Thursday, April 10, 2014

On the Origin of the Genes of Viruses - 7

Atoms & molecules don't age?
In previous posts of this series abiotic evolution was highlighted because the concept seems to not be talked about.

Microbiologists and biologists tend to begin with "our planet was formed some 4.56 billion years ago."

I don't like leaving out the previous billions of years of abiotic evolution, so on relevant Dredd Blog posts I mention that just-as-important epoch because the evolution of non-living things is actually the bigger picture  (On the Origin of the Genes of Viruses - 5, On the Origin of the Genes of Viruses - 6).

That molecular machines have evolved for a much longer period of time than biological organisms have is not merely the imagining of a science fiction novel, rather, it is the result of the observation of the machinations of, among many other examples, the modern RNA/DNA associated molecular machines known as the ribosome and the ribozyme.

The macro molecular machine factories which are older than the Earth are still with us and are doing just fine thank you.

We are discussing the observations that have been written down in scientific papers about non-living molecular machines which are utilized by today's viruses:
Virus infection involves coordination of a series of molecular machines, including entry machines, replication machines, assembly machines, and genome packaging machines, leading to the production of infectious virions.
Although viruses had been considered as merely dull, static containers, and protectors of genomes, this false concept was replaced by the realization that viruses are beautiful intricate machines, essential to biological evolution, capable of invading cells, stealthily avoiding the protective barriers of the host, usurping the host's synthetic machinery for their own survival and able to self assemble into complex molecular machines. Indeed it has become apparent that the capabilities of viral machines far exceed those to the simple enzymes first studied in the mid-twentieth century. This book is a partial description of some of the amazing things accomplished by viruses in infecting a host and replicating themselves.
(Viral Molecular Machines). The full understanding of viruses involves not only the molecules that the viral molecular machines are constructed from, but it also involves understanding of the atoms which the molecules are constructed of:
One of the principal goals in biology is to be able to fully understand the mechanisms of an organism in atomic detail. Viruses offer the best opportunities to achieve this goal. Written by leaders in the respective fields, this book examines a variety of viral molecular machines ...
(The Uncertain Gene - 10, quoting from "Viral Molecular Machines", ibid). Atoms, molecules, and molecular machines made from them are not alive, they are abiotic.

We could look for non-living fossils that had to be self-replicating until they began to rely on the dynamics of biotic (living) entities, cells, but that "going looking" has fooled even the experts at times:
Twenty years ago the palaeontological community gasped as geoscientists revealed evidence for the oldest bacterial fossils on the planet. Now, a report in Nature Geoscience shows that the filament structures that were so important in the fossil descriptions are not remnants of ancient life, but instead composed of inorganic material.
(Journal Nature, "Filamentous figments in the Apex Cherts"). But they were not looking for what I am looking for, i.e., early "fossils" of abiotic evolution.

They were looking for the earliest fossils of biotic evolution (we must careful not to "find" what we are looking for before we find it, eh?).

Anyway, so far a micro sized ribozyme in a non-living virus has not yet been detected here on Earth:
Although RNA seems well suited to form the basis for a self-replicating set of biochemical catalysts, it is unlikely that RNA was the first kind of molecule to do so. From a purely chemical standpoint, it is difficult to imagine how long RNA molecules could be formed initially by purely nonenzymatic means. For one thing, the precursors of RNA, the ribonucleotides, are difficult to form nonenzymatically. Moreover, the formation of RNA requires that a long series of 3′ to 5′ phosphodiester linkages form in the face of a set of competing reactions, including hydrolysis, 2′ to 5′ linkages, 5′ to 5′ linkages, and so on. Given these problems, it has been suggested that the first molecules to possess both catalytic activity and information storage capabilities may have been polymers that resemble RNA but are chemically simpler (Figure 6-93). We do not have any remnants of these compounds in present-day cells, nor do such compounds leave fossil records. Nonetheless, the relative simplicity of these “RNA-like polymers” make them better candidates than RNA itself for the first biopolymers on Earth that had both information storage capacity and catalytic activity.
(The RNA World and the Origins of Life). Perhaps it is time to focus now, here on Earth, on finding a fossilized pre-life micro-sized ribosome or ribozyme.

