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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Vydané v:Molecular biology and evolution Ročník 37; číslo 12; s. 3576 - 3600
Hlavní autori: Chen, Di, Cremona, Marzia A, Qi, Zongtai, Mitra, Robi D, Chiaromonte, Francesca, Makova, Kateryna D
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States Oxford University Press 16.12.2020
Predmet:
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
transposition
fixation
integration
LINE-1
transposable elements
ISSN:0737-4038, 1537-1719, 1537-1719
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Shrnutí: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.
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Di Chen and Marzia A. Cremona contributed equally to this work.
ISSN:0737-4038
1537-1719
1537-1719
DOI:10.1093/molbev/msaa194