Human L1 Transposition Dynamics Unraveled with Functional Data Analysis

Long INterspersed Elements-1 (L1s) constitute >17% of the human genome and still actively transpose in it. Characterizing L1 transposition across the genome is critical for understanding genome evolution and somatic mutations. However, to date, L1 insertion and fixation patterns have not been stu...

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Veröffentlicht in:Molecular biology and evolution Jg. 37; H. 12; S. 3576 - 3600
Hauptverfasser: Chen, Di, Cremona, Marzia A, Qi, Zongtai, Mitra, Robi D, Chiaromonte, Francesca, Makova, Kateryna D
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Oxford University Press 16.12.2020
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ISSN:0737-4038, 1537-1719, 1537-1719
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Abstract Long INterspersed Elements-1 (L1s) constitute >17% of the human genome and still actively transpose in it. Characterizing L1 transposition across the genome is critical for understanding genome evolution and somatic mutations. However, to date, L1 insertion and fixation patterns have not been studied comprehensively. To fill this gap, we investigated three genome-wide data sets of L1s that integrated at different evolutionary times: 17,037 de novo L1s (from an L1 insertion cell-line experiment conducted in-house), and 1,212 polymorphic and 1,205 human-specific L1s (from public databases). We characterized 49 genomic features—proxying chromatin accessibility, transcriptional activity, replication, recombination, etc.—in the ±50 kb flanks of these elements. These features were contrasted between the three L1 data sets and L1-free regions using state-of-the-art Functional Data Analysis statistical methods, which treat high-resolution data as mathematical functions. Our results indicate that de novo, polymorphic, and human-specific L1s are surrounded by different genomic features acting at specific locations and scales. This led to an integrative model of L1 transposition, according to which L1s preferentially integrate into open-chromatin regions enriched in non-B DNA motifs, whereas they are fixed in regions largely free of purifying selection—depleted of genes and noncoding most conserved elements. Intriguingly, our results suggest that L1 insertions modify local genomic landscape by extending CpG methylation and increasing mononucleotide microsatellite density. Altogether, our findings substantially facilitate understanding of L1 integration and fixation preferences, pave the way for uncovering their role in aging and cancer, and inform their use as mutagenesis tools in genetic studies.
AbstractList Long INterspersed Elements-1 (L1s) constitute >17% of the human genome and still actively transpose in it. Characterizing L1 transposition across the genome is critical for understanding genome evolution and somatic mutations. However, to date, L1 insertion and fixation patterns have not been studied comprehensively. To fill this gap, we investigated three genome-wide data sets of L1s that integrated at different evolutionary times: 17,037 de novo L1s (from an L1 insertion cell-line experiment conducted in-house), and 1,212 polymorphic and 1,205 human-specific L1s (from public databases). We characterized 49 genomic features-proxying chromatin accessibility, transcriptional activity, replication, recombination, etc.-in the ±50 kb flanks of these elements. These features were contrasted between the three L1 data sets and L1-free regions using state-of-the-art Functional Data Analysis statistical methods, which treat high-resolution data as mathematical functions. Our results indicate that de novo, polymorphic, and human-specific L1s are surrounded by different genomic features acting at specific locations and scales. This led to an integrative model of L1 transposition, according to which L1s preferentially integrate into open-chromatin regions enriched in non-B DNA motifs, whereas they are fixed in regions largely free of purifying selection-depleted of genes and noncoding most conserved elements. Intriguingly, our results suggest that L1 insertions modify local genomic landscape by extending CpG methylation and increasing mononucleotide microsatellite density. Altogether, our findings substantially facilitate understanding of L1 integration and fixation preferences, pave the way for uncovering their role in aging and cancer, and inform their use as mutagenesis tools in genetic studies.
