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Targeted Sequencing Reveals Somatic Retrotransposition Events in Human Brain

NEW YORK (GenomeWeb News) – An international team has found evidence that retrotransposons from three different families are active in somatic brain cells, the group described its findings online yesterday in Nature.

Using a targeted sequencing method called retrotransposon capture sequencing, or RC-seq, the researchers look for L1, Alu, and SVA family retrotransposon insertion sites in two areas of the human brain. Along with integration sites that seem to correspond to germline activity of these mobile genetic elements, they also saw thousands of potential insertion sites stemming from somatic retrotransposons activity in the brain, including many retrotransposition events affecting protein-coding sequences that are typically expressed in the brain.

"Our results demonstrate that retrotransposons mobilize to protein-coding genes differentially expressed and active in the brain," corresponding author Geoffrey Faulkner, a genetics and genomics researcher at the University of Edinburgh, and co-authors wrote. "Thus, somatic genome mosaicism driven by retrotransposition may reshape the genetic circuitry that underpins normal and abnormal neurobiological processes."

As mobile genetic elements flit about the genome, they sometimes produce the sorts of deleterious mutations and copy number changes that have been associated with cancer or other disease, the study authors explained. To minimize this mutagenic potential, epigenetic mechanisms tend to keep the activity of many retrotransposons in check in somatic cells. But recent studies suggest there are exceptions to this somatic suppression, they added, with L1 transposons showing activity in some brain cells.

"[I]t is not known where somatic L1 insertions occur in the genome," the researchers wrote, "nor, considering that open chromatin is susceptible to Li integration, whether these events disproportionately affect protein-coding loci expressed in the brain."

To look at this in more detail, the researchers isolated genomic DNA from five parts of the brain each in samples from three individuals who donated their brains post-mortem to the Netherlands Brain Bank.

After screening the five sub-regions of the brain for L1-related copy number changes, they focused in on the hippocampus and caudate nucleus, regions that seemed to have the highest and lowest L1 copy number variation in the initial screening experiment.

For the sequencing portion of the study, the team captured L1, Alu, and SVA retrotransposons sequences using custom NimbleGen Sequence Capture 2.1M arrays before sequencing the retrotransposons with the Illumina GAIIx.

The researchers tracked down retrotransposons insertion sites by looking for individual reads with ends that mapped to two different loci in the human reference genome. They then differentiated between germline and somatic insertions by comparing RC-seq data from the brain samples and from pooled donor blood samples.

Along with apparent germline mutations caused by L1, Alu, or SVA genetic elements, the team found thousands of possible somatic insertions in the hippocampus and caudate nucleus, including 7,743 L1 insertions, 13,692 Alu insertions, and 1,350 SVA insertions.

Moreover, many of these potential insertions sites corresponded to parts of the genome containing protein-coding genes, particularly genes that tend to be active and/or differentially expressed in the brain, researchers reported, a pattern not detected for the germline insertions.

"Overall, L1, Alu, and, to a more limited extent, SVA mobilization produced a large number of insertions that affected protein-coding genes," they wrote.

Results of the current study "indicate that somatic L1 and Alu mobilization fundamentally alters the genetic landscape of the human brain," the authors added, "and that retrotransposition is the primary mechanism underlying this phenomenon."

Those involved in the study noted that additional research is needed to not only explore the somatic retrotransposition variability that may exist between individuals and populations, but also to get a handle on the consequences of these events.

"Ultimately, direct identification of transcripts disrupted by somatic retrotransposition, together with its epigenetic regulation, may provide insights into the molecular processes underlying human cognition, neurodevelopmental disorders, and neoplastic transformation," they concluded.