Interested in genomics, retrotransposons, structural variation, DNA methylation, dark loci, brain aging or Alzheimer’s disease?

Check out our new Oxford Nanopore Technologies DNA sequencing-based analysis of the aged human brain with and without tau pathology: biorxiv.org/content/10.110...

While lead author Paulino Ramirez set off on this endeavor because we wanted to know if somatic retrotransposition is elevated in human brains harboring pathogenic forms of tau (google “Frost tau retrotransposon” for the backstory), we learned a lot of other stuff along the way. There’s a ton of data in the manuscript – a little something for everyone (or at least those of you who are still reading) and definitely too much for a LinkedIn thread. 

Some tidbits:

I’m particularly excited by presence of structural variants (some are transposable element insertions) within dark loci in close proximity (sometimes overlapping) to Alzheimer’s disease-associated SNPs. We identify a likely active L1-Ta element at 13q.12.3 in the aged brain based on promoter demethylation, as well as likely source loci for L1Hs and HERV-K transcripts in tau-affected brains. DNA methylation is, on average, depleted at centromeres and within alpha satellites at early stages of tau deposition.

Our take-home message on retrotransposons is that somatic insertions are likely not elevated in Alzheimer’s disease. The toxic effects of retrotransposon activation in tauopathies are likely driven by dsRNAs, eccDNA, viral-like proteins and/or DNA damage that results from failed attempts at insertion.

This project was a long time coming and trialed other strategies prior to nanopore – thanks to our coauthors Dr. Wenyan Sun, Dr. Habil Zare, Shiva Kazempour Dehkordi, Dr. Bernard Fongang, and Dr. Kevin Bieniek for help along the way and to the Rainwater Foundation and National Institute of Neurological Disorders and Stroke (NINDS) for funding.