July 21, 2006 | David F. Coppedge

Cell Backup Systems Challenge Evolution, Show Design Principles

Has an intelligent design paper been published in the Proceedings of the National Academy of Sciences?1  Read the abstract and decide whether this research supports Darwinism or design:

Functional redundancies, generated by gene duplications, are highly widespread throughout all known genomes.  One consequence of these redundancies is a tremendous increase to the robustness of organisms to mutations and other stresses.  Yet, this very robustness also renders redundancy evolutionarily unstable, and it is, thus, predicted to have only a transient lifetime.  In contrast, numerous reports describe instances of functional overlaps that have been conserved throughout extended evolutionary periods.  More interestingly, many such backed-up genes were shown to be transcriptionally responsive to the intactness of their redundant partner and are up-regulated if the latter is mutationally inactivated.  By manual inspection of the literature, we have compiled a list of such “responsive backup circuits” in a diverse list of species.  Reviewing these responsive backup circuits, we extract recurring principles characterizing their regulation.  We then apply modeling approaches to explore further their dynamic properties.  Our results demonstrate that responsive backup circuits may function as ideal devices for filtering nongenetic noise from transcriptional pathways and obtaining regulatory precisionWe thus challenge the view that such redundancies are simply leftovers of ancient duplications and suggest they are an additional component to the sophisticated machinery of cellular regulation.  In this respect, we suggest that compensation for gene loss is merely a side effect of sophisticated design principles using functional redundancy.

The three authors, all from the Weizmann Institute in Rehovot, Israel, speak freely of the evolution of this phenomenon in their paper; they also, interestingly, refer to design and design principles just as often:

In particular, we suggest the existence of regulatory designs that exploit redundancy to achieve functionalities such as control of noise in gene expression or extreme flexibility in gene regulation.  In this respect, we suggest that compensation for gene loss is merely a side effect of sophisticated design principles using functional redundancy.
    Clues for regulatory designs controlling redundancy were obtained first in a recent study…

They call these cases of functional redundancy responsive backup circuits (RBCs).  Interestingly, they found some cases where one RBC is regulated by another RBC.  Though often the two backup copies were differently regulated, they could become coregulated under certain environmental conditions.  The team also found that some of these functionally redundant genes are found all the way from yeast to mammals; this is sometimes called “evolutionary conservation” but actually describes stasis, not evolution.
    The authors do not deny that these backup systems evolved somehow: “For a single cell, the ability to quickly and efficiently respond to fluctuating environments is crucial and offers an obvious evolutionary advantage,” they postulate, suggesting that accidental duplication of genes was co-opted for this purpose.  They do not get into any details of how this might have happened, however, and their analysis seems more interested on the complexity and design benefit of the systems.
    Their criteria for functional backups were stated thus: “Two lines of evidence could indicate a function’s direct benefit from existing redundancy: first is the evolutionary conservation of the functional overlap, and second is a nontrivial regulatory design that utilizes it.”  How many such systems exist in nature they could not say, because there have not been enough studies.  Many functionally equivalent copies of enzymes (isozymes) are known.  The genes that produce them are often regulated by different pathways.  Under stress, however, some can become coregulated to provide robustness against environmental irregularities or damaging mutations.

The model that emerges is that although many isozymes are specialized for different environmental regimes, alarm signals induced by particular stress stimuli may call for their synergistic coexpression.  Here, RBCs provide functional specialization together with extreme flexibility in gene control that could be activated when sufficient stress has been applied.  For example, in yeast, glucose serves as a regulatory input for alternating between aerobic and anaerobic growth.  Its presence is detected by two separate and independent signaling pathways, one probing intracellular glucose concentrations and the other probing extracellular concentrations.

They searched the literature and found several interesting ones that are described in detail in the paper.  “In all these cases, the common denominator is that one of the two duplicates is under repression in wild type and that that repression is relieved upon its partner’s mutation.”
    This raises an interesting question – one that could have been asked by someone in the intelligent design movement.  They even answer a possible objection with a design principle:

