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More Hints of Order in the Genome

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Genomics has come a long way since the central dogma (the notion that DNA is the master controller that calls all the shots) and junk DNA (the expectation that much of the genome is non-functional). If scientists ditch those old dogmas and approach the genome expecting to find reasons for things, they often do.

Synonymous Mutations

To-may-to or to-mah-to? The British write flavour; the Americans write flavor, but generally each understands the other without too much difficulty. Genomes, too, have alternate ways of spelling things: GGU and GGC in messenger RNA both spell glycine. No big deal, thought geneticists; these “silent” mutations cause no change in the resulting protein. At the University of Notre Dame, however, biochemists are finding that the differences in spelling are not just background noise; they alter the protein’s folding. Is that good or bad?

“Synonymous mutations were long considered to be genomic background noise, but we found they do indeed lead to altered protein folding, and in turn impair cell function,” said Patricia Clark, the Rev. John Cardinal O’Hara professor of biochemistry at the University of Notre Dame, and lead author of the study. “Our results show that synonymous variations in our DNA sequences — which account for most of our genetic variation — can have a significant impact on shaping the fitness level of cellular proteins.”

Surely many of these mutations are harmful, as are random mutations in humans that cause genetic disease. But E. coli has been around for a long time. Wouldn’t the species have gone extinct by now with the accumulation of defective spellings if they are always deleterious? Other work has suggested a “secret code” in synonymous variations that fine-tunes expression rates or regulates the supply of a given protein based on environmental conditions. The news release only mentions impairments caused by synonymous variations, but Notre Dame team’s paper in PNAS suggests some possible advantages:

Synonymous codon substitutions alter the mRNA coding sequence but preserve the encoded amino acid sequence. For this reason, these substitutions were historically considered to be phenotypically silent and often disregarded in studies of human genetic variation. In recent years, however, it has become clear that synonymous substitutions can significantly alter protein function in vivo through a wide variety of mechanisms that can change protein level, translational accuracy, secretion efficiency, the final folded structure and posttranslational modifications. The full range of synonymous codon effects on protein production is, however, still emerging, and much remains to be learned regarding the precise mechanisms that regulate these effects. [Emphasis added.]

A design perspective would consider every possible function before rendering a judgment that all synonymous variations reduce fitness.

Proofreading

Keeping the genome accurate to a high degree preserves it from collapsing due to error catastrophe. At the time of cell division, proofreading enzymes (what a concept!) perform this vital function. Chelsea R. Bulock et al., writing in PNAS, have found one duplication enzyme that proofreads itself while proofreading its partner! “DNA polymerase δ proofreads errors made by DNA polymerase ε,” the paper is titled.

Polδ and Polε are the two major replicative polymerases in eukaryotes, but their precise roles at the replication fork remain a subject of debate. A bulk of data supports a model where Polε and Polδ synthesize leading and lagging DNA strands, respectively. However, this model has been difficult to reconcile with the fact that mutations in Polδ have much stronger consequences for genome stability than equivalent mutations in Polε. We provide direct evidence for a long-entertained idea that Polδ can proofread errors made by Polε in addition to its own errors, thus, making a more prominent contribution to mutation avoidance. This paper provides an essential advance in the understanding of the mechanism of eukaryotic DNA replication.

In other words, Polδ is a proofreader of a proofreader. The paper says that Polδ is a “versatile extrinsic proofreading enzyme.” One could think of it as a supervisor checking the work of a subordinate, or better yet, as an auditor or inspector able to fix errors before they cause harm to the product. Why would this be necessary during replication? The authors see a seniority system:

Thus, the high efficiency of Polδ at correcting errors made by Polε may result from a combination of two factors: the high proclivity of Polε to yield to another polymerase and the greater flexibility and robustness of Polδ when associating with new primer termini.

One proofreader is amazing to consider “evolving” by a Darwinian mechanism. A proofreader of a proofreader is astonishing. Consider, too, that this proofreading operation occurs in the dark by feel, automatically, without eyes to see.

