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Paper Shows that “Mutational Load” Arguments Don’t Refute ENCODE

Evolution News

When the ENCODE project first proposed, on the basis of direct empirical research, that 80 percent of the genome may be biochemically functional, a huge prediction of intelligent design was fulfilled. Evolutionary biologists saw the writing on the wall and were quick to fight back. Perhaps one of ENCODE’s staunchest critics has been Dan Graur, a molecular evolutionary biologist at the University of Houston. He argued in 2017 in the journal Genome, Biology and Evolution that ENCODE’s empirically based conclusions could not possibly be correct because “Mutational load considerations lead to the conclusion that the functional fraction within the human genome cannot exceed 15%.” What exactly is “mutational load”?

Mutational load is based upon the principal that populations of organisms can only tolerate a certain number of deleterious mutations before they reach a critical level and the population crashes. If every element of a genome is functional, then every possible mutation stands to have a non-neutral effect, and could be potentially deleterious. But if only a small portion of the genome is functional, then most mutations will happen to occur in functionally unimportant regions, and this spreads out mutations in a manner that greatly decreases the likelihood of experiencing a deleterious mutation. Thus, when your genome is filled with “junk,” you can tolerate a much higher “mutational load.” 

Making Assumptions

If one makes certain assumptions about mutation rates, population sizes, and the percentage of mutations that are deleterious, one can estimate our “mutational load” — and back-calculate the percentage of our genome that must be functional. That sure sounds like a lot of assumptions that Graur made in his calculations. Back in 2017, Evolution News critiqued many of Graur’s dubious assumptions, but assume for the moment that his arguments are all correct. What are the implications?

Under Graur’s view, in one sense much of the genome is “junk” but in another sense his arguments actually imply that every single part of the genome has a very important purpose: to allow the human population to endure a much larger “mutational load.” Thus, even if he is correct that most of the genome isn’t “biochemically functional,” he’d be wrong to say that the rest of the genome has no purpose; its purpose is to diminish the likelihood that organisms will experience deleterious mutations. That sounds like a pretty important function, doesn’t it? 

Serious Criticisms

But it seems like this thought experiment is probably not necessary because now in 2020 serious criticisms have been made of the assumptions in Graur’s “mutational load” arguments. Recently three scientists writing in the journal Genome Biology and Evolution noted that these arguments wrongly assume that there could potentially exist a person with no deleterious mutations in their genome:

Our approach is different from previous work that compared mean fitness at mutation-selection equilibrium with the fitness of an individual who has no deleterious mutations; we show that such an individual is exceedingly unlikely to exist. We find that the functional fraction is not very likely to be limited substantially by mutational load, and that any such limit, if it exists, depends strongly on the selection coefficients of new deleterious mutations.

By comparing the population mean fitness at mutation-selection equilibrium to that of an individual who possesses no deleterious mutations, Graur (2017) reached the conclusion that, for likely values of the human per-base deleterious mutation rate, the functional fraction must be small. 

In this article, we present a different approach to analyzing mutational load and the human functional fraction. We do not take the fitness of an individual with zero deleterious mutations to be a meaningful value, because in a finite population of realistic size such an individual will never exist. Instead, we consider the fitness of the fittest individual likely to exist in a finite population. We conclude — while making no claims about the actual functional fraction as determined by comparative studies—that a mutational load argument is unlikely to set a low limit on the functional fraction of the human genome, and that any attempt to set such a limit must take into account the fitness effects of new deleterious mutations. [Emphasis added.]

Zero Deleterious Mutations?

Because no individual can exist with zero deleterious mutations, the maximum realizable fitness of the “fittest” person in a population is not ideal: “A main point of this article is that no individual with the theoretical maximum fitness, given the fitness model, will ever exist in a real population.” 

Additionally, they note that mutational load arguments against a highly functional genome are heavily dependent upon selection coefficients of new deleterious mutations. Only for very high values of these selection coefficients is any meaningful limit imposed on the proportion of the genome that is functional (f). They thus find that “when considering the likely maximum realized fitness in a finite population, the limit to f [the fraction of the genome that is functional] is by no means low.” 

They end their paper as follows:

Our conclusion is simply that an argument from mutational load does not appear to be particularly limiting on f.

Will this be the end of the debate over mutational load and ENCODE? Undoubtedly, no. Graur is an eminent scientist — about whom the journal Science said, “Graur’s atheism inflamed his anger at ENCODE.” In an online talk, Graur explained what’s at stake:

If the human genome is indeed devoid of junk DNA as implied by the ENCODE project, then a long, undirected evolutionary process cannot explain the human genome. If, on the other hand, organisms are designed, then all DNA, or as much as possible, is expected to exhibit function. If ENCODE is right, then evolution is wrong. 

He then admits in the talk that his goal is to “Kill ENCODE.”

Dr. Graur should be commended for his honesty, which makes clear that there’s a lot at stake here. We should not expect ENCODE-critics to go away quietly. But if this latest paper indicates anything, it’s that “mutational load” arguments aren’t the ENCODE-killers that they have been made out to be.

Photo credit: Jarrod Doll, via Flickr.