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Studies Offer Clues to Role of Mobile Elements in Human Diversity and Disease

By Andrea Anderson

NEW YORK (GenomeWeb News) – A trio of new papers in Cell are highlighting the frequency and functional consequences of transposon insertions in the human genome.

In the first of these, researchers from the University of Maryland and Emory University developed a method called "transposon-Seq" to preferentially sequence Alu and long interspersed element-1 (L1 or LINE) mobile elements in normal or tumor genomes from 76 individuals. They found that recent, rare retrotransposon events occur frequently in the general population, with 10 to 15 new germline insertions cropping up per genome.

"The new method allowed us to look at this for the first time," senior author Scott Devine, a researcher at the University of Maryland, told GenomeWeb Daily News. "We confirmed this hypothesis that there were a lot of new insertions happening in personal genomes."

"It's pretty extensive mutagenesis of the genome," he added, "which, in turn, you would expect to have a pretty profound effect on people — on traits and diseases."

In particular, the team found that L1 transposon insertions appear to be common in lung tumor samples, potentially due to methylation changes that free these mobile elements from their normal constraints and let them hop around in the genomes of somatic cells.

Researchers suspect that the human genome contained millions, or perhaps even hundreds of millions, of undetected transposon insertions. Some of these insertion sites have been detected using gel-based transposon display assays that involve amplifying DNA fragments by PCR using primers targeting transposons and nearby restriction sites. Other insertions have been detected via genome resequencing.

But systematically tracking down insertion sites across the genome has been challenging, Devine explained.

For the current study, he and his co-workers developed a high-throughput method for finding Alu and L1 or LINE retrotransposon insertions in the genome. These mobile elements are among the most common and active in the human genome, Devine noted.

The transposon-seq approach involved generating junction fragments similar to those produced in the transposon display assay. Rather than running these fragments on gels, though, the team used sequencing to characterize fragments from across the genome.

"It's kind of like targeted sequencing of the subset of the genome that has a transposon in it," Devine explained.

After testing the approach on 4,600 L1 insertion sites using Sanger sequencing, the researchers scaled up the approach using Roche 454 sequencing.

Overall, the team evaluated 76 human genomes: 24 ethnically diverse samples from anonymous individuals in the Coriell Polymorphism Discovery Panel, 14 more known individuals from Coriell, eight tumor-derived cell lines, and 30 tumors and matched controls.

In the process, the researchers identified 1,145 L1 and Alu insertions that hadn't been found before. Based on their sequence characteristics, these insertions appear to be young and very active, Devine said, noting that most also appear to be quite rare.

"It supports a model where there's lots of new insertions happening per generation," he said. "There's this massive mutagenesis experiment going on as a population — we basically confirmed that idea."

The researchers also found L1 insertions in a lung tumor-derived cell line, consistent with past studies suggesting transposons might contribute to oncogenesis.

And when they looked at 10 brain tumor samples and 20 primary non-small cell lung tumor samples, the team found that six of the 20 lung tumors contained at least one new somatic insertion.

"Although additional studies will be necessary to determine the full spectrum of cancer genomes that are permissive for Alu and L1 mobilization, these data indicate that lung tumor genomes are highly permissive for L1 mobilization," the researchers wrote.

Moreover, the team's subsequent analyses suggest these L1 insertions are linked to changes in DNA methylation, leading them to speculate that decreased methylation may create conditions in which mobile elements can move around somatic cell genomes.

Down the road, the team plans to look at other tumor types and delve more fully into individual tumors to see if insertions in tumors tend to affect specific genes. The researchers are also interested in exploring how insertions may influence human genetic diversity in general.

Meanwhile, a Johns Hopkins University team used an array-based method called "transposon insertion profiling by microarray," or TIP-chip, to find polymorphic L1 insertions in the genome and assess how such variants influence structural variation.

Based on their analyses of X-chromosome TIP-chip data for 75 men and whole-genome TIP-chip data for a dozen individuals, the team argued that insertions caused by a type of L1 elements called "transcribed L1, subset a" or L1(Ta)s represent a poorly characterized source of structural variation in the human genome.

"Genome-wide TIP-chip studies of several individuals show that L1(Ta)s are extremely polymorphic and an underappreciated type of [structural variation] underlying human genetic diversity," the team concluded.

Finally, in a third Cell paper, researchers from the University of Michigan and elsewhere used fosmid-based, paired-end sequencing to find dozens of new, highly active or "hot" L1 sequences in the genomes of individuals from various human populations.

"[O]ur data support the hypothesis that hot L1s are actively retrotransposing in modern-day human genomes," they wrote, "and suggest that some of the L1 alleles identified here could serve as source elements for disease-producing L1 insertions."

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