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dc.contributor.advisorYang, Ivana
dc.contributor.authorPacheco, Ashley
dc.contributor.committeememberLaw, Amanda
dc.contributor.committeememberNovins, Douglas
dc.contributor.committeememberSantorico, Stephanie
dc.contributor.committeememberSikela, James
dc.contributor.committeememberShaikh, Tamim
dc.date.accessioned2019-05-17T20:03:30Z
dc.date.available2021-05-16T19:43:49Z
dc.date.submitted2019
dc.descriptionIncludes bibliographical references.
dc.descriptionSpring
dc.description.abstractThe MIR137HG gene encoding microRNA-137 (miR-137) is associated with risk for schizophrenia (SZ) through genetic and functional studies, however, the molecular mechanisms underlying risk remain unknown. Through this work we characterize MIR137HG genetic risk architecture and describe novel regulatory mechanisms that contribute to neurodevelopment and potential etiology for SZ. Case-control haplotype analyses revealed novel MIR137HG common and rare haplotype associations. Multiple genetic variants contribute to these diagnostic associations including a nearby variable number tandem repeat (VNTR) element. Through transcript characterization at early and late developmental time points we found novel del-miR-137 splice variants that down regulate mature miR-137 expression through alternative 5′ splicing within the pre-miR-137 sequence in exon 3. Importantly, we found significant positive associations between del-miR-137 transcripts and early development as well as VNTR length. We present a novel regulatory mechanism for miR-137 through increased regional GC% content and localization of the microRNA biogenesis regulator methyl-CpG-binding protein 2 (MECP2). Additionally, we describe putative novel competitive endogenous RNA (ceRNA) function for del-miR-137 transcripts. Through sequence structure analysis we describe a potential isomiR of miR-137 overlapping the canonical sequence. Lastly, we detail genetic variants in the context of human evolution and overall associations with complex disease.
dc.identifierPacheco_ucdenveramc_1639D_10634.pdf
dc.identifier.urihttps://hdl.handle.net/10968/3456
dc.languageEnglish
dc.publisherUniversity of Colorado at Denver, Anschutz Medical Campus. Health Sciences Library
dc.rightsCopyright of the original work is retained by the author.
dc.rights.accessEmbargo Expires: 05/16/2021
dc.subject.meshSchizophrenia
dc.subject.meshMicroRNAs
dc.titleCharacterizing MIR137HG variation and contribution to risk for schizophrenia
dc.typeThesis
dcterms.embargo.expires2021-05-16
thesis.degree.disciplineHuman Medical Genetics & Genomics
thesis.degree.grantorUniversity of Colorado at Denver, Anschutz Medical Campus
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)


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