The extent to which genomic functional redundancies have influenced the way we think about biology can be appreciated simply by inspecting the vast number of times the word “redundancy” is specifically referred to in the biomedical literature (Fig. 5, which is published as supporting information on the PNAS web site).  Particularly interesting is the abundance with which it is addressed in studies of developmental biology (Fig. 5).  In fact, it is here that concepts such as “genetic buffering” and “canalization” first had been suggested.  Furthermore, the robustness of the developmental phenotypes such as body morphologies and patterning have been repeatedly demonstrated.  So the question is, are these redundancies simply leftovers of ancient duplications, or are they an additional component to the sophisticated machinery of cellular regulation?
    In criticism, one may argue that many of the reported redundancies do not actually represent functionally equivalent genes but rather reflect only partial functional overlap.  In fact, knockout phenotypes have been described for a number of developmental genes that have redundant partners.  For these reasons, it has been suggested to define redundancy as a measure of correlated, rather than degenerate, gene functions.  Although these facts may suggest that redundancies have not evolved for the sake of buffering mutations, it has, in our opinion, little relevance to the question of whether they serve a functional role.  The interesting question is, then, can such a functional role for the duplicated state be inferred from the way the two genes are regulated?

Along that line, they found that the amount of upregulation of one gene was often dependent on the regulation of the other.  This suggested to them that the sum of the expression of the two copies is nearly constant as a buffer against noise in the system.  When one line gets noisy, due to a mutation, the other responds with more signal.  They call this “dosage-dependent linear response.”  In some cases during development, the responsive overlap decreases as the organism grows.  In short, “The abundance of redundancies occurring in genes related to developmental processes, and their functional role as master regulators (Fig. 5) may be taken to suggest their utilization in either the flexibility or robustness of regulatory control.”
    Some examples they give are even more complex.  RBCs may also be implicated in the resistance of some organisms to multiple drugs.  In some cases, each isoform can compensate equally for the other; in others, one of the forms is the main (the controller) and the other acts as the backup (the responder), only coming into play when the primary goes sour.  “One of the most profound and insightful of these recurring regulatory themes,” they exclaim, “is that, although both genes are capable of some functional compensation, disruption of the responder produces a significantly less deleterious phenotype than disruption of the controller”.  In evolutionary terms, why would the backup copy be better?

A simple potential interpretation may suggest that although the controller is the key player performing some essential biological role, the responder is merely a less efficient substitute.  Yet, accepting the notion that redundancy could not have evolved for the sake of buffering mutations, this interpretation still is severely lacking.
    A different, and more biologically reasonable, hypothesis accounting these asymmetries is that one of the functions of the responder is to buffer dosage fluctuations of the controller.  This buffering capacity requires a functional overlap that also manifests itself in compensations against the more rare event of gene loss.  Other models accounting for this assymetry are discussed further in this work, but our main point of argument is that this complex regulation of functionally redundant, yet evolutionarily conserved genes, strongly indicates utilization of redundancy.

Their next subsection is called “Regulatory Designs.”  What emerges from their discussion of how each gene can regulate its partner is a complex picture: in one case, “redundancy is embedded within a more complex interaction network that includes a unidirectional responsive circuit in which the controller (dlx3) also represses its own transcription, whereas the responder (dlx7) is a positive autoregulator.”  More examples like this are described.  They predicted, and found, that RBCs could also regulate “downstream processes from variation and fluctuations arising from nongenetic noise.”  The net result is that by using these functional backup systems, the organism has more robustness against perturbations, yet more flexibility in a dynamic environment.
    What is the fruit of this research?  Why should scientists look for these “regulatory designs” in the cell?  They offer an intriguing example.  It is known that one form of human muscular dystrophy occurs when a member of an RBC suffers a mutation.  Studies of this pair in mice, however, shows that the other member can respond by upregulating its expression.  It is thought a similar response might occur in humans.  “Inspired by the compensatory effect demonstrated by this RBC in mice, its artificial induction in humans by means of gene therapy has been suggested.  Although such modalities have not yet been realized, they suggest a fruitful possibility.

1Kafri, Levy and Pilpel, “The regulatory utilization of genetic redundancy through responsive backup circuits,” Proceedings of the National Academy of Sciences USA, 10.1073/pnas.0604883103, published online before print July 21, 2006

This is really a remarkable paper filled with inspiring possibilities.  If we can just think design instead of years of mindless mutations, we might find cures for debilitating diseases.  This paper has much of the obligatory evolutionspeak, but what does Darwinian thinking really contribute?  Nothing.  Although the researchers paid lip service to the evolutionary explanation that members of RBC pairs might have arisen through gene duplication, and that the coregulation might have provided a selectable fitness advantage, such language is really nothing more than the usual aftermarket sales pitch on the designed product.  The real heart of their argument was that design exists, it is functional, and we can learn from it in ways that could help mankind.  The future of design-theoretic science looks bright.

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