Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes

Abstract

Long interspersed nuclear element–1 (L1) retrotransposons are mobile repetitive elements that are abundant in the human genome. L1 elements propagate through RNA intermediates. In the germ line, neighboring, nonrepetitive sequences are occasionally mobilized by the L1 machinery, a process called 3′ transduction. Because 3′ transductions are potentially mutagenic, we explored the extent to which they occur somatically during tumorigenesis. Studying cancer genomes from 244 patients, we found that tumors from 53% of the patients had somatic retrotranspositions, of which 24% were 3′ transductions. Fingerprinting of donor L1s revealed that a handful of source L1 elements in a tumor can spawn from tens to hundreds of 3′ transductions, which can themselves seed further retrotranspositions. The activity of individual L1 elements fluctuated during tumor evolution and correlated with L1 promoter hypomethylation. The 3′ transductions disseminated genes, exons, and regulatory elements to new locations, most often to heterochromatic regions of the genome.

Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells

“…Primers were designed to amplify all the breakpoints (Supplemental Table 3). The short-fragment PCR reactions were performed as previously described (Tubio et al 2014). With respect to long-range PCR, elongation time was increased 1 min per 1 kb.…”

“…These may range from simple chromosomal rearrangements (Campbell et al 2008) to more complex, compound patterns, such as chromothripsis (Stephens et al 2011) and chromoplexy (Baca et al 2013), or mobilization of transposable elements (Lee et al 2012;Tubio et al 2014). Intrachromosomal rearrangements are generally more common than interchromosomal rearrangements, indicating a higher likelihood of joining a double-strand break in a chromosome to another break in the same chromosome despite the availability of a much larger quantity of nuclear DNA from other chromosomes (Stephens et al 2009).…”

A hot L1 retrotransposon evades somatic repression and initiates human colorectal cancer

“…Until recently, L1 elements were thought to be mobilized primarily in the germline and then silenced in somatic cells throughout adulthood. However, several recent reports have shown that L1 elements are active in at least some adult somatic tissues, including the brain (Muotri et al 2005;Coufal et al 2009;Baillie et al 2011;Evrony et al 2012;Upton et al 2015) and epithelial somatic tumors Iskow et al 2010;Lee et al 2012;Solyom et al 2012;Shukla et al 2013;Helman et al 2014;Tubio et al 2014;Doucet-O'Hare et al 2015;Ewing et al 2015;Rodic et al 2015). These observations have led to the suggestion that L1 might play a role in initiating human cancers by mutating specific oncogenes or tumor suppressor genes in somatic cells.…”

Reading LINEs within the cocaine addicted brain

“…Attempts to confirm several putatively novel L1 insertions were unsuccessful possibly due to characteristics of the L1 retrotransposition process, including L1‐mediated deletion of flanking gDNA and 3′ transductions, which occur frequently (Richardson et al., 2015; Tubio et al., 2014). The use of gDNA produced via WGA may have caused chimeras and/or rearrangements of the source material (Evrony et al., 2012), making PCR validation difficult.…”

“…Somatic mutations by other types of repetitive elements and pseudogenes, dependent upon the L1‐encoded machinery for mobility, have been documented to cause several human diseases (Richardson et al., 2015). Somatic L1 retrotransposition events occur often during embryogenesis (Kano et al., 2009) and in cancerous tissues (Tubio et al., 2014). Numerous studies have shown that L1s can mobilize in both mouse and human brains (Baillie et al., 2011; Evrony et al., 2015; Hazen et al., 2016; Muotri et al., 2005).…”