The Landscape of L1 Retrotransposons in the Human Genome Is Shaped by Pre-insertion Sequence Biases and Post-insertion Selection

Abstract

Highlights d High-throughput insertion site profiling of a LINE-1 (L1) element by ATLAS-seq d Insertion is influenced strongly by DNA sequence but only weakly by chromatin state d L1 integration preferences suggest a link with host DNA replication d Post-insertion selection reshapes L1 distribution across functional genomic regions

Somatic transposition in theDrosophilaintestine occurs in active chromatin and is associated with tumor suppressor gene inactivation

“…Indeed, we show that the distribution of TE insertions is not random, but influenced by the genome sequence composition as well as by the local chromatin state. Gut retrotransposon insertions are enriched in transcriptionally active, enhancer-like chromatin, a bias that is similar to the insertion site preferences previously observed for the murine leukemia virus (MLV) and the PiggyBac transposon in human T-cell cultures (Gogol-Döring et al 2016;Sultana et al 2017Sultana et al , 2019. Similarly, recent analysis of TE insertion site preferences in human cancer genomes revealed enrichment in DNase hypersensitive open chromatin and depletion in histone H3K9me3-rich heterochromatin (Rodriguez-Martin et al 2020).…”

What Doesn't Kill You Makes You Stronger: Transposons as Dual Players in Chromatin Regulation and Genomic Variation

“…It is important to note that, given the 3′ to 5′ nature of canonical LINE1 retrotransposition, a mutation can only be classified as a LINE1 insertion if it is long enough to extent past the polyA tail of the mRNA and into sequences diagnostic of LINE1; ii) LINE1 activity drives the retrotransposition of SINE/Alu elements, themselves major modulators of genomic variation; iii) it is possible that the endonuclease activity of LINE1 ORF2 may have mutagenic effects independent of retrotransposition; iv) LINE1 and SINE elements can impact short tandem repeats, particularly AT‐rich ones, which are abundant in the genome and have much higher mutation rates than non‐repeat regions; v) due to their repetitive nature, LINE1 and SINE elements can induce large‐scale genomic variants such as duplications, inversions, and deletions via recombination . In addition, two recent studies reveal surprises with regards to the insertion preferences (or lack thereof) of LINE1 in the human genome . Despite the enrichment for LINE1 elements at gene‐poor, heterochromatin regions, these studies show that de novo insertions of LINE1, while restricted by degenerate, short nucleotide motifs, have no preference to any particular chromatin feature except for replication timing, suggesting a link to host DNA replication .…”

“…In addition, two recent studies reveal surprises with regards to the insertion preferences (or lack thereof) of LINE1 in the human genome . Despite the enrichment for LINE1 elements at gene‐poor, heterochromatin regions, these studies show that de novo insertions of LINE1, while restricted by degenerate, short nucleotide motifs, have no preference to any particular chromatin feature except for replication timing, suggesting a link to host DNA replication . Thus, LINE1 is a much more versatile mutagen than previously thought, and is then subject to the powerful forces of natural selection during evolution, to potentially lead to its enrichment at heterochromatin.…”

Disentangling the determinants of transposable elements dynamics in vertebrate genomes using empirical evidences and simulations

“…It is commonly observed for several retrotransposons in a variety of species [8,40,41]. However, in humans, L1 may actually not display strong preference for open chromatin and is more constrained by local replication timing [42, 43]. In the green anole, LINEs and LTR-RTs do not display strong evidence of preferential insertion in regions of high recombination, which tend to harbor less fixed elements.…”