Redundancy in the genetic code has long been recognised. Most amino acids can be specified in multiple ways (2-6 synonymous codons). More recently, it has also become known that synonymous codons are non-random, stimulating thought as to why this should be (see here). Since codon usage biases characterise both prokaryotic and eukaryotic genomes, is it possible that they are accidents of evolutionary history? This seems to be ruled out by pervasive evidences of conservation. Since the biases are not removed by mutations, it is inferred that "observed codon preferences in mammalian genomes [. . .] appear to be under selection" (p.1367.) Such a conclusion is reached by deduction from evolutionary theory. If specific (synonymous) codons do not matter when manufacturing proteins, is it possible they are relevant to the regulation of genetic processes? Since there is a presumption favouring simplicity in the minds of most geneticists, this research question has only recently been taken up. There are many synonymous codons when coding for proteins, but are they synonymous if they are also coding regulatory instructions?
"Genomes also contain a parallel regulatory code specifying recognition sequences for transcription factors (TFs), and the genetic and regulatory codes have been assumed to operate independently of one another and to be segregated physically into the coding and noncoding genomic compartments. However, the potential for some coding exons to accommodate transcriptional enhancers or splicing signals has long been recognized." (p.1367)
The challenge of the Human Genome Project has given way to searching for an understanding of multiple overlapping genetic codes. (source here)
With the availability of large amounts of genome data, it is possible to test many hypotheses relevant to the functionality of DNA sequences. The data set used is impressive:
"To define intersections between the regulatory and genetic codes, we generated nucleotideresolution maps of TF occupancy in 81 diverse human cell types using genomic deoxyribonuclease I (DNaseI) footprinting. Collectively, we defined 11,598,043 distinct 6- to 40-base pair (bp) footprints genome-wide (~1,018,514 per cell type), 216,304 of which localized completely within protein-coding exons (~24,842 per cell type). Approximately 14% of all human coding bases contact a TF in at least one cell type (average 1.1% per cell type), and 86.9% of genes contained coding TF footprints (average 33% per cell type)." (p.1367)
A summary of the main findings of the research team is provided in a Perspectives essay by Weatheritt and Babu. The hypothesis of two co-existing codes is fully justified by the evidence. According to the press release: "scientists were stunned to discover that genomes use the genetic code to write two separate languages."
"How widespread is the phenomenon of "regulatory" codes that overlap the genetic code, and how do they constrain the evolution of protein sequences? Stergachis et al. address these questions for the transcription factor-binding regulatory code. They use deoxyribonuclease I (DNase I) footprinting to map transcription factor occupancy (a protein bound to DNA can protect that region from enzymatic cleavage) at nucleotide resolution across the human genome in 81 diverse cell types. The authors determined that ~14% of the codons within 86.9% of human genes are occupied by transcription factors. Such regions, called "duons", therefore encode two types of information: one that is interpreted by the genetic code to make proteins and the other, by the transcription factor-binding regulatory code to influence gene expression. This requirement for transcription factors to bind within protein-coding regions of the genome has led to a considerable bias in codon usage and choice of amino acids, in a manner that is constrained by the binding motif of each transcription factor." (p.1325)
Weatheritt and Babu go further. They suggest a general principle: that redundancy in the genetic code opens the door for, not one, but many regulatory codes that can operate within protein-coding regions of the genome. One research question of the future is: how many overlapping codes can be tolerated by the genetic code?
"This "binding" code joins other "regulatory" codes that govern chromatin organization, enhancers, mRNA structure, mRNA splicing, microRNA target sites, translational efficiency, and cotranslational folding, all of which have been proposed to constrain codon choice, and thus protein evolution." (p.1325)
It should be noted that these research findings do not tell us what binding a transcription factor actually achieves. The field of gene regulation is in its infancy. The research team notes that TF binding "may serve multiple functional roles" but that their analysis is "agnostic" to this functionality. Weatheritt and Babu conclude:
"The investigation of overlapping codes opens new vistas on the functional interpretation of variation in coding regions and makes it clear that the story of the genetic code has not yet run its course." (p.1326)
This discussion of genetic codes is only meaningful if it is recognised that the genome is a carrier of complex specified information. The essence of life is not to be found in chemistry, but in the information carried within the cell. Chemicals are used to carry biological information, but the chemicals are not themselves information. The research team recognises this when they say:
"Our results indicate that simultaneous encoding of amino acid and regulatory information within exons is a major functional feature of complex genomes. The information architecture of the received genetic code is optimized for superimposition of additional information and this intrinsic flexibility has been extensively exploited by natural selection." (p.1371-2)
There is a problem with the last few words of the above quotation. The flexible information architecture is said to be exploited "by natural selection", yet this claim has not emerged from a study of evidences. Rather, the theoretical framework of neo-Darwinism provides the context for interpreting the evidences, so that all signs of complexity and functionality are automatically associated with the operation of natural selection. Yet, we have no evidence to show that natural selection can either produce or refine complex specified biological information.
