Thursday, April 25, 2013

The Microbiome Blurs the Lines Between Genes and Environment

On the lecture circuit this past couple of months, Ive given talks about the hologenome (link to video post), which is the term being used by 
From Wikicommons
some to refer to the collection of eukaryotic cells and microbial cells that make up the organism. By far, the most common and intriguing question I get is whether the microbiome is a (i) phenotype, (ii) genotype, or the (iii) environment. Quite honestly, its more complicated than you might think at first. Genes involved in immunity select for the presence of certain microbes, making the microbiome almost like a phenotype that is encoded for. Microbes are also genotypes themselves with their genomes providing life-serving functions that our genome does not encode for. Finally, microbes are in and part of the external environment, and the nuclear genome could live with a microbiome much like the organism lives with a certain ph or moisture. This question is a rabbit hole that we can go deep into. To my surprise, Science 2.0 just recently posted this excellent article below on the very issue raised here. It's well worth a read, a nap, and then another read. Then read the comments section as well. What do you think? As always, I welcome your thoughts on how far down the rabbit hole we can go.

Natural Selection And Microbiota
By Gerhard Adam | April 16th 2013 01:00 AM | 7 comments | Print | E-mail | Track Comments
There is no question that Darwin's tremendous insight into the mechanisms by which evolution occurred was one of the singularly most significant events in biology.  Similarly with the discovery of DNA and genetics, the processes by which organisms were formed received a similar boost.  So the purpose of this article is not to argue that Darwin or genetics is wrong.  Instead, the point is to suggest that it is necessarily incomplete.  In the same way that Darwin's work was incomplete because he lacked the necessary information about genetics.  The modern evolutionary synthesis is also incomplete, because it fails to extend the issues of natural selection in an organism's development to their co-evolutionary partners; the microbes.

"Evolution is cleverer than you are" Orgel's rule.

Nowhere does this ring more true than in examining the incompleteness of what we understand about the process of life perpetuating itself.

Naive group selection gave rise to gene-centricism, from which we acquired kin selection and inclusive fitness theories.  Every one of which takes an essentially linear view of natural selection.  Parents pass on their genes to offspring, which are selected for, in turn passing on their traits.  The gene is considered the unit of selection, so that it is characterized, metaphorically, as being "selfish" in its interest of having greater representation in future generations.  Behavioral traits, such as cooperation and altruism, are explained by suggesting that we benefit by assisting other genes to be passed into future generations, as long as we are related in some fashion.  As a result, there is a supposed genetic explanation for every permutation of traits that exists, even those that have zero biological fitness.  Hopefully an alternative view may offer a different perspective on such thinking.

This all presents a nice concise package, except that it isn't the full story and it may not even be fully true.

In the first place, we have to recognize that this entire story presumes a level of biological isolation that simply doesn't exist.  Every organism must cope with the environment that it exists in, while simultaneously serving as an environment for many other creatures.  Each exerts an influence on its environment, as well as the environment exerting influences in return.

There is no isolation.

Therefore, one of the first problems we encounter is the notion that the gene is the unit of selection.  Certainly recent work in epigenetics has demonstrated that there are other influences that can determine whether a gene is expressed or not, so it is clear that the gene cannot singularly be responsible for the traits an organism exhibits, if it can't actually ensure that it is expressed, or how it is expressed. Moreover, the concept of "selfishness" is demonstrably wrong because every instance where such behavior manifests, results in the destruction of the organism (segregator distorter genes, carcinomas, etc.).  Therefore, we should dispense with the notion of the gene being the singular unit of selection, and simply concede that it is a means of selection.  In other words, it simply carries the "message" which may be utilized or ignored as determined by other processes.

This has already largely been recognized, since genetic expression may be influenced by environmental factors, but nevertheless, the persistent view that the genes are the "blueprint"pervades most views of evolution.  There is no question that the gene is the means by which information is replicated and passed between generations.  That isn't in dispute.  However, this is only one stage of a multi-stage operation that will ultimately result in a viable organism that is capable of competing and whose fitness will determine "success" or "failure".

However, we have some new insights to consider and they are quite radical.  In the first place, we are not the "owners" of our bodies.  We are outnumbered in our own bodies, by microbes by a ratio of over 10 to 1.  The genomes represented by these microbes outnumbers our own by 100 to 1.  

In studying germ-free (GF) mice we can now see that genes are insufficient to produce a viable organism.  Of course, there have already been strong hints of that in many other animal species.  After all, what does it mean to produce a termite genetically, if one doesn't account for the symbiotic protozoans necessary to digest its food?  There are many other such relationships, that are conveniently termed symbiotic, but in truth represent absolutely essential traits on which the creature has evolved to depend on.

