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Four More DNA Bases?

As technology allows us to delve ever deeper into the inner workings of the cell, we continue to find layer-upon-layer of complexity. DNA, in particular, is an incredibly complex information-bearing molecule that bears the hallmarks of design.

The individual nucleotides that make up DNA are strung together in a particular order to code for particular functions. The characteristics of DNA are analogous to those of a written language with a four-letter alphabet of A, C, T, and G (or adenine, cytosine, thymine, and guanine).

DNA Methylation
What if small adjustments to the letters, A, C, T, or G, also translated into a different function? This would add another level of complexity to the already highly complex genetic code. So what if we change C just a little bit and call it "mC." This is like adding additional information by which a language can operate. Think of it like adding a tilde (~) or an umlaut (?) over a letter as is used in Spanish and German. This means the letters are read slightly differently. Last year an article came out describing a 5th and 6th nucleotide base to DNA. Recently another article reports on 7th and 8th bases. In actuality these "new" bases are all derivatives of cytosine (C). And as this recent Science paper points out, these derivatives may be chemical intermediates that occur when converting from "mC" to "C." While these discoveries of cytosine derivatives may not be quite as exciting as brand new bases, it does have implications for the argument for design.

One of the bases, the 5th base, is cytosine with a methyl group on it (chemically, this would be -CH3), labeled "mC" above. Structurally, the methylated cytosine causes the DNA double helix to coil just a little tighter than its non-methylated counterpart, "C" above. This tighter coil likely "silences" genes -- they are not transcribed. The lead author for the papers reporting on these bases, Yi Zhang, states that "5-methylcytosine [mC]...arises when a chemical tag or methyl group is tacked onto a cytosine. This methylation is associated with gene silencing, as it causes the DNA's double helix to fold even tighter upon itself." While this is an interesting discovery, his group also found that these cytosine derivatives are observed in mouse embryonic stem cells and may be implicated in stem cell reprogramming.

Methylated DNA, which is just DNA with methylated cytosines, has several other functions. A 2008 SciTable Nature Education article reports that methylated DNA plays a role in several cell processes: embryonic development, genomic imprinting, X-chromosome inactivation, and preservation of chromosome stability. Errors in methylation may be linked to certain diseases and tumor formation.

Zhang's recent Science article identifies Tet proteins as the proteins that likely catalyze several of the steps (and possibly all of the steps) in cytosine de-methylation -- in other words, going from mC to C. His group identified cytosine derivatives, the 7th and 8th bases, in genomic DNA as the product of a Tet protein catalyzed reaction. The researchers knew to look for these derivatives because they are exactly what one would expect to find in a cytosine de-methylation process.

Tet Proteins Catalyze De-methylation: Additional Complexity
As recent studies have shown, when the Tet proteins in mouse embryonic stem cells are shut down, scientists observe a difference in how the inner cell mass develops, as well as in overall stem cell self-renewal. This confirms the role of DNA methylation as influencing stem-cell activity. Furthermore, researchers found that Tet proteins regulate the expression of a gene called Nanog which Zhang found "helps stem cells reproduce themselves and keep their pluripotentcy." (From Physorg's report on the March 2011 Nature articles). Nanog is a gene, and genes are made up of DNA. So Tet proteins are probably regulating Nanog through methylation.

Zhang points out that Tet proteins and their role in methylating DNA are interesting because they can either silence genes that cause cells to divide or they can activate pluripotency genes in stem cells, which basically makes them divide and form various types of cells. It depends on the level and location of methylation or de-methylation. As Zhang points out in an interview: "We found that its role in regulating transcription is complicated. It's not simply activating or repressing genes -- it depends on the context" (emphasis added).

This is just a sample of some of the research that has come out on Tet proteins and DNA methylation. In the body, proteins that play important roles often have complex regulation systems. As a review article in The Journal of Molecular Cell Biology points out, Tet proteins certainly do:

The TET proteins are involved in a wide range of cellular processes and tightly regulated to ensure appropriate localization and activity. The domains in these proteins and early experiments suggested a role in RNAP II transcription and splicing, possibly coupling these processes, but subsequent studies have shown that TET proteins are also involved in a wide range of other processes, including repressing RNAP III transcription, DNA repair and RNA transport in neurons. The mechanism of TET protein activity, regulation of their cellular localization and the domains of the proteins involved in various processes remain to be clarified.

This level of complexity, the interaction between Tet proteins and methylation, is remarkably intricate, and even Nature acknowledged the finely tuned nature of DNA methylation. See here for several articles on the topic that are available by subscription as well as a summary of what the journal calls "Fine-tuning DNA methylation by Tet proteins." In fact this process is so finely tuned that it looks more like a complicated piece of engineering than the results of an unguided process.

If these layers of complexity seem a bit overwhelming, then you are beginning to get the point. This level of interplay among DNA, proteins, and cellular process is difficult to account for under a neo-Darwinian paradigm, given the limits of natural selection acting on mutations. We are not just talking about one little chemical reaction on a cytosine molecule, but an entire interplay of reactions that will either methylate or de-methylate to a specific extent, resulting in specific cellular functions. Neo-Darwinism is an unguided process, but DNA methylation exhibits layer upon layer of complexity that, in any other circumstance, would be considered a work of remarkable engineering. The more we learn about DNA, the more compelling the argument for design becomes.