MaxPD wrote:About the Prions (@Kytescall & @PsYcHoTiC_MaDmAn) ; The part about prions in the article was based mainly upon Lindquist et al. research on the inheritability of prions in yeast. It has been noted that Yeast and other kinds of fungi also have the "Prion proteins" which are those proteins which are affected by the prions. Prions are epigenetic factors as they manage to change the phenotype through the misfolding of the proteins, without changing the genetic code. Lindquist et al. argue that these misfoldings could be considered kind of like mutations that do not involve the genetic code, and that some misfoldings could actually be beneficial in some case (Just like mutations). The offspring would then have the proteins folded differently as well, and thus this would be passed on from mother to offspring. The whole prion deal is still not well understood; there is no general consensus about how the prion gets the prion proteins to misfold like them, and I believe there is still some controversy about Lindquist et al.'s interpretation.

[1] A new, recent term has also started to creep into usage, this being the term "Epiproteomics" which deals with protein structure and function through Posttranslational modifications and folding.

[2] While there may be no consensus about what drives protein conversion to prions in the presence of other prions, to the best of my knowledge there is evidence in the literature attesting to the possibility of RNA playing a role in said converstion.

Much evidence supports the hypothesis that the infectious agents of prion diseases are devoid of nucleic acid, and instead are composed of a specific infectious protein1. This protein, PrPSc, seems to be generated by template-induced conformational change of a normally expressed glycoprotein, PrPC (ref. 2). Although numerous studies have established the conversion of PrPC to PrPSc as the central pathogenic event of prion disease, it is unknown whether cellular factors other than PrPC might be required to stimulate efficient PrPSc production. We investigated the biochemical amplification of protease-resistant PrPSc-like protein (PrPres) using a modified version3 of the protein-misfolding cyclic amplification method4. Here we report that stoichiometric transformation of PrPC to PrPres in vitro requires specific RNA molecules. Notably, whereas mammalian RNA preparations stimulate in vitro amplification of PrPres, RNA preparations from invertebrate species do not. Our findings suggest that host-encoded stimulatory RNA molecules may have a role in the pathogenesis of prion disease. They also provide a practical approach to improve the sensitivity of diagnostic techniques based on PrPres amplification.

Full paper here http://www.blc.arizona.edu/courses/MCB4 ... Prions.pdf

Prion proteins that trigger a cascade of protein misfolding in the brain are suspected of being the sole transmissible cause of some brain-destroying diseases. But nucleic acids could be their partner in crime.

The seductive notion that a modified host protein might be the sole infectious agent of transmissible spongiform encephalopathies (TSEs) has tantalized the scientific world since the idea was suggested more than 30 years ago1. The ensuing 'prion hypothesis' was developed following the discovery that a host-cell protein called prion protein (PrPC) can exist in TSEs in an abnormal form (PrPSc).

Full paper here at http://www.biosino.org/tech/425673ar.pdf

As concepts evolve in mammalian and yeast prion biology, rather preliminary research investigating the interplay between prion and RNA processes are gaining momentum. The yeast prion [PSI+] represents an aggregated state of the translation termination factor Sup35 resulting in the tendency of ribosomes to readthrough stop codons. This “nonsense suppression” activity is investigated for its possible physiological role to engender on Saccharomyces cerevisiae the ability to respond to stress or variable growth conditions and thereby act as a capacitor to evolve. The interaction between prion and RNA is a two way street—the cell may have adopted RNA processes in translation to govern the presence of prions and the [PSI+] prion's nonsense suppressor phenotype may exhibit different growth phenotypes by its control of translation termination. RNA processes in the mammalian cell also effect and are affected by prions.

http://jb.oxfordjournals.org/content/140/2/167.abstract

In the past decade, the interaction between prions and nucleic acids has garnered significant attention from the scientific community. For many years, the participation of RNA and/or DNA in prion pathology has been largely ruled out by the “protein-only” hypothesis, but this is now being reconsidered. Experimental data now indicate that nucleic acids (particularly RNA), besides being carriers of genetic information, function as important key components during development, physiological responsiveness and cellular signaling. This revelation has brought a new perspective to prion pathology. Here we discuss the role of RNA molecules in prion protein aggregation and the resulting cellular toxicity. We combine our most recent findings with existing literature to shed new light on this exciting field of research.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2634520/

This old paper here at http://www.mad-cow.org/prion_mRNA.html may also be of note, and that entails the in-silico analysis of prion protein mRNA.

