View Full Version : Genetics are complex and dynamic/brain phenotypes


Amtram
04-22-13, 05:15 PM
I wanted to share a couple of things with everyone that I found when catching up with some of my science sites. Mostly because I find them fascinating, and relevant to understanding what underlies neurodiversity, but also because I want to share genetics as they really are.

There seems to be an assumption that genetics are deterministic - that they are considered to be absolute instructions - and that anything that disproves that disproves genetics. However, this is far from the truth, and as I've often said, anyone who believes that genetics is destiny doesn't really understand genetics. It's also incorrect to assume that it's simple enough to change that a single environmental factor can have a dramatic impact on a person's entire genome. The way genetics and epigenetics work from conception to death is so much more elegant and interesting, even when it's hard to understand.

Wiring the Brain (http://www.wiringthebrain.com/2013/03/the-genetics-of-emergent-phenotypes.html) has a new entry that explains the genetics of neurological phenotypes. The author focuses on schizophrenia, epilepsy, autism, and microcephaly, but gives a detailed and professional explanation of what I've tried to explain about how the brain is built by genes - large numbers of genes with specific mutations and in specific combinations, not just a one-to one relationship between gene and lobe - and how the genes that program how the brain works have impact that is just as important as the genes that build the cells themselves. Read it through. You may have to read it more than once, and click through some of the links.

Virginia Hughes' (http://phenomena.nationalgeographic.com/2013/04/05/why-i-keep-harping-on-the-dynamic-genome/#.UWMDTvmptp8.twitter) article is a little less specific to the brain, but very readable - easier to understand the underlying qualities of genetics that are addressed in the previous article. If you have trouble with some of the terminology or ideas in that, read this one first and then go back. There are also a lot of links that explain specific genetic concepts that are also in pretty clear language.

My hope is that some of this might help to illustrate that acknowledging the actual role and impact of genes, how they work, and how environment needs to be looked at in a specific and appropriate manner does not mean that you need to pick one thing or the other. You just need to be accurate and realistic, because there's nothing magical about either.

Tyler Durden
04-22-13, 06:57 PM
Second link I liked, also highlights the polarized opinions that tend to emerge on ADDF.... wow just got serious deja vu... weird.

Would have liked more information on transposons, more explanations as to what determines whether and why would they jump "randomly"?

I liked the quote "DNA and its dances with an ever changing environment", might steal that one for later.

The first link on the other hand...

More in the way of detailed descriptions with very little if anything in the way of explanations, no real answers.

I am all for increasing understanding, and sure it might be interesting to some to describe various brain disorders in detail but I do ask myself, what is the point if you cannot explain why such detrimental conditions occur in humans in the first place, or do anything about it? Surely the main goal is for there to be positive repurcussions? It does seem to end up being ultimately kind of pointless.

Recently saw a video about a child who lost half her brain, given the extent of plasticity in a young child, how much more 'dynamic' environmental influence would there be at earlier stages of brain development...

immabum
04-22-13, 07:20 PM
I think the detailed understanding gives us a better picture of how and why our current medications work and why they may not work as well for others.

The explanation (of env variables) may be of lesser importance seeing as a pretty good 'answer'(medications) has already been found. If there were simple environmental fixes (eg folic acid supplements/spina bifida) I'm sure docs/patients would be a lot more gung ho.

Tyler Durden
04-22-13, 07:24 PM
Medications generally work by accident, not by design... So the information works as it allows you to create explanations that work in retrospect... Result!

I would call the environmental fixes you are speaking of more equivalent to pharmaceutical than environmental solutions. (using an internal/external distinction)

How about prevention?

Amtram
04-22-13, 07:28 PM
There is only one prevention for genetic disorders. Well, two, actually, but neither of them terribly appealing. Somehow, I don't think that too many people in this community would be in favor of eradicating ADHD by preventing people with ADHD from being conceived or born.

And for many of us, life with ADHD, even untreated, is still better than the alternative.

immabum
04-22-13, 07:40 PM
Yup serendipity is common in medicine...eg Proscar for prostates -->someone noticed the guys had more hair. Yay! Another hair loss med.

Yup people tend to want results/fix. The asthmatic wants a bronchodilator. They want to breathe now. The evolutionary how/when/why might mean very little to them. Perhaps they could read more about molecular mimicry and antigenicity or helminth theory and how parasites helped us in the past (interesting topic actually)
Bottom line is...they have the condition and they have a solution that works pretty well. If the easy environmental fix was there -it should have been figured out a long long time ago.

