{"doi":"10.1101/gr.089789.108","title":"Diverse <i>cis</i> factors controlling <i>Alu</i> retrotransposition: What causes <i>Alu</i> elements to die?","abstract":"<jats:p>The human genome contains nearly 1.1 million <jats:italic>Alu</jats:italic> elements comprising roughly 11% of its total DNA content. <jats:italic>Alu</jats:italic> elements use a copy and paste retrotransposition mechanism that can result in de novo disease insertion alleles. There are nearly 900,000 old <jats:italic>Alu</jats:italic> elements from subfamilies S and J that appear to be almost completely inactive, and about 200,000 from subfamily Y or younger, which include a few thousand copies of the Ya5 subfamily which makes up the majority of current activity. Given the much higher copy number of the older <jats:italic>Alu</jats:italic> subfamilies, it is not known why all of the active <jats:italic>Alu</jats:italic> elements belong to the younger subfamilies. We present a systematic analysis evaluating the observed sequence variation in the different sections of an <jats:italic>Alu</jats:italic> element on retrotransposition. The length of the longest number of uninterrupted adenines in the A-tail, the degree of A-tail heterogeneity, the length of the 3′ unique end after the A-tail and before the RNA polymerase III terminator, and random mutations found in the right monomer all modulate the retrotransposition efficiency. These changes occur over different evolutionary time frames. The combined impact of sequence changes in all of these regions explains why young <jats:italic>Alu</jats:italic>s are currently causing disease through retrotransposition, and the old <jats:italic>Alu</jats:italic>s have lost their ability to retrotranspose. We present a predictive model to evaluate the retrotransposition capability of individual <jats:italic>Alu</jats:italic> elements and successfully applied it to identify the first putative source element for a disease-causing <jats:italic>Alu</jats:italic> insertion in a patient with cystic fibrosis.</jats:p>","journal":"Genome Research","year":2009,"id":34570,"datarank":3.0370951123767567,"base_score":4.653960350157523,"endowment":4.653960350157523,"self_citation_contribution":0.6980940525236285,"citation_network_contribution":2.339001059853128,"self_endowment_contribution":0.6980940525236285,"citer_contribution":2.339001059853128,"corpus_percentile":null,"corpus_rank":null,"citation_count":104,"citer_count":74,"citers_with_citation_signal":64,"citers_with_endowment":64,"datacite_reuse_total":24,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":178846,"name":"Astrid M. Roy-Engel","orcid":null,"position":1,"is_corresponding":false},{"id":178847,"name":"Dale J. Hedges","orcid":null,"position":2,"is_corresponding":false},{"id":12933,"name":"Prescott L. Deininger","orcid":"0000-0002-1067-3028","position":3,"is_corresponding":false},{"id":178845,"name":"Matthew S. Comeaux","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":4.653960350157523,"endowment":4.653960350157523,"datacite_reuse_total":24,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19273617","pmcid":null,"openalex_id":"https://openalex.org/W2109533720","authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":9,"citation_trend":[{"year":2012,"count":6},{"year":2013,"count":6},{"year":2014,"count":2},{"year":2015,"count":4},{"year":2016,"count":6},{"year":2017,"count":9},{"year":2018,"count":4},{"year":2019,"count":4},{"year":2020,"count":2},{"year":2021,"count":22},{"year":2022,"count":4},{"year":2023,"count":2},{"year":2024,"count":8},{"year":2025,"count":2}],"oa_status":"hybrid","license":"other-oa","oa_locations":[{"url":"https://genome.cshlp.org/content/19/4/545.full.pdf","host_type":"journal"},{"url":"https://genome.cshlp.org/content/19/4/545.full.pdf","host_type":"HYBRID"},{"url":"https://genome.cshlp.org/content/19/4/545.full.pdf","host_type":"publisher"},{"url":"https://syndication.highwire.org/content/doi/10.1101/gr.089789.108","host_type":"publisher"},{"url":"https://doi.org/10.1101/gr.089789.108","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/19273617","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/2665774","host_type":"repository"}],"fields_of_study":["Chromosomal and Genetic Variations","Genomics and Phylogenetic Studies","Advanced biosensing and bioanalysis techniques","Biology","Medicine"],"mesh_terms":["Base Sequence","HeLa Cells","Humans","Molecular Sequence Data","Mutation","Poly A","Polymorphism, Genetic","Regulatory Sequences, Nucleic Acid","RNA, Messenger","Sequence Homology, Nucleic Acid","Blotting, Northern","Genome, Human","Retroelements","Cystic Fibrosis Transmembrane Conductance Regulator","Alu Elements","Reverse Transcriptase Polymerase Chain Reaction"],"keywords":["Retrotransposon","Alu element","Biology","Genetics","Subfamily","Genome","Human genome","Gene","Transposable element"],"sdg_mappings":[],"linked_datasets":[{"doi":"10.6084/m9.figshare.14355280.v1","title":"Additional file 10 of Diversity of short interspersed nuclear elements (SINEs) in lepidopteran insects and evidence of horizontal SINE transfer between baculovirus and lepidopteran 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