effort has been put toward characterizing classical long proteins in development and disease, there is a vast, unexplored landscape of small open reading frames (smORFs) throughout the transcriptome that potentially encode functional peptide products. Small open reading frames can also be found upstream of known proteins in the leader sequences of protein-coding mRNAs. These upstream ORFs (uORFs) have been studied for their regulatory potential in the context of individual genes, but the function and translation status of the vast majority of uORFs was unknown. In this work, I combine ribosome profiling and computational analysis to elucidate the extent and role of small ORF translation in lincRNAs and transcript leader sequences across vertebrate species.

ISBN: 9781369100686Subjects--Topical Terms:

530508
Genetics.

Found in Translation: Characterizing the Prevalence, Translation, and Regulatory Potential of Small Open Reading Frames in Vertebrates.
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245 1 0 $a Found in Translation: Characterizing the Prevalence, Translation, and Regulatory Potential of Small Open Reading Frames in Vertebrates.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2016
300 $a 130 p.
500 $a Source: Dissertation Abstracts International, Volume: 77-12(E), Section: B.
500 $a Adviser: Antonio Giraldez.
502 $a Thesis (Ph.D.)--Yale University, 2016.
520 $a Identification of the coding elements in the genome is a fundamental step toward understanding the building blocks of living systems. While much effort has been put toward characterizing classical long proteins in development and disease, there is a vast, unexplored landscape of small open reading frames (smORFs) throughout the transcriptome that potentially encode functional peptide products. Small open reading frames can also be found upstream of known proteins in the leader sequences of protein-coding mRNAs. These upstream ORFs (uORFs) have been studied for their regulatory potential in the context of individual genes, but the function and translation status of the vast majority of uORFs was unknown. In this work, I combine ribosome profiling and computational analysis to elucidate the extent and role of small ORF translation in lincRNAs and transcript leader sequences across vertebrate species.
520 $a Refinement of the ribosome profiling protocol yielded individual nucleotide resolution of ribosome-protected fragments after size-selection. I developed an algorithm called ORFScore, which takes advantage of the trinucleotide periodicity of these footprints to classify translated ORFs transcriptome-wide. This method was first applied to previously annotated coding mRNAs, identifying the canonical CDS with >99% specificity. Application of ORFScore to predicted lincRNA transcripts in zebrafish and human exposed several hundred translated small ORFs, bringing the non-coding status of these transcripts into question. The analysis also identified translated small ORFs in known protein-coding mRNAs. Mass spectrometry experiments validated a subset of these ORFs, and a complementary conservation-based approach identified a subset of conserved, translated smORFs for further functional study. Together, these results identified a previously unexplored class of potential small peptides with implications for lincRNA translation and regulation.
520 $a Outside of lincRNAs, the majority of non-canonical translation detected by ORFScore occurred in the transcript leader sequences (TLSs, S'UTRs) of protein-coding genes. Sequence analysis showed that upstream ORFs are highly prevalent across human, mouse, and zebrafish, and ribosome profiling data in zebrafish provided evidence that a majority of uORFs are translated at some level. Though most uORFs are not conserved at the level of peptide sequence, transcriptome-wide investigation revealed a broad repressive effect of uORFs on both translation and steady-state mRNA levels across vertebrate species. Sequence analysis showed this repression to be dependent on features such as CDS overlap and uORF density, an effect confirmed by reporter experiments in vivo. The features determining repressiveness show evidence of selection, indicating that evolution has favored uORFs amenable to regulation over constitutively repressive uORFs and overlapping ORFs. These results provide insight into the regulatory capacity of transcript leader sequences and their potent capacity to modulate gene expression across vertebrates.
590 $a School code: 0265.
650 4 $a Genetics. $3 530508
650 4 $a Bioinformatics. $3 553671
650 4 $a Evolution & development. $3 3172418
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710 2 $a Yale University. $3 515640
773 0 $t Dissertation Abstracts International $g 77-12B(E).
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