One of the biggest problems with the whole GE concept is the completely bonkers(effectively physically impossible) assumption that the DFE of mutations must remain essentially constant no matter how highly adapted an organism is. That simply does not make physical sense. I dare say, it has to be physically impossible for this to be the case.
Living organisms are entities of atoms and molecules that function according to the laws of physics. They have weight, their constituents are held together by inter and intramolecular forces of attraction, and they must spend energy to perform their life-essential functions. This implies there are some absolute limits for how effective any given function in an organism can become.
At some point it will not be physically possible to improve some aspect of an organism in a way that contributes to it’s reproductive fitness, without that either compromising some other aspect of it’s physiology, or hitting some hard, fundamental physical limit.
There is going to be some relationship between the organisms total weight due to it’s mass, and it’s energy expenditure required to maintain this total mass. There will be some global optimum where it physically cannot grow bigger without the material of which it is made collapsing, or it will require more energy to maintain it’s body than it can ever hope to collect and consume.
At that point, this aspect of the organism’s physiology that contributes to it’s fitness cannot be further improved. That means there are no more beneficial mutations that can contribute to this part of the organism. That means the distribution of fitness effects of mutations, when at the top of the fitness peak, has been skewered entirely to neutral and deleterious. Either mutations are strictly neutral, or they are deleterious.
The most obvious example I can think of is enzymes. There is an absolute limit to how effective an enzyme can become where it cannot be further improved. This limit is defined by how fast the substrate can diffuse into the active site. It does not matter that it might be possible to make the enzyme able to pull electrons off the substrate even faster, because it would still have to wait for a new substrate molecule to diffuse into the active site. That means when a large fraction of the enzymes in your genome are approaching global, or even local optima, the DFE of mutations for them will start to skew more towards neutral and deleterious. The corollary of this is that, when you move further down towards lower fitness, many more beneficial mutations become available that were not available at or close to the top.
This explains why it cannot be true, in terms of absolute numbers, that the DFE of mutations is constant. There cannot be a fixed relationship between beneficial and deleterious mutations. Their relative numbers must change and reflect the level of fitness for the organism. Highly adapted organisms must have many more deleterious mutations available to them than very poorly adapted organisms.
Another related factor that also affects the DFE of mutations, and shows that it cannot be constant, is the phenomenon of diminishing returns espistasis. As I wrote in the DFE of mutations thread:
In reading one of the papers from the LTEE the concept of diminishing returns epistasis was mentioned, which also helps explain why it has to be physically true that the shape of the curve for the DFE of mutations must change over time as organisms become either more less well adapted.
Imagine an organism A that has some reproductive rate, and then a beneficial mutation occurs that increases it’s expected number of offspring by one. Now if this organism normally is expected to produce 100 offspring, and it has one more, it has improved it’s number of offspring by 1%.
Now imagine another organism B that has twice the reproductive rate that A had, and then this organism suffers the same mutation A did. It produces 200 offspring normally, and now can add one more. But now the mutation only has a 0.5% effect of improvement.
But that would imply the selection coefficient for this mutations has decreased. As the organism has gotten more fit, the effects of individual mutations have gotten smaller in proportion.
An analogy is that you are to push a heavy car that has run out of fuel to the nearest gas station. When you do it alone it’s very hard, but if you get another person to help, it’s half as hard, but then if you get one more, you’re doing a 3rd the work, and then with a fourth, a quarter the work. The gain from every additional person helping push the car becomes smaller and smaller, to the point of being neglible. When you’re 30 people pushing the car, you probably can’t even feel if any single person decides to take a break.
Again it is trivial to think of real examples where real biochemistry would result in mutations exhibiting diminishing returns epistasis due to the fitness-level of the organism. Where gaining two more ATP molecules per second means much less to an organism that can generate 1 billion per second than it does to an organism that can generate 1 million per second. Which means the same mutation that adds two more ATP molecules per second, can have a literally thousand-fold smaller effect for the highly adapted organism, than for the poorly adapted organism. Which means that the DFE of mutations has shifted, it can’t be constant.
So they can’t be constant in terms of absolute proportions benefical:deleterious, and they can’t be constant in terms of their magnitudes.