High-Order Structure

Now that genetics is long past the heady days of finding that DNA forms a code that is translated, additional discoveries continue to show additional “codes” and factors that contribute to genomic function. One factor is the high-order structure of DNA. Researchers at South Korea’s UNIST center have explored further into the formation of this structure, which involves chromatin wrapping around histone proteins so that long strands of DNA can fit within the compact space of the cell nucleus. As with everything else in genomics, the structure doesn’t just happen. It requires a lot of help.

Regulation of histone proteins allows the DNA strands become more tightly or loosely coiled during the processes of DNA replication and gene expression. However, problems may arise when histones clump together or when DNA strands intertwine. Indeed, the misregulation of chromatin structures could result in aberrant gene expression and can ultimately lead to developmental disorders or cancers.

Histone chaperones are those proteins, responsible for adding and removing specific histones [found] at the wrong time and place during the DNA packaging process. Thus, they also play a key role in the assembly and disassembly of chromatin.

Cryo-EM imaging allowed the team to envision the molecular structure of some of these chaperone proteins. Their paper in Nature Communications begins, “The fundamental unit of chromatin, the nucleosome, is an intricate structure that requires histone chaperones for assembly.” Their cryo-EM images of one particular chaperone named Abo1 reveals a six-fold symmetry with precise locations for docking to histones, its hexameric ring “thus creating a unique pocket where histones could bind” with energy from ATP. “Not only is Abo1 distinct as a histone chaperone,” they write, “but Abo1 is also unique compared to other canonical AAA+ protein structures.” Like Lego blocks, Abo1 features “tight knob-and-hole packing of individual subunits” plus linkers and other binding sites, such as for ATP. And unlike static blocks, these blocks undergo conformational changes as they work.

Such sophistication is far beyond the old picture of DNA as a master molecule directing all the work. It couldn’t work without the help of many precision machines like this.

More Samples from the Literature

These stories are mere samples from a vast and growing literature indicating higher order in the genome than expected. Here are some more samples readers may wish to investigate:

Researchers at the University of Seville found additional factors involved in the repair of DNA strand breaks. These repairs are essential for the maintenance of genome integrity. The factors they discovered help maintain the right tension in cohesin molecules that hold the chromosomes together until the right time to separate. The news was relayed by EurekAlert! and published in Nature Communications.

Remember Paley’s Watch? Researchers at the University of Basel discovered that “Inner ‘clockwork’ sets the time for cell division in bacteria.” In PNAS and in Nature Communications, the Basel team elucidates the structure and function of a small signaling molecule that starts the “clock,” which then informs the cell about the right time to reproduce. They report in the news release:

A team at the Biozentrum of the University of Basel, led by Prof. Urs Jenal has now identified a central switch for reproduction in the model bacterium Caulobacter crescentus: the signaling molecule c-di-GMP. In their current study, published in the journal Nature Communications, they report that this molecule initiates a “clock-like” mechanism, which determines whether individual bacteria reproduce.

Proteins must fold properly to perform their functions. Small proteins usually fold successfully on their own, but large ones can fall into several misfolding traps that are equally likely as the canonical fold. It appears that the “sequence of the sequence” in a gene has something to do with this. “Interestingly, many of these proteins’ sequences contain conserved rare codons that may slow down synthesis at this optimal window,” explain Amir Bitran et al. in a January 21 paper in PNAS, discovering that “Cotranslational folding” (i.e., folding that begins as the polypeptide exits the ribosome) “allows misfolding-prone proteins to circumvent deep kinetic traps.” 

Design advocates and evolutionists need to fathom what they are dealing with when discussing origins. There’s nothing like some low-level detail to put the challenge in perspective.

Image credit: Caulobacter crescentus, by University of Basel, Swiss Nanoscience Institute/Biozentrum, via EurekAlert!