The Mobile Element Locator Tool (MELT): population-scale mobile element discovery and biology

Abstract

Mobile element insertions (MEIs) represent ∼25% of all structural variants in human genomes. Moreover, when they disrupt genes, MEIs can influence human traits and diseases. Therefore, MEIs should be fully discovered along with other forms of genetic variation in whole genome sequencing (WGS) projects involving population genetics, human diseases, and clinical genomics. Here, we describe the Mobile Element Locator Tool (MELT), which was developed as part of the 1000 Genomes Project to perform MEI discovery on a population scale. Using both Illumina WGS data and simulations, we demonstrate that MELT outperforms existing MEI discovery tools in terms of speed, scalability, specificity, and sensitivity, while also detecting a broader spectrum of MEI-associated features. Several run modes were developed to perform MEI discovery on local and cloud systems. In addition to using MELT to discover MEIs in modern humans as part of the 1000 Genomes Project, we also used it to discover MEIs in chimpanzees and ancient (Neanderthal and Denisovan) hominids. We detected diverse patterns of MEI stratification across these populations that likely were caused by (1) diverse rates of MEI production from source elements, (2) diverse patterns of MEI inheritance, and (3) the introgression of ancient MEIs into modern human genomes. Overall, our study provides the most comprehensive map of MEIs to date spanning chimpanzees, ancient hominids, and modern humans and reveals new aspects of MEI biology in these lineages. We also demonstrate that MELT is a robust platform for MEI discovery and analysis in a variety of experimental settings.

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

“…Among these, one insertion originated from a donor L1 on Chromosome 22 previously found to be responsible for tumor-specific L1 insertions in other human cancer types (Pitkanen et al 2014;Tubio et al 2014;Paterson et al 2015). An increasing body of evidence suggests that a particular subset of retrotransposition-competent L1 loci tend to be recurrent contributors to genomic instability in human malignancies and cancer cell lines (Tubio et al 2014;Philippe et al 2016;Scott et al 2016;Gardner et al 2017). Indeed, here we found that the promoter region of the TTC28 donor L1 was largely demethylated in both nontumor liver and matched ICC tumor cells, as a prior study found for a Chromosome 17 donor L1 responsible for APC exon mutagenesis in a colorectal cancer patient (Scott et al 2016).…”

“…Indeed, the finding that Mdr2 −/− mice accommodate tumor-specific L1 retrotransposition is particularly interesting, as these genomic alterations occur alongside massive gene amplifications (Iannelli et al 2014). All four tumor-specific mouse L1 insertions were full-length and therefore likely to retain retrotransposition competence, allowing them to serve as potential donor L1s for subsequent tumor-specific retrotransposition events, as previously observed in human malignancies (Tubio et al 2014;Gardner et al 2017).…”

“…Hence, at least some mouse L1 families may be highly predisposed to generate full-length offspring L1 insertions in the germline (Hardies et al 2000;Richardson et al 2017) as well as in cancer cells. In contrast, L1 insertions detected in human tumors are predominantly 5 ′ truncated (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, 2016Ewing et al 2015;Paterson et al 2015;Rodic et al 2015;Scott et al 2016) and involve structural rearrangements at a higher frequency than for L1 insertions arising in the human germline (Gardner et al 2017). These differences are apparent even among hominids.…”

“…These differences are apparent even among hominids. For example, the rate of germline L1 5 ′ inversion appears to be lower in chimpanzee than in human (Gardner et al 2017). Whether these observations reflect species-specific differences in the enzymatic properties of L1s or the cellular environment in which retrotransposition events occur, including host factors such as the APOBEC (also known as AID) proteins that are more diverse in humans than in rodents (Goodier 2016), remains to be determined.…”

“…Analysis of the 3 ′ transduced sequence identified a donor L1 on Chromosome 22 and intronic to the gene TTC28. Recent studies of 3 ′ transduction-bearing L1 insertions in tumor samples pointed to this element as a highly active donor L1 in human tumor cells (Pitkanen et al 2014;Tubio et al 2014;Paterson et al 2015;Philippe et al 2016;Gardner et al 2017). We therefore performed targeted bisulfite sequencing of the complete donor L1 promoter region, which was significantly demethylated in patient ICC.75 tumor compared to matched nontumor liver (P < 0.0001, paired t-test, two tailed) (Fig.…”