{"id":{"repo_id":"mit","oai_identifier":"oai:dspace.mit.edu:1721.1/164489"},"canonical_url":"https://search.dev.ndltd.org/etd/mit/oai:dspace.mit.edu:1721.1/164489","repository":{"repo_id":"mit","name":"MIT","base_url":"https://dspace.mit.edu/oai/request"},"display":{"title":"Quantitative modeling of 5' splice site subclass regulation and evolution","abstract":"Pre-mRNA splicing is an essential molecular process required for eukaryotic gene expression. In this thesis, I present a previously unknown mechanism of splicing regulation where a family of splicing factors, the LUC7 family, compete to differentially impact 5→ splice site (5→ SS) selection in a sequence-dependent manner. I quantitatively characterize two major subclasses of 5→ SS in eukaryotes and outline distinctive features of 5→ SS in exons affected by the three human LUC7 paralogs: LUC7L2 and LUC7L enhance splicing of “right-handed” 5→ SS that exhibit stronger consensus matching on the intron side of the nearly-invariant / GU, while LUC7L3 boosts splicing of “left-handed” 5→ SS with stronger consensus matching upstream of the /GU. Using a range of experimental systems, from human cells to mutant plants, I show that LUC7 paralogs have opposing effects on these two 5→ SS subclasses and that this regulatory mechanism likely originated in the last common ancestor of animals and plants over 1.5 billion years ago. I further evaluate a competing model of 5→ SS subclass regulation involving METTL16- mediated U6 snRNA modification and reconcile both models by devising computational tools that identify sequence features predictive splicing dysregulation in transcriptome-wide datasets. Finally, I examine the evolutionary dynamics of left- and right-handed 5→ SS and propose a model of intron evolution in which codon and intron phase constraints in protein-coding genes shape both minor-to-major intron conversion and transitions between left- and right- 5→ SS subclasses.","abstract_html":"Pre-mRNA splicing is an essential molecular process required for eukaryotic gene expression. In this thesis, I present a previously unknown mechanism of splicing regulation where a family of splicing factors, the LUC7 family, compete to differentially impact 5→ splice site (5→ SS) selection in a sequence-dependent manner. I quantitatively characterize two major subclasses of 5→ SS in eukaryotes and outline distinctive features of 5→ SS in exons affected by the three human LUC7 paralogs: LUC7L2 and LUC7L enhance splicing of “right-handed” 5→ SS that exhibit stronger consensus matching on the intron side of the nearly-invariant / GU, while LUC7L3 boosts splicing of “left-handed” 5→ SS with stronger consensus matching upstream of the /GU. Using a range of experimental systems, from human cells to mutant plants, I show that LUC7 paralogs have opposing effects on these two 5→ SS subclasses and that this regulatory mechanism likely originated in the last common ancestor of animals and plants over 1.5 billion years ago. I further evaluate a competing model of 5→ SS subclass regulation involving METTL16- mediated U6 snRNA modification and reconcile both models by devising computational tools that identify sequence features predictive splicing dysregulation in transcriptome-wide datasets. Finally, I examine the evolutionary dynamics of left- and right-handed 5→ SS and propose a model of intron evolution in which codon and intron phase constraints in protein-coding genes shape both minor-to-major intron conversion and transitions between left- and right- 5→ SS subclasses.","abstract_has_math":false,"creators":["Kenny, Connor Jens"],"institution":"Massachusetts Institute of Technology","degree_name":"Doctoral","degree_level":null,"degree_discipline":null,"degree_department":"Massachusetts Institute of Technology. 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In this thesis, I present a previously unknown mechanism of splicing regulation where a family of splicing factors, the LUC7 family, compete to differentially impact 5→ splice site (5→ SS) selection in a sequence-dependent manner. I quantitatively characterize two major subclasses of 5→ SS in eukaryotes and outline distinctive features of 5→ SS in exons affected by the three human LUC7 paralogs: LUC7L2 and LUC7L enhance splicing of “right-handed” 5→ SS that exhibit stronger consensus matching on the intron side of the nearly-invariant / GU, while LUC7L3 boosts splicing of “left-handed” 5→ SS with stronger consensus matching upstream of the /GU. Using a range of experimental systems, from human cells to mutant plants, I show that LUC7 paralogs have opposing effects on these two 5→ SS subclasses and that this regulatory mechanism likely originated in the last common ancestor of animals and plants over 1.5 billion years ago. I further evaluate a competing model of 5→ SS subclass regulation involving METTL16- mediated U6 snRNA modification and reconcile both models by devising computational tools that identify sequence features predictive splicing dysregulation in transcriptome-wide datasets. Finally, I examine the evolutionary dynamics of left- and right-handed 5→ SS and propose a model of intron evolution in which codon and intron phase constraints in protein-coding genes shape both minor-to-major intron conversion and transitions between left- and right- 5→ SS subclasses."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Ph.D."]},{"key":"dc:title","label":"Title","values":["Quantitative modeling of 5' splice site subclass regulation and evolution"]}]}],"canonical_facts":{"dc:contributor.advisor":["Burge, Christopher B."],"dc:contributor.department":["Massachusetts Institute of Technology. Department of Biology"],"dc:creator":["Kenny, Connor Jens"],"dc:date.accessioned":["2026-01-12T19:40:03Z"],"dc:date.available":["2026-01-12T19:40:03Z"],"dc:date.issued":["2025-09"],"dc:description.abstract":["Pre-mRNA splicing is an essential molecular process required for eukaryotic gene expression. In this thesis, I present a previously unknown mechanism of splicing regulation where a family of splicing factors, the LUC7 family, compete to differentially impact 5→ splice site (5→ SS) selection in a sequence-dependent manner. I quantitatively characterize two major subclasses of 5→ SS in eukaryotes and outline distinctive features of 5→ SS in exons affected by the three human LUC7 paralogs: LUC7L2 and LUC7L enhance splicing of “right-handed” 5→ SS that exhibit stronger consensus matching on the intron side of the nearly-invariant / GU, while LUC7L3 boosts splicing of “left-handed” 5→ SS with stronger consensus matching upstream of the /GU. Using a range of experimental systems, from human cells to mutant plants, I show that LUC7 paralogs have opposing effects on these two 5→ SS subclasses and that this regulatory mechanism likely originated in the last common ancestor of animals and plants over 1.5 billion years ago. I further evaluate a competing model of 5→ SS subclass regulation involving METTL16- mediated U6 snRNA modification and reconcile both models by devising computational tools that identify sequence features predictive splicing dysregulation in transcriptome-wide datasets. Finally, I examine the evolutionary dynamics of left- and right-handed 5→ SS and propose a model of intron evolution in which codon and intron phase constraints in protein-coding genes shape both minor-to-major intron conversion and transitions between left- and right- 5→ SS subclasses."],"dc:description.degree":["Ph.D."],"dc:identifier.uri":["https://hdl.handle.net/1721.1/164489"],"dc:publisher":["Massachusetts Institute of Technology"],"dc:rights":["In Copyright - Educational Use Permitted","Copyright retained by author(s)"],"dc:rights.uri":["https://rightsstatements.org/page/InC-EDU/1.0/"],"dc:title":["Quantitative modeling of 5' splice site subclass regulation and evolution"],"dc:type":["Thesis"],"thesis:degree_name":["Doctoral","Doctor of Philosophy"]},"updated_at":"2026-07-22T22:20:44Z"}