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dc.contributor.advisorOliver Rando, MD, PhD
dc.contributor.authorShea, Jeremy M.
dc.date2022-08-11T08:08:45.000
dc.date.accessioned2022-08-23T16:06:48Z
dc.date.available2022-08-23T16:06:48Z
dc.date.issued2015-03-19
dc.date.submitted2015-07-23
dc.identifier.doi10.13028/M27S3C
dc.identifier.urihttp://hdl.handle.net/20.500.14038/32122
dc.description.abstractThe following work demonstrates that paternal diet controls medically important metabolic phenotypes in offspring. We observe transmission of dietary information to the zygote via sperm, and this information evades reprogramming that typically occurs after fertilization. Cytosine methylation is implicated as a major contributor to meiotic epigenetic inheritance in several transgenerational phenomena. Our extensive characterization of the sperm methylome reveals that diet does not significantly affect methylation patterns. However, we find that extensive epivariability in the sperm epigenome makes important contributions to offspring variation. Importantly, coordinate cytosine methylation and copy number changes over the ribosomal DNA locus contributes to variation in offspring metabolism. Thus, rDNA variability acts independently of postadolescent paternal diet to influence offspring metabolism. Therefore, at least two mechanisms exist for epigenetically controlling offspring metabolism: stochastic epivariation and diet acting by an unknown mechanism to further modulate metabolism. This work argues that an offspring's phenotype can no longer be viewed solely as the result of genetic interactions with the developmental environment - the additional influences of paternal environment and inherited epigenetic variability must also be considered. These findings reveal novel contributions to metabolism that could revolutionize how we think about the risk factors for human health and disease.
dc.language.isoen_US
dc.rightsCopyright is held by the author, with all rights reserved.
dc.subjectDissertations, UMMS
dc.subjectGenomic Imprinting
dc.subjectMetabolism
dc.subjectInheritance Patterns
dc.subjectPaternal Exposure
dc.subjectDNA Methylation
dc.subjectDNA, Ribosomal DNA, Ribosomal
dc.subjectDiet
dc.subjectEpigenesis, Genetic
dc.subjectEpigenomics
dc.subjectFertilization
dc.subjectPhenotype
dc.subjectSpermatozoa
dc.subjectGenomic Imprinting
dc.subjectMetabolism
dc.subjectInheritance Patterns
dc.subjectPaternal Exposure
dc.subjectDNA Methylation
dc.subjectDNA
dc.subjectRibosomal DNA
dc.subjectDiet
dc.subjectGenetic Epigenesis
dc.subjectEpigenomics
dc.subjectFertilization
dc.subjectPhenotype
dc.subjectSpermatozoa
dc.subjectBiology
dc.subjectCellular and Molecular Physiology
dc.subjectGenetics and Genomics
dc.subjectGenomics
dc.titlePaternal Effects on Metabolism in Mammals: A Dissertation
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1758&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/759
dc.legacy.embargo2016-03-25T00:00:00-07:00
dc.identifier.contextkey7361412
refterms.dateFOA2022-08-30T16:26:59Z
html.description.abstract<p>The following work demonstrates that paternal diet controls medically important metabolic phenotypes in offspring. We observe transmission of dietary information to the zygote via sperm, and this information evades reprogramming that typically occurs after fertilization. Cytosine methylation is implicated as a major contributor to meiotic epigenetic inheritance in several transgenerational phenomena. Our extensive characterization of the sperm methylome reveals that diet does not significantly affect methylation patterns. However, we find that extensive epivariability in the sperm epigenome makes important contributions to offspring variation. Importantly, coordinate cytosine methylation and copy number changes over the ribosomal DNA locus contributes to variation in offspring metabolism. Thus, rDNA variability acts independently of postadolescent paternal diet to influence offspring metabolism. Therefore, at least two mechanisms exist for epigenetically controlling offspring metabolism: stochastic epivariation and diet acting by an unknown mechanism to further modulate metabolism. This work argues that an offspring's phenotype can no longer be viewed solely as the result of genetic interactions with the developmental environment - the additional influences of paternal environment and inherited epigenetic variability must also be considered. These findings reveal novel contributions to metabolism that could revolutionize how we think about the risk factors for human health and disease.</p>
dc.identifier.submissionpathgsbs_diss/759
dc.contributor.departmentBiochemistry and Molecular Pharmacology
dc.description.thesisprogramInterdisciplinary Graduate Program


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