Some links:
Prion research @ MIT
Lindquist's publications
Lecture on Prions by Lindquist
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Lamarck thought that the traits which the parents acquired during their lifetime would be passed onto their offspring. That is, someone who trained his running a lot would have better runners as children, who could then train more their running and have offspring which were even better. So, what the parents do is passed onto their offspring.

As has already been pointed out, the constraint that epigenetics has in terms of the extant genome and a limited range of what it can do both clearly illustrate why Epigenetics is NOT Lamarckism.

Epigenetics looks at all of the changes that affect the phenotype without touching the genotype. This includes the prions, like stated above, which affect the phenotype by changing the way the proteins are folded but do not touch the genotype at all. However, the most studied area of epigenetics is the expression of genes. Genes are activated and silenced during the development of the organism, and extrinsic factors play a role in how the genes are activated and silenced. The effects that the environment can have on the expression might be due to adaptation like Daphnia sp.'s morpholical plasticity and other organisms, or they may just be a by-product. (For example, it is known that frog eggs in higher temperature will usually hatch with a lower body mass, and I believe this is due to a biophysical/chemical constraint rather than due to adaptation. I'm not sure though).

Knowing the mechanisms underlying each of the processes you mentioned will require in depth investigation of the transition from gene to phene.

For example, if Daphnia are exposed to their predator the midge larva during their development, the gene expression will change, and their morphology will be different. Their heads and tails will elongate, make it harder for the predator to ingest them. However; the Daphnia that are in this elongated state have less offspring. This is know as antagonistic pleiotropy - The activation of the gene which will increase fitness in one way (Reducing risk of death due to predation) but will reduce fitness in another way (reduced offspring).* Thus, the Daphnia have evolved this epigenetic mechanism - If there if the Daphnia senses the molecules of the predator in the water, its development will go in the pointy direction, reducing the risk of death.. If not, then the Daphnia's morphology will remain neutral and it will have more offspring. This is called "norm of reaction". That is, environmental cues affect the development of certain phenotypes.

This is an interesting example and is an illustration of just one of the many ways by which phenotypic plasticity may occur or be regulated.

This lecture from Yale talks about different reaction norms. The whole course is very interesting.



*If someone could tell me if I am correct in this, I would appreciate it. I know that antagonistic pleiotropy is when one gene affects more than one traits in the phenotype; some of them being helpful and the other being detrimental. However, I am not sure if this specific case would be considered a.p. because the reduced offspring is not necessarily coded by the gene but is rather a by-product of the use of energy or maybe space constraints. (Although, it is a direct effect of the gene in the sense that its activation is the cause).

The expression patterns that are triggered by the environmental cues would appear to me to be antagonistically pleiotropic.

I'm all for giving Lamarck a little more credit than he currently receives for coming up with an internally consistent theory for evolution where no one had before, but what this article is suggesting seems crazy to me.

First of all, this might just be me (I'm only a student), but I've never heard an example of a prion having an adaptive function. I would like to see the yeast studies he says he's getting this from. More importantly, though, how could natural selection ever favor hanging on to an old program (like webbing between the toes) in case it comes up in the evolutionary future? If there was no selection pressure for webbing in the intervening time, then the prion would be allowed to become riddled with errors and probably not just be able to turn the toe webbing program back on. I know it was just a hypothetical example, but what's so hard to believe about a change in the development program so that the skin between the digits wasn't sloughed leading to webbed toes?