Long INterspersed Elements-1 (L1s) constitute >17% of the human genome and still actively transpose in it. Characterizing L1 transposition across the genome is critical for understanding genome evolution and somatic mutations. However, to date, L1 insertion and fixation patterns have not been studied comprehensively. To fill this gap, we investigated three genome-wide data sets of L1s that integrated at different evolutionary times: 17,037 de novo L1s (from an L1 insertion cell-line experiment conducted in-house), and 1,212 polymorphic and 1,205 human-specific L1s (from public databases). We characterized 49 genomic features-proxying chromatin accessibility, transcriptional activity, replication, recombination, etc.-in the ±50 kb flanks of these elements. These features were contrasted between the three L1 data sets and L1-free regions using state-of-the-art Functional Data Analysis statistical methods, which treat high-resolution data as mathematical functions. Our results indicate that de novo, polymorphic, and human-specific L1s are surrounded by different genomic features acting at specific locations and scales. This led to an integrative model of L1 transposition, according to which L1s preferentially integrate into open-chromatin regions enriched in non-B DNA motifs, whereas they are fixed in regions largely free of purifying selection-depleted of genes and noncoding most conserved elements. Intriguingly, our results suggest that L1 insertions modify local genomic landscape by extending CpG methylation and increasing mononucleotide microsatellite density. Altogether, our findings substantially facilitate understanding of L1 integration and fixation preferences, pave the way for uncovering their role in aging and cancer, and inform their use as mutagenesis tools in genetic studies.Long INterspersed Elements-1 (L1s) constitute >17% of the human genome and still actively transpose in it. Characterizing L1 transposition across the genome is critical for understanding genome evolution and somatic mutations. However, to date, L1 insertion and fixation patterns have not been studied comprehensively. To fill this gap, we investigated three genome-wide data sets of L1s that integrated at different evolutionary times: 17,037 de novo L1s (from an L1 insertion cell-line experiment conducted in-house), and 1,212 polymorphic and 1,205 human-specific L1s (from public databases). We characterized 49 genomic features-proxying chromatin accessibility, transcriptional activity, replication, recombination, etc.-in the ±50 kb flanks of these elements. These features were contrasted between the three L1 data sets and L1-free regions using state-of-the-art Functional Data Analysis statistical methods, which treat high-resolution data as mathematical functions. Our results indicate that de novo, polymorphic, and human-specific L1s are surrounded by different genomic features acting at specific locations and scales. This led to an integrative model of L1 transposition, according to which L1s preferentially integrate into open-chromatin regions enriched in non-B DNA motifs, whereas they are fixed in regions largely free of purifying selection-depleted of genes and noncoding most conserved elements. Intriguingly, our results suggest that L1 insertions modify local genomic landscape by extending CpG methylation and increasing mononucleotide microsatellite density. Altogether, our findings substantially facilitate understanding of L1 integration and fixation preferences, pave the way for uncovering their role in aging and cancer, and inform their use as mutagenesis tools in genetic studies.
Author Chiaromonte, Francesca
Makova, Kateryna D
Qi, Zongtai
Chen, Di
Cremona, Marzia A
Mitra, Robi D
AuthorAffiliation 2 Department of Statistics, The Pennsylvania State University , University Park, PA
3 Department of Operations and Decision Systems, Université Laval , Québec, Canada
1 Intercollege Graduate Degree Program in Genetics, The Huck Institutes of the Life Sciences, The Pennsylvania State University , University Park, PA
4 Department of Genetics and Center for Genome Sciences and Systems Biology, Washington University School of Medicine , St. Louis, MO
5 EMbeDS, Sant’Anna School of Advanced Studies , Pisa, Italy
6 The Huck Institutes of the Life Sciences, Center for Medical Genomics, The Pennsylvania State University , University Park, PA
7 Department of Biology, The Pennsylvania State University , University Park, PA
AuthorAffiliation_xml – name: 4 Department of Genetics and Center for Genome Sciences and Systems Biology, Washington University School of Medicine , St. Louis, MO
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– name: 7 Department of Biology, The Pennsylvania State University , University Park, PA
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  organization: The Huck Institutes of the Life Sciences, Center for Medical Genomics, The Pennsylvania State University, University Park, PA
BackLink https://www.ncbi.nlm.nih.gov/pubmed/32722770$$D View this record in MEDLINE/PubMed
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crossref_primary_10_3390_genes12060918
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ContentType Journal Article
Copyright The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com 2020
The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Copyright_xml – notice: The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com 2020
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Issue 12
Keywords transposition
fixation
integration
LINE-1
transposable elements
Language English
License This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
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The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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Notes ObjectType-Article-1
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content type line 23
Di Chen and Marzia A. Cremona contributed equally to this work.
ORCID 0000-0002-6212-9526
OpenAccessLink https://www.ncbi.nlm.nih.gov/pmc/articles/7743743
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PublicationTitle Molecular biology and evolution
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  article-title: Whole-genome resequencing allows detection of many rare LINE-1 insertion alleles in humans
  publication-title: Genome Res
  doi: 10.1101/gr.114777.110
– volume: 14
  start-page: 603
  issue: 6
  year: 2004
  ident: 2020121613440458100_msaa194-B69
  article-title: Evolutionary impact of human Alu repetitive elements
  publication-title: Curr Opin Genet Dev
  doi: 10.1016/j.gde.2004.08.008
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Snippet Long INterspersed Elements-1 (L1s) constitute >17% of the human genome and still actively transpose in it. Characterizing L1 transposition across the genome is...
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SourceType Open Access Repository
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StartPage 3576
SubjectTerms Biological Evolution
Chromatin
Data analysis
Datasets
Discoveries
DNA methylation
DNA Transposable Elements
Functionals
Functions (mathematics)
Genome, Human
Genomes
Genomics
Humans
Insertion
Long Interspersed Nucleotide Elements
Mathematical functions
Models, Genetic
Mutagenesis
Mutagenesis, Insertional
Statistical methods
Transposition
Title Human L1 Transposition Dynamics Unraveled with Functional Data Analysis
URI https://www.ncbi.nlm.nih.gov/pubmed/32722770
https://www.proquest.com/docview/3171297103
https://www.proquest.com/docview/2428416183
https://pubmed.ncbi.nlm.nih.gov/PMC7743743
Volume 37
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