This is the problem that makes my brain melt when I try to think about genetics and mutational load. The naive idea is that a species, S, has a correct genome, G, but mutations build up, increasing with each generation. Presumably mutations build up until they are common enough that back-mutations are a thing. Then there is an equilibrium. In a fecund species, each individual has many children, but most have a higher mutational load, many have the save mutational load, and a lucky few have a smaller mutational load, closer to G, the correct genome. Differential reproductive success then maintains the equilibrium.
I don't see how the numbers are supposed to work out for large mammals, with each female having under a dozen offspring. To have a decent chance of a back-mutation, the typical member of the species would need one twelfth of their genome to be deleterious mutations.
Meanwhile, people are thinking about using CRISPR to correct the human genome, creating unusually happy, healthy people. The underlying thought is that the correct genome is best. But why do we think that the correct genome works at all?
Most of the population is in a shell at a distance from the correct genome, the number at the center is actually quite low. Given the combinatorics, with two to the millions of possible genomes, but populations in the millions, the number at the center, or even close, is actually zero. Maybe the correct genome codes for a sickly, miserable individual?
My current guess is that the evolution of large mammals with few offspring is constrained by genetic load considerations. It is not sufficient, (or even necessary) for the correct genome to be any good. There needs to be a big blob of mediocrity in genome space. The species exists as a shell of individuals on the edge of the blob of mediocrity. The blob needs to be huge, so that individuals whose genome is one twelfth mutations are still in the blob. Then there can be an equilibrium between back-mutations, taking offspring towards the interior of the blob and other mutations, taking offspring out of the blob and out of the gene pool.
This potentially solves the Fermi paradox. Can creatures such as humans actually exist in this universe? It is not enough for natural selection to discover a good genome. Natural selection has to discover a huge blob of mediocrity. Such blobs might be vastly rarer than we realize.
This potentially shits on the CRISPR master race. There might be nothing special about the interior of the huge blob of mediocrity.