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Genome evolution goes digital

June 02, 2020

Dr. Alan Herbert from InsideOutBio describes ground-breaking research in a paper published online today by Royal Society Open Science. The study focuses on the digital genome that uses programmable DNA-based on-off switches to change the readout of genetic information. The digital rewiring of the genome involves switch elements called flipons. Flipons fast track the evolution of multi-cellular organisms. The flipon strategy is less risky evolution based only on mutations.

Dr. Herbert says "Previously coding by DNA was described as analog. Going digital has greatly increased the genome's storage capacity. Different programs can be run by compiling the information differently."

Flipons are DNA sequences capable of adopting different DNA conformations. They act as on-off switches. Each switch alters the program read out from the DNA code. Flipon settings change with context. Each setting leads to a different set of instructions for the cell to follow. Examples of how flipons act are provided by innate immune responses and by DNA damage repair pathways. Flipon conformation determines whether or not these pathways are active.

Flipons fast track the evolution of multi-cellular organisms. They spread through the genome through a copy and paste mechanism. They work as an on-off switch to change how cells compile their operating instructions. Flipons are programmable. Organisms can optimize flipon settings by learning. Those clades that learn best survive better. They adapt and reproduce faster than their competition.

There are different classes of flipon: Z-flipons can form left-handed DNA by flipping over the bases in right handed DNA. The flip happens in active genes and helps localize RNA processing complexes to that region. T-flipons have three strands to form triplexes. They localize the RNAs needed to program a particular outcome. G-flipons are four stranded structures that initiate repair programs after DNA damage.

Flipons enable the compilation of many different messages from a single genomic sequence. They generate more diversity than is possible by mutation or by DNA rearrangements. Flipons elaborate on already successful adaptations without destroying them. The newly compiled transcripts work with the old to enhance survival.

Flipons can be programmed in many different ways. DNA modifications affect how easily they flip from an off-state to an on-state. Proteins also regulate flipon conformation. The programming requires work. Energy is traded for information. The trade-off generates a larger message space to explore and exploit. When flipons freeze in one state of the other, often disease results. Examples of Mendelian disease due to flipons are given in the paper.

The flipon strategy is less risky than other forms of evolution. Previously the focus has been on DNA mutation as the key driver of change. Mutations cause an alteration in the DNA sequence that codes for a protein. The process is random and difficult to reverse. In contrast, flipons are programmable and reversible. Flipons only change how messages are compiled from DNA. They do not alter the DNA coding sequence. They generate variability without the risks associated with mutation. Natural selection depends on variability to find the best way for an organism to survive and reproduce.

The paper focuses on the role of ALU repeat elements in the digital rewiring of the genome. These elements comprise about 11% of the human genome. They spread by a copy and paste that depends on reverse transcription onto their RNA into DNA. They are thought to account for some of the differences between human and apes. Once the invader, these ALU elements now enhance the evolution of their host.
About InsideOutBio: InsideOutBio is a start-up focused on developing a novel class of proprietary therapeutics to 'light' up tumors for the immune system to kill by reprogramming self/nonself pathways within cancer cells. Dr. Herbert leads discovery at InsideOutBio. His work on Z-DNA was foundational to the discovery of flipons. These statements about InsideOutBio comply with Safe-Harbor laws. They are forward-looking and involve known and unknown risks and uncertainties. They are not guarantees of future performance and undue reliance should not be placed on them.


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