“The hypothesis that evolvability – the capacity to evolve by natural selection – is itself the object of natural selection is highly intriguing but remains controversial due in large part to a paucity of direct experimental evidence“ (Graves et al., 2013, p. e 1003766).
As Graves et al. states, the concept of Evolvability is controversial. The authors go on to say that there are two primary reasons for the debate: 1) evolvability, as the term has traditionally been used, addresses evolution at the population level and therefore must be subject to the comparatively weak forces that drive natural selection at that level; and 2) the concept of evolvability, it has been argued, would require foresight by natural selection, which most biological scientists disregard (myself included).
At the level of the gene, however, these arguments may lose ground. Not being a population geneticist, I won’t pretend to know what I’m talking about in regards to point #1, so I won’t even try. However, the idea that the selection for evolvability necessitates some sort of cognizant foresight appears to me to be sophistry, a reasoning which sounds convincing but is actually false.
Artwork by Ericailcane.
From my studies in genomics across different types of genes and different species, I suspect that evolvability can be selected for because 1) it provides an immediate neutral or positive advantage to a given gene; and 2) the sequences which often underlie dynamic evolvability, e.g., repetitive DNA such as transposons, segmental duplications, and other smaller copy numbers, have the potential to promote even further mutability in those same genes over time. In short, repeat sequences tend to breed even more repeat sequences. And some classes of genes appear to be able to take advantage of and work with this large repetitive content, which is most often housed within the intronic regions. However, some genes cannot maintain their necessary functions with large repetitive content, such as the housekeeping genes, and therefore have evolved to keep the numbers at a tight minimum.
My guess is that through most of evolutionary history, new repetitive content which was not immediately detrimental was instead initially neutral. Insertions, expansions, deletions, or inversions which provided some sort of positive adaptation may have arisen more slowly and were not immediately realized. Take for instance Alu element insertions which, when they do insert into an exon and become part of one of the gene’s untranslated regions (UTR), usually the element requires further mutation over the millenia to eventually become part of the protein-coding sequence, if, that is, it ever does (unpublished data). Many repetitive elements may also be exapted to serve as regulatory sequences, even if it is to prevent their own transcription.
That repetitive content, however, adds a certain level of instability to a gene and makes further expansions, deletions, inversions, or insertions even more likely, perpetuating a snowball cycle. For example, it is known that common fragile sites, the most unstable regions in the DNA, frequently house very large genes . These large genes, in turn, very often house extremely large transposable element content. Somehow, these genes still manage to function with such large intronic content, although I don’t believe it is currently understood how that occurs. Nevertheless, these genes seem to have adapted well enough.
I suspect, and am in a long process of investigating, that certain gene groups’ propensity towards mutation has been selected for, especially amongst genes which are closely related (I guess that’s a no-brainer), but also possibly amongst genes which share similar functions, such as tumor suppressors. Ultimately, I hypothesize that repetitive content has shaped the expansion and tissue-specification of certain genes, and subsequently the activity of those genes has driven further repetitive expansions. I guess time will tell whether that’s true or not. More to come later!
I’m a newbie when it come to gene evolution and natural selection but there are two principle that I stand on, namely that the genome of all the individuals on the planet are highly conserved with about 1.5% of the genes undergoing genetic rearrangement (planetwide population) and that most case of autism evolved from such rearrangement which is why we don’t see any causative gene of autism outside x-fragile. Am I correct with these findings? (and yes, I know about VPA induced autism and ultrasound induced autism).
Hi, Alain. Thanks for your questions. Genes across species are definitely highly conserved, not only in the homologues humans and other organisms share, but also in the specific amino acid sequences those genes are used to produce. So, yes, when it comes to the protein products, comparatively little has changed over hundreds of millions of years.
On the other hand, the DNA itself can be highly variable, with intergenic (between genes) and intronic (untranslated sequences) regions houses considerably greater variability. I don’t honestly have percentage figures off the top of my head, since most cross-species comparisons have focused on gene sequences rather than the larger DNA itself. I would suspect that there’s considerably greater variability in the latter across species, which probably leads to some of the greatest differences between species because intronic and intergenic regions often house regulatory sequences that can alter tissue specificity (brain vs. liver) and differences in transcript (RNA) splicing. (Most genes, though they have a single sequence, can produce different spliced versions of RNA transcripts based on their epigenetic binding partners.)
As for autism, I think you might be referring to the copy number variations (CNV) that have been found in some people with the condition. CNVs have definitely been found in autism to a significant extent, but they still only account for a minority of cases. In fact, at present state, it appears that genetically-derived forms of autism are in the minority and the etiology of the remainder of the autistic population probably involves epigenetic factors, i.e., the molecules that bind to DNA and basically tell it what to do.
