Genome complexity: defining epistqaxis (Introduction)

by David Turell , Tuesday, August 01, 2023, 16:05 (270 days ago) @ David Turell

The unexpected when genes combine effects:

https://www.quantamagazine.org/how-genetic-surprises-complicate-the-old-doctrine-of-dna...

"Does an unseen force lurk within genetics? Biologists have made enormous strides over the past 100 years in understanding the role of the millions of parcels that convey our genetic information — DNA, RNA and proteins. But they have also learned about undetectable interactions between these biochemical agents, hiding in their midst like ghosts in the machine, complicating our quest to learn the secrets of life, one gene at a time. These interactions all fit under the umbrella of “epistasis” — not exactly a new idea in biology, but one whose influence and importance are only now being fully appreciated. (my bold)

"Geneticist Daniel Weinreich and colleagues suggested that epistasis is akin to the “surprise” at the effects of mutations when they combine, given what we know about them individually. Whenever a life form’s observable attributes differ from what the DNA would lead you to expect, epistasis may be to blame. Imagine that you know of two hypothetical mutations associated with a flower stem that’s ordinarily 40 centimeters long: Mutation A is associated with a long stem (say, 50 centimeters), and mutation B confers a short stem (30 centimeters). You might expect the mutations to cancel each other out, leaving a flower with a normal-length stem. Or perhaps the combination of mutations adds their independent lengths together, resulting in an extra-long stem (80 centimeters). But instead they end up producing an extra-short stem (10 centimeters). Geneticists would say that there is a nonlinear relationship between the effects of mutations A and B, which gives you the surprising outcome. This is a signature of epistasis.

***

"Predicting how genes will work might be tricky, but we can’t set the bar so high that it requires knowing everything about every gene (and mutation). Such a reality would make many of our efforts hopelessly messy. Alas, the only reasonable response to this objection is a common one in science: It is not nature’s job to make itself easy to study, or to submit to our assumptions. Life is complex. We must let it be.

***

"...a new idea called global epistasis suggests that the ghost might not be so ghostly. With our hypothetical flower-stem mutations A and B, a global epistasis approach would suggest that the effects of adding mutation B to any genome (whether or not it contains mutation A) will follow a set pattern. Perhaps mutation B acts like a negative amplifier of other mutations, and when in the presence of a mutation that confers a long stem, it reverses the effect. These kinds of patterns have already been observed in several systems independently. How widespread this global epistasis is, and to which systems it applies, is still the object of current research. But it is exciting to know that there might be a way to predict the surprise.

"The “ghost in the machine” metaphor was originally used to discuss the mind-body duality problem, the distinction between the nonphysical mind and the mechanical body it controls. It has often been invoked to describe the fear that we might not be building what we think we are — whether it’s increasingly intelligent machines or our understanding of subtly interacting genetic codes. And indeed, bioengineering is where epistasis might cause us the most trouble. Anyone who wants to engineer new livestock (or designer babies) with desirable traits, one mutation at a time, will need to contend with the constant specter of unforeseen consequences — to say nothing of the enormous ethical issues.

"These ghosts make the work of geneticists that much more challenging, true. But they also make the biological world that much more fantastic."

Comment: Mendelian genetics was very simplistic, dominant or recessive like adding two plus two and getting four. The study of the genome doesn't offer simplicity. We may know the relationship of a gene to a characteristic, but we do not know how the gene exerts its influence. Until we do epistaxis will frustrate us. The 'ghost in the machine' is the mind of teh designer.