Yup primary prevention would be the ideal solution for most conditions. How are we going to protect ourselves against stress or the environment?

Tyler Durden
04-22-13, 07:42 PM
Prioritize human health over profit...

Amtram
04-22-13, 07:44 PM
There are neurological phenotypes. The features the conditions have in common demonstrate that a phenotype or endophenotype is likely. Both articles explain why, and how this might occur (because it has been demonstrated to occur this way in the cited and other instances). I see few assumptions in the articles, rather, evidence and hypotheses based on evidence, and explanations. Perhaps you could point to specific statements made in the articles that you feel are simply guesswork, and provide sources for your own contradictory evidence?

Amtram
04-22-13, 08:16 PM
From the first article:

Why are some brain disorders so common? Schizophrenia, autism and epilepsy each affect about 1% of the world’s population, over their lifetimes. Why are the specific phenotypes associated with those conditions so frequent? More generally, why do particular phenotypes exist at all? What constrains or determines the types of phenotypes we observe, out of all the variations we could conceive of? Why does a system like the brain fail in particular ways when the genetic program is messed with? Here, I consider how the difference between “concrete” and “emergent” properties of the brain may provide an explanation, or at least a useful conceptual framework.

There is now compelling evidence (http://www.ncbi.nlm.nih.gov/pubmed/20832285) that disorders like epilepsy, schizophrenia and autism can be caused by mutations in any of a very large number of different genes (sometimes singly, sometimes in combinations). This is fundamentally changing the way we think about these disorders. It is no longer tenable to consider them as unitary categories. Instead, it is very clear that the underlying etiology is extremely heterogeneous – possibly more so than for any other human disease.

How can this fact be explained? Why is it that mutations in so many different genes (perhaps thousands) can give rise to the specific phenotypes associated with those disorders?

The article goes into great detail explaining all of this. It also addresses the ways we have of evaluating environmental effect without the need to invoke magical thinking. It explains functional organizations and their role in emergent systems. It describes how behaviors or characteristics of neurological phenotypes are actually properties of the genetic adaptation rather than deficiencies compared to the norm. It explains that there is a complex interplay of different genetic factors that lead to the emergence of the phenotype, and that understanding the organizational hierarchies of genes and the brain can lead to better understanding of other emergent neurological phenotypes.

I don't see anything there about pharmaceutical profitability, or treatment goals, or any other speculation about what we might do with this information as we acquire and refine it, because that would be pointless.

immabum
04-22-13, 08:24 PM
Right and i stated before....there is always going to be money involved. That's the pragmatic reality. For example if 'alternative medicine' is truly philanthropic and prioritizes human health -it wouldn't be the billion dollar behemoth it currently is.

The knowledge of how ADHD changes/mutates is interesting...but in the end is just 'jeopardy trivia'/academic unless it is able to produce a viable solution/treatment.
The changes/mutations found thus far are more effective in sharpening our current meds vs finding environmental factors causing these changes. Pretty much everything causes mutations. Can't shut down the world and live in a bubble.

Amtram
04-22-13, 08:37 PM
However, there is still a hierarchy to the goals, and the knowledge and understanding for its own sake precedes the goal of figuring out what to do with it. And, as immabum noted, at least the profits are preceded by actual investigation rather than being based on suppositions that defy the laws of physics or contradict everything we know about biology.

We, as the members of whatever phenotype we end up being in, are obviously going to be invested in the efficacy of the treatment outcomes, while the researchers generally don't get much of the pot when those treatments are developed. For them, the knowing and figuring out is the goal. For us, knowing what they know helps us discern what information is evidence-based, why and how it works (or doesn't), protects us from wasteful spending on fraudulent treatments.

Amtram
04-22-13, 09:16 PM
The ultimate phenotype of an organism is thus emergent in the more common sense of that word – it is something that arises over time. This emphasises the need to consider developmental trajectories when trying to understand the highly heterogeneous etiology of these disorders.

http://4.bp.blogspot.com/-FWYAZ-Qq7vo/UUsGUWJpCoI/AAAAAAAAAaE/PpNXa6IWnEU/s320/attractor+states.jpg (http://4.bp.blogspot.com/-FWYAZ-Qq7vo/UUsGUWJpCoI/AAAAAAAAAaE/PpNXa6IWnEU/s1600/attractor+states.jpg) Modified from: Kitano, 2004 (http://www-users.york.ac.uk/%7Elsdc1/SysBiol/kitano.robustness.naturegenetics.2004.pdf) Complex, dynamic systems tend to gravitate towards certain stable patterns of activity and interactions in the network. Such patterns are called “basins of attraction” or “attractors (http://en.wikipedia.org/wiki/Attractor)”, for short. You can think about them like hollows in a flat sheet, with the current network state represented by the position of a ball rolling over this landscape. The flat bits of this landscape represent unstable, fluid states that are likely to change. The hollows represent more stable states – particular patterns of activity of the network that are easy to get into and hard to get out of. Generally speaking, the deepest such basin will represent the typical pattern of brain physiology. It takes a big push to get the ball up and out of this basin. But there are other basins – alternative stable states and the pathophysiological state we recognise as psychosis may be one of those.