The thing about genetic causes of autism is that they are extremely varied, which is why it’s been slow-going in research so far. It’s hard to find the common threads, even with all our big computers pumping out Big Data. So that’s probably been the biggest road block to finding simple causes to a complex condition. Not only is it probably complex for a single individual, but it’s REALLY complex across a heterogeneous population. I suspect there are commonalities, however, and I’m currently working on that line of research, as of course are others.
As for different genes associated with autistic conditions, there are actually over 100 acknowledged sydromic forms of autism, including Fragile X. But there are definitely many many others. However, they still would only account for a minority of cases of the larger population of autistics.
By the way, even though I’m a HUGE proponent for the safer use of ultrasound, I just want to clarify that, while it’s hypothesized that its use might be playing a role in the etiology of some cases of autism, that hasn’t yet been fully supported. So that’s still a work in progress. VPA + autism has more support.
Thanks for asking. 🙂
‘Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. the average de novo mutation rate is 1.20 × 10(-8) per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child’.
Kong et al 2012
Very interesting. Have anything on recombination rates?
A very few articles on recombination rates or recombination in de novo sperm mutation rates have been published. Here’s two that might interest you. They are full text and a tough read for a non-expert like me. What are your thoughts?
Thanks for the references, Robert. They look good. I’ll have to give them a read and give feedback.
I took time to let that paragraph sink in:
As for different genes associated with autistic conditions, there are actually over 100 acknowledged syndromic forms of autism, including Fragile X. But there are definitely many many others. However, they still would only account for a minority of cases of the larger population of autistics.
let’s start first with this:
As for different genes associated with autistic conditions, there are actually over 100 acknowledged sydromic forms of autism, including Fragile X.
Do you have some reference to that statement? A textbook or a review?
However, they still would only account for a minority of cases of the larger population of autistics.
Regarding genetic cause of autism, why genetics is still a minority?
I’m aware of the antibodies studies of the mothers which account for 20% of the cases (from the brain & mind institute in California). Wouldn’t that account for a genetic cause?
Not to toot my own horn, but ‘Toot’. I have a paper on the orgins of de novo gene mutations in genetic syndromes associated with high autism risk:
Click to access 1378464956.pdf
Nice toot. 🙂 Have downloaded and will be reading, Robert. Thanks!
Downloaded it and will read it in a moment.
Hi, Alain. Regarding your first question, here’s an excellent article that does a good job summarizing the genetic syndromes associated with autism and was the one I was particularly thinking of:
If you can’t get access to the full article (it doesn’t appear to be Open Access) and want to read it, just email me (my contact info is listed in the left-hand sidebar above) and I can send you a PDF.
As for your second question, genetically-associated forms of autism fall into two general categories, which are strictly nominal mind you and don’t necessarily reflect what’s actually going on biologically but are at least the way we tend to use them. On the one hand, there are forms of autism which we would probably consider more stereotypical but which are associated with acknowledged risk genes, such as Neurexin1 (NRXN1). Mind you, those individuals with a NRXN1 mutation and autism are still a small minority of the larger autistic population. Then on the other hand there are other conditions that have a known genetic mutation and are fully syndromic, in that they usually have physical deformation of some sort, perhaps specific facial features, alterations to the hands/feet, etc., but also often have co-occurring autism. Fragile X is a good example of this. Usually the conditions in this latter category tend to be much better understood as to how the mutation ultimately caused all these features. This is primarily due to the fact that many of these mutations directly affect the coding sequence of a gene and may ultimately change the gene product into something poorly functional or even knock it out altogether. In many cases such as with NRXN1, mutations are often in what are more likely gene regulatory sequences, not coding sequences, so they probably don’t suppress a gene product altogether but may have subtler effects, such as altering which transcripts of a gene (a single gene usually can code for multiple RNA products depending on how it’s spliced back together) are produced.
This is a long way of saying that the studies you linked that talked about antibody production in mothers of autistics are “genetic” in the sense that they certainly reflect genetic changes in the immune cells producing the antibodies (immune cells use mutation constantly to make new unique antibodies to increase the likelihood of identifying a dangerous antigen– this is a form of genetic recombination called V(D)J recombination and is used every day by the adaptive immune system). But they are not necessarily reflective of genetic changes to the basic genome that all cells have, the one that is inherited.
So when someone talks about a “genetic” form of autism, it means that either 1) there is a specific mutation that all the cells in that person’s body likely share, or 2) that all or most of the cells in a specific organ share, e.g., the brain. Usually, we’re referring (or assuming) #1. In the case of variations in antibody production in mothers, it could be associated with a genetic mutation, but that would need to be tested. More than likely, however, it’s probably reflective of environmentally-induced changes to hormones/immune system that shift immune regulation towards increased antibody production, which subsequently increases the likelihood of the immune system producing autoimmune-related antibodies which target self rather than non-self; it’s really a process of probability: the more antibodies you produce, the more you increase the likelihood that you’ll create an antibody that attacks your own tissues. Obviously, that could be a real problem for a developing baby if those antibodies are able to cross the placental barrier.