-by Mike Gene

I think that most people find lagging strand synthesis during DNA replication to be counter-intuitive, especially when compared to the more streamlined and efficient process of leading strand synthesis. In fact, so counter-intuitive is it that some have argued lagging strand synthesis speaks against a design-based origin. As one scientist told me, "Anyone who teaches genetics at the undergraduate level would appreciate quickly that this feature is so bizarre, so nonsensical, so foolish as to defy logical or teleological explanation. I don't think ID has an answer to this issue."

Yet a couple of undergraduate textbooks do provide our first clues to understanding this "clumsy" lagging strand synthesis from a telic perspective:

Given the complexity of this model, one may wonder why cells don't simply produce an enzyme that synthesizes DNA in the 3' to 5' direction. One possible answer is related to the need for error correction during DNA replication. About one out of every 10,000 nucleotides incorporated during DNA replication is incorrectly base-paired with the template DNA strand. Such mistakes are usually corrected by a proofreading mechanism, which utilizes the same DNA polymerase molecule that catalyzes DNA synthesis. Proofreading is made possible by the fact that the DNA polymerase exhibits a 3'-exonuclease activity, which catalyzes the removal improperly base-paired nucleotides from the 3' end of the polynucleotide chain. This proofreading capability improves the fidelity of DNA replication to the point where an average of only one error occurs for every billion base pairs replicated. If cells did contain an enzyme capable of synthesizing DNA in the 3' to 5' direction, proofreading would not work because a DNA chain growing in the 3' to 5' direction would contain a nucleotide triphosphate at its 5' end. If this 5' nucleotide were an incorrect base that needed to be removed during proofreading, its removal would eliminate the triphosphate group that provides the free energy that allows DNA polymerase to add nucleotides to a growing DNA chain. Hence no further elongation of the DNA chain could take place. - Kleinsmith, LJ. and Kish, VM. Principles of Cell and Molecular Biology, 2nd ed.

and

Thus, the existence of lagging strand synthesis may actually be a place exhibiting a foresight that imparts priority to accuracy of replication over efficiency (design often entails making such judgments, where one property is emphasized at the expense of another). Further support for detecting the trace of mind is found in the charging of tRNA molecules, which also employ a proofreading process that exhibits the same basic design logic (as I will discuss later).

Lagging strand synthesis would also seem more of a problem for the non-teleological perspective which can not draw upon foresight. How? Proofreading is supposed to be a latecomer. This means, for millions of years, genomes were being replicated without proofreading. Now, it would seem that any genome that evolved a 3'-to-5' polymerase would now be able to replicate more quickly. And since evolution has no foresight, this polymerase would quickly spread and replace the 5'-to-3' function on the "lagging strand" (since evolution cares only about one thing - getting out more offspring). Then, proofreading evolved. Meaning half the progeny would be more faithfully replicated than the other half. This, itself, would seem to be selected for, since evolution depends on variability in order to respond to the changing environment. Bottom line? The non-teleological view leads us to expect a 3'-to-5' polymerase and thus no lagging strand synthesis. That is, while lagging strand synthesis makes sense from a teleological viewpoint employing foresight, it doesn't make much sense from the non-teleological viewpoint.

After giving this issue a little more thought, applying telic notions of proof-reading, I was able to successfully infer yet another aspect of biotic reality. I've long privately opined that the coupling of lagging leading strand synthesis through the joined polymerase machinery was akin to putting a brake on a run away train. I then began to think that the modular design of lagging strand synthesis actually provides a great opportunity for regulation (through braking when needed). Thus, it would seem to be a good target for checkpoint surveillance. So I did a little PubMed surfing expecting to find support for this hypothesis and once again, ID thinking guided me successfully:

Trends Biochem Sci 1997 Nov;22(11):424-427
The DNA polymerase alpha-primase complex couples DNA replication, cell-cycle progression and DNA-damage response.

Foiani M, Lucchini G, Plevani P.

The highly conserved DNA polymerase alpha-primase complex (pol-prism) is the only eukaryotic DNA polymerase that can initiate DNA synthesis de novo. It is required both for the initiation of DNA replication at chromosomal origins and for the discontinuous synthesis of Okazaki fragments on the lagging strand of the replication fork. The dual role of pol-prim makes it a likely target for mechanisms that control cell-cycle S-phase entry and progression.

