Introducing the brain: a role of retrotransposons (Introduction)

by David Turell @, Wednesday, January 12, 2022, 18:40 (8 days ago) @ David Turell

Still a confusing process:

"Retrotransposons that are specific to mammals; the common LINE-1 (L1) element, for example, comprises a class of transposons that salt our genomes to the tune of a couple hundred-thousand genetic mini-islands. That's about 20% of our total sequence. Of the few thousand L1s that are still mostly full-length, only about 100 or so have maintained their full coding potential, i.e., are still able to move around the genome by retrotransposition. This involves a copy-and-paste mechanism using a reverse transcriptase specified in their second and final open reading frame, commonly designated as ORF2.


"The essential ubiquity of retrotransposition has seemingly caught much of the biological community by surprise in the sense that it can suddenly, and often very neatly, explain away many of their most vexing unanswered questions and pursuits. For example, it now appears that all (or at least 300,000) of our genome's critical regulatory regions—the enhancers and promoters at the front of genes—ultimately derive from remnants of retroviral inserts. Some have even suggested that mitochondrial localization sequences could have evolved or been inserted by retrotransposons. Furthermore, many of our traditional genes are now understood to descend from the good-old run-of-the-mill retroviral gag, pol, or env genes that were co-opted for a new use.


"The viral epiphany began in earnest some time ago, when the idea that retrotransposons were genetic parasites that evolved to be active only in germ cells (which could propagate them) was roundly dispelled by Fred Gage at the Salk Institute in 2005. His group demonstrated that full-blown somatic cells, particularly neuronal precursor cells of the hippocampus, are ready and willing hosts for the transposition party. While estimates vary widely, work by his lab and others suggests that developing neurons might each be hit with a dozen or transposition events en route to maturity. This implies that our brains, and likely our bodies as well, are significantly mosaic in the sense that neighboring cells of much the same putative phenotype can have notably different genome architectures due to opportune transposition events.

"Alongside these prodigious announcements was a parallel observation that much more of the genome is actually transcribed than had formerly been appreciated. Rather than just a few genes being expressed here or there, studies revealed that upwards of 80 percent of our entire genome is likely translated into some kind of RNA. With half a genome's worth of retroviral additions, many of these transcriptions are undoubtedly retrotransposons one sort or another.


"As the importance of DNA damage and repair is increasingy understood, it becomes apparent that competition for restorative nucleotides in nervous systems must be cutthroat. Adenine nucleotides must be relatively abundant and held far from equilibrium for energetic reasons while guanine nucletides must be properly balanced among their cyclic and multiply phosphorylated forms according to their signaling requirements. Access to nucletides and maintaining their levels in just the right ratios for reliable repair and mitochondrial replication can now be increasingly comprehended to be the major organizing and driving force underlying neural structure. Many the same observations regarding the providence of DNA damage and repair processes might be equally applied to cancer. Each kind of cell and organelle has their own unique suite of nucleotide synthesis, salvage and repair proteins, and correspondingly, their preferred nucleotide levels and codon preferences.

"Perhaps the best way we currently have to penetrate and comprehend this complex network of nucletide-controlling enzymes is to start with the bases that sit at the critical point of DNA and RNA—what we might call the thymine-uracil nexus. Since polymerases don't distinguish between deoxyUracil (principally dUTP) and thiamine, dUTP predictably finds its way into both into our endogenous DNA, and also into any viral DNA intermediates that infect us. Both we and viruses therefore retain an extensive palette of uracil glycosylases to promptly fix any uracil-corrupted DNA. We also have a complimentary arsenal of dUTP-degrading enzymes to reduce free dUTP levels or convert their bases to cytosines. Interestingly, assimilated retroviruses that have degraded or morphed into retrotransposons still often retain uracil glycosylases of one form or another. While these are now active areas of drug discovery, particularly for antiviral drugs that might be specific to foreign uracil glycosylases, it is a relatively new field and much remains to be explored."

Comment: that the genome in our complex brain is highly active is no surprise, considering its ability to complexify. I might add the viral source of retrotransposons fits my theory that God uses viruses to code changes in evolution. Note also the whole genome is active so where is 'junk'?

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