The search for the mystical Earth based non-cellular ribosome and/or ribozyme will have to be limited to very carefully examining old rocks, gems, and the like.

Overcoming the complexity involved when imagining an RNA ribosome and ribozyme that can replicate, and which existed before cells evolved, is daunting.

Especially when considering how it must work:
Prominent current ideas on how life emerged on Earth include an RNA world hypothesis in which RNA performed informational as well as catalytic functions
Hammerhead ribozyme HH9
in the absence of both DNA and protein. Demonstration of a self-replicative system based on ribonucleic acid polymers as both information carriers and catalysts would lend support to such a scenario. A pivotal component of this system would be an RNA dependent RNA polymerase ribozyme capable of replicating its own RNA gene. Recent work from the Holliger group at the Laboratory for Molecular Biology in Cambridge has provided synthetic ribozymes that just might foreshadow the future engineering of such self-replicative systems.
Perhaps the closest parallel to the described ribozymes is found among RNA vira that express RNA dependent RNA polymerases, some of which utilize a primer.

A truly self-replicating RNA polymerase ribozyme based system would require that the ribozyme fully replicate its own RNA gene (unlike present day DNA dependent RNA polymerases that do not transcribe the promoter region), including any ssC19 type docking sites on the template. The encoding RNA gene would have to be relatively unstructured to allow efficient primer extension of the entire sequence, and there would need to be a mechanism for strand separation to enable replicative turnover. Even if these requirements can be met, the present ribozymes capable of maximally synthesizing a 95 nt RNA transcript would still fall short of copying their own gene of 187 nt thus precluding their immediate use for self-sustained replication.
(A ribozyme transcribed by a ribozyme, PDF version). The Hammerhead Ribozyme (HHR) has been found in a surprising number of genomes.

That includes genomes of the virus realm (e.g. The ubiquitous hammerhead ribozyme), and in point of fact it was first found in the viral / sub-viral realm:
The first hammerheads were discovered in viroids and plant satellite RNA viruses where they process RNA transcripts containing multimeric genomes to yield individual genomic RNAs. Representatives of this ribozyme class have been studied extensively for the past 25 years because their small size and fundamental catalytic activity make them excellent models for RNA structure-function research.
(Identification of Hammerhead Ribozymes). The Hammerhead ribozyme HH9, shown in the graphic just above, is RNA based, and is composed of Cytocene, Guanine, Adenine, and Uracil (C,G,A,U).

Similar candidates for pre-cellular virus ribosomes or ribozymes might be found in non-living ancient virus-like entities that were the forerunners of some of these:

"Defective interfering (DI) RNAs are subviral RNAs produced during multiplication of RNA viruses by the error-prone viral replicase. DI-RNAs are parasitic RNAs that are derived from and associated with the parent virus, taking advantage of viral-coded protein factors for their multiplication. Recent advances in the field of DI RNA biology has led to a greater understanding about generation and evolution of DI-RNAs as well as the mechanism of symptom attenuation. Moreover, DI-RNAs are versatile tools in the hands of virologists and are used as less complex surrogate templates to understand the biology of their helper viruses. The ease of their genetic manipulation has resulted in rapid discoveries on cis-acting RNA replication elements required for replication and recombination. DI-RNAs have been further exploited to discover host factors that modulate Tomato bushy stunt virus replication, as well as viral RNA recombination. This review discusses the current models on generation and evolution of DI-RNAs, the roles of viral and host factors in DI-RNA replication, and the mechanisms of disease attenuation." (Defective Interfering RNAs)
satellite virus / helper virus