Upon obtaining the article, what did I find?:

All the available data suggest that DNA primase is likely to be one of the final targets of the checkpoint pathway(s) coupling DNA replication to DNA damage response. This assumption is consistent with the biochemical properties of DNA primase, whose priming activity is likely required to bypass a DNA lesion in order to resume DNA synthesis downstream of the damage. Therefore, in the presence of chromosomal lesions, it is possible that DNA primase activity must be inhibited to prevent priming downstream of the damage, and to slow down DNA replication, thus, providing enough time to repair the lesions.

I emphasized the last point because it is almost literally what I conceived prior to doing the literature search.

So, there are two lessons from this "foolish system that defied teleological or logical explanation."

1. Proof-reading on two levels (exonucleolytic and lesion repair) gives us a good teleological and logical explanation for existence of lagging strand synthesis.
2. By not giving up and instead trying to better understand the logical basis of this system (a conceptual concern), I was able to come up with yet another prediction about cell biology that appears to have thus far been confirmed.

Of course, periodically I have encountered people who argue that the mere fact DNA polymerase makes errors speaks against its intelligent origin. Yet even if it were possible to design an error-free DNA polymerase, an error-free mode of replication would hinder one's attempt to front-load evolution. As I will explain elsewhere, "errors" play important roles in finding the buried designs inherent in the originally designed state.

The concept of designing of evolution through front-loading suggests that two forces are at tension. We need to allow for errors to tap into the buried design, but we need a certain level of accuracy to ensure the original designs and buried designs are not erased by noise. It is thus the balance of these forces, working to carry out the designed objectives behind evolution, that is most interesting.

As far as errors go, let's get some basic facts straight first. When DNA is replicated, a new strand is synthesized by stringing together nucleotides under the direction of the template strand. Now, the new strand is synthesized at a rate of about 300-500 nucleotides/sec (in E. coli). And without the proofreading function of the 3'-5' exonuclease activity, the error rate is about 1 in 1x10^5 (proofreading takes the error rate down to a range of ca. 1x10^10). But to truly appreciate how good this is, one must consider that the basis for discrimination is very subtle as the four nucleotides are quite similar. Normally, A binds to T and G binds to C, but mismatching is clearly possible as H-bonds can form between C/A and T/G (through wobble-like interactions). I have not read of any free energy calculations, but I suspect the differences between Watson-Crick base-pairing and some of these other forms of base-pairing are small to non-existent. In fact, what is interesting about DNA pol I from E. coli is that it discriminates through subtle conformational shifts that depend on the base pair conforming to the geometry of standard Watson-Crick base-pairs (where non-WC base-pairs have only a modestly different geometry with respect to distances between the C-1' carbons of the sugars and with respect to bond angles).

To use an analogy, the DNA polymerase is not reading a string of red, green, white, and black beads. It is reading four beads that are closely continuous shades of gray. We're talking about discrimination near the threshold where the basis for discrimination begins to fade away. And we're talking about doing it very quickly and very well .

Now, why do cells require proofreading? Apparently, even though DNA pol is about as good as you can get, this is not sufficient for faithfully replicating the amount of information needed to sustain and propagate life. Life is more than complexity; it is specified complexity. Of course, one might want to argue that a designer should have designed another form of genetic material, or perhaps another Universe with a different set of Laws (for those who think the designer is God), simply in order to do without the handful of gene products needed to proofread. But this "should have" argument is purely a speculative metaphysical argument where we have not a single shred of evidence that these other imaginary and undefined states would be any better. For example, say we design genetic material whose characters are easier to distinguish. Easy to imagine, eh? But what does this mean in terms of the metabolic machinery needed to make the characters? Would we trade the few proofreading gene products for even more character-synthesizing enzymes that might require even more energy? Would a template strand with very different characters be more "bumpy" so that it slows the polymerase or makes it harder to package the genetic material?

Proofreading simply means that life is built around specificity at a micro-level so small that the ability to specify is nearly unobtainable. That is, just about at the threshold where specificity becomes possible, there we find the process we call life. This doesn't speak of kludginess to me (a membrane bag full of random second order reactions speaks more of kludginess). It speaks of design at a very impressive level.