What exactly do you mean by prions having an "adaptive" function, Holly?

I was taught that they are simply viral proteins that misfold and induce other proteins to misfold. I did a little reading on them, since you asked, and it looks our knowledge of prions has really increased since I first learned of them!

I meant "adaptive" in the way the article was suggesting-- triggering different developmental programs and what not. But I honestly didn't know when I posted that that they had any place in a healthy organism.

Well, it so happens that when prions were originally discovered they were thought to be proteins that could replicate themselves, the fact that they replicate by affecting the folding of normal proteins means that they could potentially affect the function of those proteins, and if such proteins are involved in morphological phenotypes I think it wouldn't be surprising to see that they could have a phenotypic effect.

And viral proteins? Could you please clarify in what sense you mean 'viral'?

jodiebug wrote:
More importantly, though, how could natural selection ever favor hanging on to an old program (like webbing between the toes) in case it comes up in the evolutionary future?

1) Developmental programs are a function of gene interactions.
2) If a said interaction is not deleterious it can be preserved, especially if the involved genes are conserved due to selection for other functions.

GenesForLife wrote:

jodiebug wrote:
More importantly, though, how could natural selection ever favor hanging on to an old program (like webbing between the toes) in case it comes up in the evolutionary future?

1) Developmental programs are a function of gene interactions.
2) If a said interaction is not deleterious it can be preserved, especially if the involved genes are conserved due to selection for other functions.

Yes, that is true, but as Gerd B. Muller and others have noted, there are various ways [such as the non-programmed physical properties of involved tissues-eg bone density is dependent on gravity] and the dynamics of developmental interactions [such as in epigenetics] can cause the innovation that is then subjected to selection. This does not contradict Neo-Darwinism, but rather supplements it.

In this scenario, convergent evolution can be better explained without resorting to teleological causation. In other words, epigenetic interaction of the developing embryo with it's environment comes first, and genetic programing follows. This does not overthrow NS, but rather gives one more powerful driver to evolution, especially as it is directional like NS , whereas genetic drift and migrations are not. [Sexual selection is directional, but it cuts both ways, as both an increaser and decreaser of organismal fitness, eg sexual conflict].

Historical contingency constrains, to some extent, the ability of the organism to explore morphospace. We know this because some innovations have occurred in some tax, but not others. [Evolvability]. But it is this emergent property of gene regulatory networks to respond first to environmental cues [epigenetics] and then encode them as fixed, rather than variable traits that ties development to evolution. Thus emergence becomes inherentcy as the organism "matures" in an evolutionary sense.
One of the problems is that we are seeing evolution, and life in it's extant form. In other words, despite the fact that 99% of all known species are extinct, evolution is getting pretty good at survival. But this may not have been true in the deep past, at the very origins of life, because of the boot-strapping involved to get to a certain viable level of fitness. In those days, sheer massive replication was the only way to "make a living". So there must have been a huge disparity in the fitness of the new genes. Hopeful monsters abounded, but few survived. In other words, K-selectionist type innovations were yet to be invented.
Today genomes are flooded [despite the large chunk of "junk genes" ] with genes of equal or almost equal fitness, as well as some detrimental ones. Natural selection can do fuck all with the Reccurrent Pharageal Nerve.
However, in other ways, evolution has learnt how to "look ahead". Senses built by genes provide real time data that genes cannot know, and ganglia and brains give an environmental modeling capacity that the genes themselves have never had. [And never will have].
"Hopeful Monsters" [HM] may not be as common now as in the deep past, but I think they still contribute to evolution as much as more small-step wise improvements, where each small change has to benefit fitness. The vast majority of "modern" HM's are of course, of very low fitness or even fatal. This does not change the fact that epigentic change and developmental processes cannot contribute to evolution. The is now some genetic basis for modular and saltational change in the organism. Gould predicted this way back in 1977. [Amoung some others].
Population genetics is not violated by considering what happens to the individual, and especially the developing individual. A vast raft of epigenetic interrelationships probably await discovery, and endocrinal and hormonal inputs into genetic regulatory networks and the innovation of pathways to produce new morphologies in answer to environmental challenges may provide new insights into how evolution works. Heterochony- "mere" changes in developmental timings in response to ecological or environmental pressures have been demonstrated in many taxa, including [of course] human beings.