"Plant viruses often contain parasites of their own, referred to as satellites. Satellite RNAs are dependent on their associated (helper) virus for both replication and encapsidation. Satellite RNAs vary from 194 to approximately 1,500 nucleotides (nt). The larger satellites (900 to 1,500 nt) contain open reading frames and express proteins in vitro and in vivo, whereas the smaller satellites (194 to 700 nt) do not appear to produce functional proteins. The smaller satellites contain a high degree of secondary structure involving 49 to 73% of their sequences, with the circular satellites containing more base pairing than the linear satellites. Many of the smaller satellites produce multimeric forms during replication. There are various models to account for their formation and role in satellite replication. Some of these smaller satellites encode ribozymes and are able to undergo autocatalytic cleavage. The enzymology of satellite replication is poorly understood, as is the replication of their helper viruses. In many cases the coreplication of satellites suppresses the replication of the helper virus genome. This is usually paralleled by a reduction in the disease induced by the helper virus; however, there are notable exceptions in which the satellite exacerbates the pathogenicity of the helper virus, albeit on only a limited number of hosts. The ameliorative satellites are being assessed as biocontrol agents of virus-induced disease. In greenhouse studies, satellites have been known to "spontaneously" appear in virus cultures. The possible origin of satellites will be briefly considered." (Satellite RNAs of plant viruses)

"Viroids are unique infectious agents that are restricted to the plant kingdom, and are composed solely of a non-protein-encoding, small (246–401 nucleotide (nt)), single-stranded circular RNA that is able to replicate autonomously in susceptible hosts ... Viroids have similarities with two other classes of RNA replicon—namely, certain satellite RNAs of plant viruses (Mayo et al, 2005) and the RNA of hepatitis delta virus (HDV; Mason et al, 2005), because their genomes all have a circular structure and they replicate through a rolling-circle mechanism.
- (Viroids: an Ariadne's thread into the RNA labyrinth)

"Prion proteins are the infectious pathogens that cause Mad Cow Disease and Creutzfeldt-Jakob disease. They occur when a normal prion protein becomes deformed and clumped. The naturally occurring prion protein is harmless and can be found in most organisms. In humans, it is found in our brain cell membrane. By contrast, the abnormally deformed prion protein is poisonous for the brain cells. Adriano Aguzzi, Professor of Neuropathology at the University of Zurich and University Hospital Zurich, has spent many years exploring why this deformation is poisonous. Aguzzi's team has now discovered that the prion protein has a kind of "switch" that controls its toxicity." (Flexible tail of the prion protein poisons brain cells)
"Our work supports the hypothesis that a protein can serve as an element of genetic inheritance. This protein–only mechanism of inheritance is propagated in much the same way as hypothesized for the transmission of the protein–only infectious agent in the spongiform encephalopathies; hence these protein factors have been called yeast prions. Our work has focused on [PSI+], a dominant cytoplasmically inherited factor that alters translational fidelity.This change in translation is produced by a self–perpetuating change in the conformation of the translation–termination factor, Sup35. Most recently, we have determined that new elements of genetic inheritance can be created by deliberate genetic engineering, opening prospects for new methods of manipulating heredity. We have also uncovered evidence that other previously unknown elements of protein–based inheritance are encoded in the yeast genome. Finally, we have begun to use yeast as a model system for studying human protein folding diseases, such as Huntington's disease. Proteins responsible for some of these diseases have properties uncannily similar to those that produce protein–based mechanisms of inheritance." -(Investigating protein conformation–based inheritance and disease in yeast).
Although the identity and general properties of prions are now well understood, the mechanism of prion infection and propagation remains mysterious.
One idea, the "Protein X" hypothesis, is that an as-yet unidentified cellular protein (Protein X) enables the conversion of PrPC to PrPSc by bringing a molecule of each of the two together into a complex.
(The Prion Molecule).
While finding molecular machines is quite easy for molecular machinists, even molecular machines with two motors, it is difficult or impossible to determine the age of a molecule or a molecular machine.

This is because they are made of atoms which do not age as living things do.

Perhaps the "fossils" have been right in front of our eyes all along, since they do not die because they are not alive?

The next post in this series is here, the previous post in this series is here.

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