In a paper published today in the peer-reviewed journal Molecules, Alan Herbert from InsideOutBio proposes that evolution can happen on a faster time scale than Darwin imagined. In fact, it happens in real time within each of us. Individuals must adapt rapidly to the many existential threats they face if they are to pass their genes onto children. They do not have the option of waiting millennia to find their better self. How then does fast evolution occur and how are adaptations transmitted to offspring?
The paper draws on recent developments in the new field of flipon genetics. In contrast to the complicated genes of classical genetics, flipon genetics uses DNA made with very simple sequences that repeat themselves over and over a number of times. The simple sequence repeats have low information content, but they have a surprising property. They can adopt alternative shapes like two stranded left-handed Z-DNA, three stranded triplexes and four-stranded quadruplexes. In the case of Z-DNA, the shape is recognized by shape-specific proteins. During infection, flipping to the Z-shape can switch off the immune response against self, or switch on a cell death pathway to prevent a virus from growing. In these setting, flipons allow rapid adaptations to infectious organisms and other threats.
Flipon genetics focuses on switches based on alternative DNA shapes, not on protein mutations. The DNA shapes encoded by flipons anchor different sets of cellular machines, each producing a different response to changes in their environment. No two cells have flipon shapes set the same way. The result is that cells respond differently to challenges. Those cells that respond best undergo selection and promote an individual’s survival.
An important feature of simple sequence repeats is a high rate of mutation, often due to errors in making new DNA when cells divide. The errors alter how easily flipons change shape. As a result, flipon shapes vary between cells, causing cells to respond differently. Over time, different clones of cells are selected, leading to tissues that differ between individuals, and even between identical twins.
Variation in simple repeat sequences have immediate effects on cells. The machinery is structure-specific and ready to engage when the flipon adopts a new shape. Changes to DNA then rapidly alter the responses of a cell to its environment. Over time, the location of flipons in gene regions that control expression of a particular response may be favored. The mutation prone sequences then create variation within an individual, producing a gradient of cellular responses to changing contents. The response that optimizes an individual’s survival can then be selected.
Simple sequence repeats have another role in evolution. They can code for patches of repeat amino acid in proteins. These have been previously associated with what are called repeat expansion diseases. In a normal cell, the peptide patches act like Velcro to still proteins together to make what are called condensates. The condensates perform many useful functions in cells and vary between individuals. The diversity in responses provides additional variation for natural selection to act upon.
An interesting question is whether the changes that are most adaptive for an individual can be passed on to the next generation. Prior work suggesting possible mechanisms are summarized. Differences between fathers and mothers in the transmission of flipons are reviewed. The strategies adopted by each sex reflect that there one egg and millions of sperm involved in creating a new individual in mammals.
InsideOutBio is an early-stage biotech company developing therapeutics for the treatment of cancer based on the role of complement proteins in self-recognition. By correctly identifying cancer cells as abnormal, the therapeutics initiate responses against them, leading to their rejection. Proof of principle has been accomplished in pre-clinical models. The company is operating remotely and has taken advantage of the new biotech ecosystem to discover and prototype the new therapeutics at low cost. The access to the enormous databases created by collaborative international efforts has helped the InsideOutBio scientists make fundamental discoveries such as those reported by Dr. Herbert in the PLOS Genetics publication. Previously Dr. Herbert discovered a family of proteins that bind the left-handed Z-DNA conformation and performed pioneering human genetic studies in the Framingham Heart Study. InsideOutBio is privately funded.
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The Simple Biology of Flipons and Condensates Enhances the Evolution of Complexity
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