Lamarckism, or at least something very similar to Lamarckism happens in bacteria. There is horizontal gene transfer in bacteria. A bacterium can gain a genes through conjugation and subsequently pass on the recently acquired gene to other bacteria. If that's not inheriting an acquired characteristic, I don't know what is.

Primate wrote:Lamarckism, or at least something very similar to Lamarckism happens in bacteria. There is horizontal gene transfer in bacteria. A bacterium can gain a genes through conjugation and subsequently pass on the recently acquired gene to other bacteria. If that's not inheriting an acquired characteristic, I don't know what is.

The difference here though would be that the causal basis of phenotypes is acquired, i.e, genes, Lamarckism entails the inheritance of acquired phenes directly, if one were to look at the classical Lamarckian explanation for giraffes with long necks, for instance, one could potentially see that the explanation there was that stretching changed the nature of offspring, with no consideration of the genetic basis involved.

Even with HGT you need to have mutations, the only difference here is that the mutant sequences that confer extra phenotypes are external in origin, this makes HGT Neodarwinian by nature, and not Lamarckian.

Federico wrote:This is what I wrote a while ago in the now defunct Richard Dawkins (RD) Forum for the thread Lamarkian Evolution:

"....The way I understand it -- but I won't bet my bippy on it -- the whole RD theory of the selfish gene is based upon the classical Darwinian evolutionary process where genes are mutated in a time frame of thousand of years and according to a scheme which would be advantageous to the individual thus to the gene itself.
The recent discovery of new mechanisms of evolution where not the gene itself is mutated but the genomic apparatus controlling gene's expression is modified by the environment within a much shorter time frame, has given new credence to Lamarkism and the possible transmission within a generation of newly acquired adaptive characteristics."

An article recently published in The NewScientist entitled "Epigenetic clue to schizophrenia and bipolar disorder " provides new evidence for an epigenetic mode of transmission of Schizophrenia and of Bipolar disorder.

"......TWIN studies have shown that people with schizophrenia and bipolar disorder have changes in gene activity caused by their environment. The finding provides the strongest evidence yet that such gene changes might cause the conditions.
Jonathan Mill at the Institute of Psychiatry, King's College London, and colleagues scanned the genome of 22 pairs of identical twins - chosen because one twin in each pair was diagnosed with schizophrenia or bipolar disorder.

"As expected, the twins had identical DNA. However, they showed significant differences in chemical "epigenetic" markings - changes that do not alter the sequence of DNA but leave chemical marks on genes that dictate how active they are. These changes were on genes that have been linked with bipolar disorder and schizophrenia.
Mill's team scanned for differences in the attachment of chemical methyl groups at 27,000 sites in the genome. Methylation normally switches genes off, and de-methylation turns them on."

"....the most significant differences, with variations of up to 20 per cent in the amount of methylation, were in the promoter "switch" for a gene called ST6GALNAC1, which has been linked with schizophrenia. The twin scans also revealed methylation differences in GPR24, a gene previously linked to bipolar disorder."

"...... [with additional, time-linked studies] [i]It might be possible then to link the alterations to environmental changes such as stressful events or diet, which have been shown to cause inheritable epigenetic changes in mice".

"I feel this is the best evidence yet, from human studies, supporting the hypothesis that epigenetic mechanisms may drive psychiatric disorders," says David Sweatt, who studies epigenetics at the University of Alabama and was not involved in the study.

I find these data fascinating, and in some way confirmatory of what I have been writing for a while, namely that mental disorders might be caused by environment- altered genes' functions similarly to some body illnesses.
It would be interesting but difficult to realize is a study of the heritability of such pathogenetic mechanism.