There is a perfectly viable alternative hypothesis to consider: that biological information is evidence for intelligent agency. The evidence we have already about the genetic code is sufficient to make the point, but new evidences of overlapping codes add weight to the hypothesis. The genetic code with redundancy overlaps with other regulatory codes in ways that test the ability of molecular biologists (intelligent agents) to understand what's happening, let alone write overlapping codes of their own as a biomimetic exercise. From time to time, leading biologists get the message, but seem at a loss to drive it forward.
"Any living being possesses an enormous amount of "intelligence", very much more than is necessary to build the most magnificent of cathedrals. Today, this "intelligence" is called "information", but it is still the same thing. It is not programmed as in a computer, but rather it is condensed on a molecular scale in the chromosomal DNA or in that of any other organelle in each cell. This "intelligence" is the sine qua non of life. If absent, no living being is imaginable. Where does it come from? This is a problem which concerns both biologists and philosophers and, at present, science seems incapable of solving it." Pierre Grasse, Evolution of Living Organisms: Evidence for a New Theory of Transformation, (New York: Academic Press, 1977, 2).
The decision to endorse a naturalistic explanation rather than advance agnosticism about the origins of hidden overlapping codes is a pointer to hidden ideologies in origins-science. It seems that as long as materialism/naturalism is presumed, then a great number of unwarranted assertions (usually linked to Darwinism or abiogenesis) go unchallenged in academic papers. As soon as it is pointed out that only intelligent agents write codes, there is an outcry that science is being subverted by religious fundamentalists. However, the converse is true: intelligent design theory is based on the evidence of complex specified information. The evidences for naturalistic alternatives all evaporate under close scrutiny.
Exonic Transcription Factor Binding Directs Codon Choice and Affects Protein Evolution
Andrew B. Stergachis, Eric Haugen, Anthony Shafer, Wenqing Fu, Benjamin Vernot, Alex Reynolds, Anthony Raubitschek, Steven Ziegler, Emily M. LeProust, Joshua M. Akey and John A. Stamatoyannopoulos.
Science, 13 December 2013, 342, 1367-1372 | DOI:10.1126/science.1243490 [pdf here]
Abstract: Genomes contain both a genetic code specifying amino acids and a regulatory code specifying transcription factor (TF) recognition sequences. We used genomic deoxyribonuclease I footprinting to map nucleotide resolution TF occupancy across the human exome in 81 diverse cell types. We found that ~15% of human codons are dual-use codons ("duons") that simultaneously specify both amino acids and TF recognition sites. Duons are highly conserved and have shaped protein evolution, and TF-imposed constraint appears to be a major driver of codon usage bias. Conversely, the regulatory code has been selectively depleted of TFs that recognize stop codons. More than 17% of single-nucleotide variants within duons directly alter TF binding. Pervasive dual encoding of amino acid and regulatory information appears to be a fundamental feature of genome evolution.
Weatheritt, R.J. and Babu, M, M. The Hidden Codes That Shape Protein Evolution,
Science, 13 December 2013, 342, 1325-1326 | DOI: 10.1126/science.1248425
Klinghoffer, D. Genome Uses Two Languages Simultaneously; Try That Yourself Sometime, Why Don't You, Evolution News & Views (December 13, 2013)
Luskin, C. Codes Within Codes: How Dual-Use Codons Challenge Statistical Methods for Inferring Natural Selection, Evolution News & Views (December 20, 2013)
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