#75. A Tripartite Genetic Code [Genetics]

GE

 Red, theory; black, fact

(Originally posted in the "Enhancers" post.) 

The filamentous alga Cladophora.

Last update: 08-19-2024

In this post, conceived while I was in a hospital, I propose that there are three genetic codes, not one. Conventional thinking says that there is just one code, which encodes the amino acid sequence of proteins into DNA. Here are the two new ones:

A morphology code for the multicellular level

08-01-2022: The interaction of semipermanent charges on chromatin, a possibility introduced in the "Enhancers" post, could structure the chromosomes into reproducible configurations within the nucleus. For instance, a chromatin segment with a net positive charge will tend to stick to a segment with a net negative charge, leading to their respective chromosomes being spot-welded at that point. An analogy from protein chemistry would be a disulfide bridge. This structuring may be followed by transmission of nuclear 3D information through the nuclear membrane to dictate the nuclear diameter along which the centrosomes separate to initiate mitosis. This, in turn, will dictate the orientation of the mitotic division plane. In the context of a growing embryo, such control of the orientation of mitosis is arguably at the origin of organ and body morphology. For example, all planes parallel will result in a filamentous organism like Cladophora. Planes free to vary in only one angle (azimuth or elevation) will produce a sheet of cells, a common element in vertebrate embryology. Programmed variation in both angles can produce a complex 3D morphology like the vertebrate skeleton. Thus we begin to see a genetic code for morphology, distinct from the classical genetic code that specifies amino acid sequences. 

<08-05-22: Possibly, each chromosome folds in a hairpin turn near the center of the nucleus and ends up occupying a specific conical solid angle. A cell generation counter or the developmental signals around the cell then activate a centrosome-maker gene in one specific chromosome and no other. This gene is then transcribed into a long noncoding RNA molecule that protrudes from a specific nuclear pore and triggers the assembly of a new centrosome just outside the nucleus at a specific azimuth and elevation. The nucleus is tethered by cytoskeletal elements such as lamin, nesprin, actin, and tubulin to focal adhesions on the the cell membrane, non-rotatably, so that all angle information can be referred to the previous mitotic orientation. The final step is dislodging the old centrosome and sweeping it into the antipodal position of the new one. This could be done by an array of microtubules growing radially out of the new centrosome but constrained to stay close to the nuclear membrane. 

Thus, there appear to be two tiers of control of mitotic orientation available: controlling which chromosome or chromosome arm produces the centrosome-maker RNA, and controlling the pattern of histone epigenetic marks in the nucleus and thus the chromatin charge pattern and thus the 3D structure into which the chromosomes assemble, and thus the mitotic angles assigned to a given chromosome.> <09-01-22: At the DNA level, the code for multicellular morphology would take the form of promoter-controlled segments that transcribe into long noncoding RNAs having a special two-domain structure: a domain that binds to a particular kind of histone-modifying enzyme and a domain that binds to a particular DNA sequence. These lncRNAs would specify, at the second tier of control, local charge changes in chromatin in a context-dependent manner.><09-14-2022: In organisms that are morphologically complex but have few chromosomes in their karyotype, such as fruit flies, the mitotic angles could be assigned to reproducible chromatin loops as well as to whole chromosomes, suggesting a 3-tiered control system.><19-08-2024: The nucleus is usually spherical or ovoid and is about ten times more rigid than the surrounding cytoplasm, features which may be related to the demands of the morphology read-out process. Consistent with this, blood is a tissue without a morphology, and the nucleated cells of the blood have nuclei that are mostly irregular and lobate. The lymphocytes found in the blood have round nuclei, however, but these cells commonly form aggregates that can be considered to possess a simple morphology.>

A morphology code for the single-cell level in cells with nuclei

<08-20-22: I further propose a third genetic code: a code for single-cell morphology, and cell morphology can be very elaborate, especially in neurons. This will probably involve storing information about cytoskeleton morphology in DNA. Neurons express especially many long noncoding RNAs, so I suggest that these transcripts can carry morphological information about cytoskeletal elements. This information could be read out by using the lncRNA as a template on which to assemble the cytoskeletal element, then removing the template by enzymic hydrolysis or by some spirane-like enzyme. Greater efficiencies could be achieved by introducing some analog of transfer RNAs. LncRNAs are already implicated in transcriptional regulation, and this might be done indirectly by an action on the protein scaffolding of the chromatin. Moreover, as you would predict from this theory, lncRNAs are abundant in cytoplasm as well as in the nucleus, and the cytoplasm contains the most conspicuous cytoskeletal structures. The template idea is similar to but goes beyond the already-established idea that lncRNAs act as scaffolds for ribonucleoprotein complexes. Since cytoskeletal elements are made from monomers of few kinds, we would expect the template to be highly repetitious, and lncRNAs are decidedly repetitious. Indeed, transposons and tandem repeats are thought to drive lncRNA evolution. See https://doi.org/10.1038/s41598-018-23334-1, in Results, subsection: "Repetitive sequences in lncRNAs," p. 4 in the PDF.>

An uncertainty principle for molecular biology?

09-02-2022: These ideas call into question the assumption that all biological order stems from primary amino acid sequences and that a glorified bacterial genome, if artfully regulated, can produce a human. Is there a fundamental limit on how high an amino acid residue can extend its influence in the structural hierarchy of biology? Even something as big as a ribosome appears to need help from ribosomal RNAs to keep its act together. However, perhaps the issue is coding parsimony.

Two more biological questions:

1. Does a cell in a multicellular organism run a metabolic simulation of the whole organism to help it carry out its specialized role more efficiently? Are these little guys thinking of us?

2. Is immune cycling the answer to preventing cancer? Let’s say you deliberately take a drug to suppress your immune vigilance for one month out of each year, then discontinue the drug to let it rebound. During suppression, the micro cancers run wild for a short time, thereby growing large enough for the immune function to easily detect them upon its return. They get whacked, of course, and the immune system learns something in the process, making it a more effective anti cancer system going forward. The analogy here would be a cat playing with a mouse it has caught. Since it is play, it is a learning activity; the cat is working on its game. Pre-civilization, human immune suppression would have happened regularly due to prolonged  environmental stressors, leading to cannier immune systems and lower cancer rates than we now experience.

This agrees with the impression I have that cancer is a disease of modern lifestyles. The following article may or may not be relevant: Coventry, B.J., Ashdown, M.L., Quinn, M.A. et al. CRP identifies homeostatic immune oscillations in cancer patients: a potential treatment targeting tool?. J Transl Med 7, 102 (2009).  https://doi.org/10.1186/1479-5876-7-102