Tuesday 28 November 2017

Muddling Through With 'Intelligently Designed' Mistakes!

Adaptive mechanisms such as activation and use of cryptic splice sites or alternative transcription start sites as well as nonsense-associated alternative splicing and skipped exons maintaining reading frame shore up a sea of mutations expected to cause premature translation termination and loss of function.
Artist: Neta Shwartz.
What can zebrafish teach us about our survival in the face of mutations? | Carnegie Institution for Science

What would you do if you were an intelligent, omniscient, omnipotent designer and found that your perfect design kept going wrong in unexpected and unpredictable ways?

Well, if you were a creationist intelligent designer it seems, you would still regard yourself as an omniscience, omnipotent, perfect designer but you would wouldn't improve your design so it didn't keep going randomly wrong - because it's already perfect! Instead, you would set about designing a clunky workaround that went some way towards rectifying those omniscient mistakes and you would settle for near enough is good enough - apparently.

This is (leaving out the intelligent designer nonsense) what researchers Steven Farber, Jennifer Anderson and colleagues, of the Carnegie Institution have show happens in the zebrafish to cope with detrimental mutations. Rather than putting up with mutations resulting in individuals failing and being removed from the population gene pool, zebrafish, and maybe lots of other species, have evolved mechanisms for coping with them by either neutralising them or at least minimising their detrimental effects.

According to the Carnegie Institution press release:

Sometimes an organism compensates for a mutation in a gene by changing how it regulates the expression of other related genes—a workaround of sorts. Other times, cells skirt errors in the process by which a gene is first transcribed from DNA into RNA and then translated from RNA into a protein to compensate for a mutation. For example, Anderson and her colleagues described cases wherein cells were able to generate RNAs that survived by splicing out a deleterious mutation. These cells would be expected to produce a protein that is missing a small piece.

“The result may not be perfect, but these compensating measures mean that the organisms can get some of the job done with a less-than-perfect protein,” Farber said. “These workarounds show that from an evolutionary perspective, we have some pretty robust mechanisms in place to keep surviving despite mutations.”

What they found was that mechanisms have evolved that intervene in the process between the translation of the DNA code into RNA and then translation of the RNA code into proteins that, for example, splice out the detrimental mutation so it is not expressed to produce a non-functional protein but a protein which might not be as good as the normal form but which works well enough.

This is an uncorrected proof.

As model organism-based research shifts from forward to reverse genetics approaches, largely due to the ease of genome editing technology, a low frequency of abnormal phenotypes is being observed in lines with mutations predicted to lead to deleterious effects on the encoded protein. In zebrafish, this low frequency is in part explained by compensation by genes of redundant or similar function, often resulting from the additional round of teleost-specific whole genome duplication within vertebrates. Here we offer additional explanations for the low frequency of mutant phenotypes. We analyzed mRNA processing in seven zebrafish lines with mutations expected to disrupt gene function, generated by CRISPR/Cas9 or ENU mutagenesis methods. Five of the seven lines showed evidence of altered mRNA processing: one through a skipped exon that did not lead to a frame shift, one through nonsense-associated splicing that did not lead to a frame shift, and three through the use of cryptic splice sites. These results highlight the need for a methodical analysis of the mRNA produced in mutant lines before making conclusions or embarking on studies that assume loss of function as a result of a given genomic change. Furthermore, recognition of the types of adaptations that can occur may inform the strategies of mutant generation.

Author summary
The recent rise of reverse genetic, gene targeting methods has allowed researchers to readily generate mutations in any gene of interest with relative ease. Should these mutations have the predicted effect on the mRNA and encoded protein, we would expect many more abnormal phenotypes than are typically being seen in reverse genetic screens. Here we set out to explore some of the reasons for this discrepancy by studying seven separate mutations in zebrafish. We present evidence that thorough cDNA sequence analysis is a key step in assessing the likelihood that a given mutation will produce hypomorphic or null alleles. This study reveals that mRNA processing in the mutant background often produces transcripts that escape nonsense-mediated decay, thereby potentially preserving gene function. By understanding the ways that cells avoid the deleterious consequences of mutations, researchers can better design reverse genetic strategies to increase the likelihood of gene disruption.

It is undoubtedly biologically wasteful to have an imperfect replication system that sometimes produces mutations that waste the reproductive effort because they are non-viable or have very reduced viability, so there is obvious evolutionary pressure to evolve a work-around, even an imperfect one.

But this represents an impossible quandary for creationists. Not only does it show that even detrimental mutations can be mitigated to some extent by natural selection operating exactly as we would expect it too, but the entire situation would never have arisen in the first place if this system had been designed by an omniscient, omnipotent intelligence.

Now, you can almost hear creationists chanting "The Fall!" to explain a fallible design (incidentally, so showing that their notion is not science as they claim, but religious superstition in disguise). But even that doesn't make sense, because what we have here is this putative designer now designing a solution to the problem of it's own creation! It it had intended its design to throw up the occasional random mutation to teach mankind some sort of lesson (with mutant zebrafish! Really?) why did it design a means of minimising the effect of it's design?

The process isn't intelligent, of course. It's what we call evolution and it works exactly as we would expect - mindless, undirrected and utilitarian, and about as far removed from intelligent as it's possible to be.

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