Therefore, one of the first conditions we must recognize is that we do not evolve alone, nor does natural selection work solely on the products of our genes.  We are dependent on our microbes for survival and selection as they are on us for their environment.

Moreover, these microbes can't just be arbitrarily introduced whenever we choose.  They are specific to individual species and even individuals within a species and must be present/introduced at critical stages of development (1).  This indicates that these microbes aren't merely some external presence that exerts an influence (2).  They are part of the process, as inextricably linked to our development as are the regulatory signals to our own cells.  Even something that is so fundamentally related to fitness, such as pregnancy, requires the involvement of microbes for success.

[NOTE:  It also doesn't appear that there is any particular uniformity of microbes to any individual beyond providing assistance in similar metabolic ways]

Failure to adhere to these developmental requirements, produces difficulty for the organism in question.

Similarly one has to consider the role of these commensal organisms and their influence on an organism's genes, because if an organism can exploit a trait that already exists, then it reduces or even eliminates the selection pressure for such a trait to be manifest in the genome.

As a result, there are traits that exist for which the genome has no "knowledge".

This raises the question of how much of our survival and response to natural selection is due to micro-organisms stepping into the breach to provide a critical service for which our genome was unprepared?  

Whatever else we may think, it is clear that viewing an organism and natural selection, from the pureperspective of genes is incomplete (3).  Therefore it may be more precise to say that genes provide the basic environment, while microbes manipulate and refine to produce a working ecosystem.  As a result, as goes their success, so goes our.  

Of course, it is too simple to begin thinking that these microbes are the "heroes" of our scenario, since it is equally important to note that many of the diseases that humans experience are equally the result of such microbes (4).  No matter how one wishes to view this; "friend or foe", the truth is that we're all in this together.

Additional references:

A study by Chung's co-author Kasper showed that mice that were raised germ-free could have their immune systems "rescued" by certain microbes up to the first several weeks of age.

A lot of the medical conditions the microbiome is being implicated in are puzzling. They seem to run in families, but no one can track down the genes involved. This may be because the effects are subtly spread between many different genes. But it may also be that some—maybe a fair few—of those genes are not to be found in the human genome at all.


(4)  Even traditional ideas about what constitutes pathogens may require some revision.


Steve Davis
"This all presents a nice concise package, (ie, the gene-centric interpretation of evolution) except that it isn't the full story and it may not even be fully true."
Gerhard, you are far too kind and gentlemanly! :)
I think the realistic version of the contribution of gene-centrism to evolution is that it is of no value at all.
After all, what can it predict?
One thing only, that the genes of fitter organisms will tend to spread in a population.
And that was put first by Fisher, who did not link it directly to evolution, but to natural selection.
Those two concepts are not the same despite the misunderstanding of gene-centrics.
And the prediction is essentially a truism - it is not an explantion of evolution.
Interestingly, Fisher was smart enough to not throw selfishness into his account - he was a numbers man.
Apart from that, a great article! :)

Gerhard Adam
Thanks ... I'm glad you finally got to make a comment :)

John Hasenkam
If I ever hear another libertarian tell me the "common good" is purely a human moral construct they can go dip their eye in hot cocky's cack ...

Genetic Circuit Allows Both Individual Freedom, Collective Good

Steve Davis
John, that's an interesting article.It brings to mind the view of the greatly under-appreciated Robert Ardrey, that the fittest groups are those that cater for both individual diversity and the stability that comes from social conformity.
Gerhard, you've raised subjects here that are covered in detail in Tom Wakeford's Liaisons of Life, a great read.

Gerhard Adam
Sounds like a good book.

What I find fascinating is examining natural selection's "blind spots".  In other words, if a particular function is provided by a microbe, then there is no selection pressure on the genome and consequently the entire organism is being selected for a trait that it can't even provide by itself [i.e. the microbe does it].

This raises all kinds of interesting questions about how often this type of thing might occur and how deep some of these ramifications may run.

Steve Davis
 "...if a particular function is provided by a microbe, then there is no selection pressure on the genome and consequently the entire organism is being selected for a trait that it can't even provide by itself."
 Ah, but Gerhard, that was explained by RD in The Extended Phenotype - the function is carried out by the microbe on instructions from the host genes!! Were you not paying attention? :)
The power of delusion is great.

Gerhard Adam
Ahh, but that's the interesting part, because it really appears to be the other way around.

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