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Principal Investigator: JOHN V. MORAN
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $319,163
Funding agency: National Institute of General Medical Sciences
Abstract
Long INterspersed Element-1 (LINE-1 or L1) transposable element derived sequences comprise
approximately 17% of human genomic DNA. Although the overwhelming majority of LINE-1s have been rendered
immobile by mutational processes over evolutionary time, an average human genome contains approximately
100 active LINE-1s that can mobilize to new genomic locations via an RNA intermediate by a process known as
retrotransposition. The retrotransposition of active LINE-1s in the germline, during early development, or in select
somatic cells continues to generate inter- and intra-individual genetic variation and can lead to sporadic cases
of human genetic diseases, including hemophilia A, hemophilia B, Duchenne muscular dystrophy, and certain
cancers. We posit that a mechanistic understanding of LINE-1 biology is essential to understand the forces that
contribute to human disease, human genetic variation, and human evolution. This proposal represents the third
competing renewal application of GM060518, and seeks ongoing support to continue our studies of LINE-1
biology. We will build upon our experience and knowledge in the field of mobile genetic elements, use insights
gained from studies of the mobility mechanisms of evolutionarily related retrotransposons, and employ a LINE-
1 cultured cell retrotransposition assay in conjunction with an integrated strategy that combines genetic,
molecular biological, biochemical, multi-omic, and computational approaches to answer cutting-edge questions
in LINE-1 biology. This proposal comprises two Aims, which build upon our extensive toolbox of reagents,
previous findings, and preliminary data. In Aim 1, we will elucidate mechanistic aspects of LINE-1
retrotransposition. In Aim 2, we will determine how host proteins act to facilitate or restrict LINE-1
retrotransposition. This project will benefit from a long-standing successful collaboration between the Moran and
Kidd laboratories at the University of Michigan and our outstanding research teams. The successful completion
of the above Specific Aims will increase our understanding how LINE-1s mobilize to new genomic locations, how
the host has evolved mechanisms to prevent unabated LINE-1 retrotransposition, and how LINE-1 has exploited
cellular proteins to aid in its retrotransposition. This knowledge also will provide insights into how LINE-1
retrotransposition contributes to human disease, human genetic variation, and human genome evolution.
Terms: <3' Untranslated Regions><3'UTR><5' Splice Site><5' Untranslated Regions><5'UTR><ATM Protein><ATM Serine/Threonine Protein Kinase><ATM kinase><ATM protein kinase><Address><Affect><Antigenic Determinants><Assay><Ataxia Telangiectasia><Ataxia Telangiectasia Mutated><Ataxia Telangiectasia Protein><Ataxia Telangiectasia Syndrome><Ataxia-Telangiectasia-Mutated protein kinase><Binding Determinants><Binding Proteins><Bioassay><Biochemical><Biological><Biological Assay><Biology><Cancers><Cell Body><Cells><Christmas Disease><Collaborations><Complex><Cultured Cells><Cytidine Aminohydrolase><Cytidine Deaminase><DNA><DNA Damage><DNA Injury><DNA Nucleases><DNA Replication><DNA Synthesis><DNA Transposable Elements><DNA biosynthesis><DNA replication factor A><DNase><Data><Deoxyribonucleases><Deoxyribonucleic Acid><Development><Duchene><Duchenne><Duchenne muscular dystrophy><Duchenne-Griesinger syndrome><EC 2.7.7.49><Ellis-van Creveld (EvC) syndrome><Engineering><Epitopes><Event><Evolution><Experimental Models><Factor IX Deficiency><Factor VIII Deficiency><Family><Foundations><Genetic><Genetic Alteration><Genetic Change><Genetic Diseases><Genetic Diversity><Genetic Variation><Genetic analyses><Genetic defect><Genomic DNA><Germ Lines><Goals><Hemophilia><Hemophilia A><Hemophilia B><Host Factor><Host Factor Protein><Human><Human Genetics><Human Genome><Immobilization><Immune Precipitation><Immunoprecipitation><Individual><Integration Host Factors><Knowledge><Laboratories><Laboratory Study><Length><Ligand Binding Protein><Ligand Binding Protein Gene><Long Interspersed Elements><Louis-Bar Syndrome><Malignant Neoplasms><Malignant Tumor><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Messenger RNA><Michigan><Mobile Genetic Elements><Modern Man><Molecular><Molecular Analysis><Mutation><ORFs><Open Reading Frames><PARP Polymerase><PARP protein><PARS><Poly(A) Tail><Poly(ADP-ribose) Polymerases><Poly(ADPribose) Polymerase><Polymerase><Process><Protein Binding><Protein Coding Region><Proteins><Pseudohypertrophic Muscular Dystrophy><RNA Splicing><RNA Transcriptase><RNA-Dependent DNA Polymerase><RNA-Directed DNA Polymerase><Reading Frames><Reagent><Research><Retrotransposition><Retrotransposon><Reverse Transcriptase><Revertase><Site><Somatic Cell><Splice Donor Sites><Splicing><Structure><Testing><Time><Transcript><Translating><Transposable Elements><Universities><Viral Gene Products><Viral Gene Proteins><Viral Proteins><X Chromosome><X-linked dilated cardiomyopathy><X-linked muscular dystrophy><X-linked recessive muscular dystrophy><Zinc Finger Domain><Zinc Finger Motifs><Zinc Fingers><access restrictions><ataxia telangiectasia mutated protein><benign X-linked recessive muscular dystrophy><biologic><bound protein><childhood pseudohypertrophic muscular dystrophy><classic X-linked recessive muscular dystrophy><developmental><endonuclease><experience><gDNA><gene locus><genetic analysis><genetic condition><genetic disorder><genetic locus><genome mutation><genomic location><genomic locus><human disease><human whole genome><insight><mRNA><mRNA Leader Sequences><malignancy><member><mild X-linked recessive muscular dystrophy><multiomics><multiple omics><neoplasm/cancer><orthopedic freezing><panomics><poly ADP polymerase><poly ADP ribose synthetase><prevent><preventing><progressive muscular dystrophy of childhood><promoter><promotor><protein protein interaction><pseudohypertrophic adult muscular dystrophy><pseudohypertrophic muscular paralysis><recruit><replication factor A><replication protein A><response><single-strand binding protein RP-A><success><virus protein>