Such alternate states may exist as by-products of the functional organisation of the system. The system architecture will have been selected to robustly generate (http://www-users.york.ac.uk/%7Elsdc1/SysBiol/kitano.robustness.naturegenetics.2004.pdf) a particular functional outcome. However, when individual components are interfered with, new functional states may emerge – ones that are unexpected and that the system has not been selected to produce. They arise instead as an emergent property of the broken system, as a specific failure mode.

It is vital to understand not just the nature of such states, but the trajectories that dynamic systems (in this case organisms) follow to get into them. (In dynamic systems, the relations between components of the system are not fixed but change over time). If we take our flat sheet and tilt it from one end, turning it into a board with channels in it, rather than hollows, then we can represent the path of a developing organism through phenotype space, over time.

http://3.bp.blogspot.com/-HvNsUmirK7Y/UUsGwO7heEI/AAAAAAAAAaM/RXLjZBTZAaQ/s320/epigenetic+landscape.jpg (http://3.bp.blogspot.com/-HvNsUmirK7Y/UUsGwO7heEI/AAAAAAAAAaM/RXLjZBTZAaQ/s1600/epigenetic+landscape.jpg)
This is Conrad Waddington’s famous “epigenetic landscape (http://en.wikipedia.org/wiki/Epigenetic_landscape)” – a powerful metaphor for understanding how dynamic systems can be channelled into specific, stable states. The shape of the landscape will be determined by an individual’s genotype – some people may have much deeper channels heading towards typical brain physiology while others may have a greater chance of heading towards particular pathophysiological states, like psychosis or epilepsy.

One reason why psychosis and epilepsy may be common states is that they can reinforce themselves, through altering the relations of components of the system. In a process known as “kindling (http://en.wikipedia.org/wiki/Kindling_model)”, seizures induce changes in neuronal networks (http://www.ncbi.nlm.nih.gov/pubmed/20944823) that render them increasingly excitable and more likely to undergo further seizures. A similar dynamic process (http://www.wiringthebrain.com/2012/10/its-not-crime-its-cover-up-reactivity_12.html), involving homeostatic processes in dopaminergic signaling pathways, may be involved in psychosis. These homeostatic mechanisms in the developing brain can, under certain circumstances, be maladaptive, pushing the network state into a particular pathophysiological pattern, in response to diverse primary insults.

That kind of information is definitely of consequence to anyone whose neural structure or function differs from the norm, in understanding the physiology and etiology of their conditions, and even in evaluating their co-morbid risks, and making reproductive choices.

Not discussing or understanding these issues is of great consequence to people who want to improve their health and reduce their health risks, as well as lower their health care costs by not being swayed by fraudulent information.

However, talking about things that are of no consequence to the purpose of the thread. . .it doesn't take a rocket scientist to know that's off-topic posts.

immabum
04-22-13, 09:35 PM
If you make money off mentally ill people, then do you want less mentally ill people?
You do the math.
Cutting costs in healthcare, poor working conditions, mothers eat into profits with time off, the list could go on for pages.

The costs of pharmaceuticals are a huge driving force behind increased healthcare spending. On a macro level you can bet the Canadian government does not want to spend more money on prescription meds. If universal healthcare is going to be sustainable....they would hack the costs paid out for meds or find cheaper more efficacious 'alternative' treatments. The America system is different...as you already know. There is no Canadian healthcare system conspiracy to make more mentally ill patients. Patients takes up bed space, hospital resources and leads to lost productivity time which ends up bringing down GDP and can put more people on employee assistance (more $$ loss) . Not to mention adding to more crime rates and incarceration. The math isn't as straightforward as it seems.

Anyways repost...but here is the epigenetic/endophenotypes paper (2011) I posted somewhere before. A French fry for everyone to enjoy :)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250517/

Amtram
04-22-13, 09:55 PM
And for people who need a little more background to get some of this, the NIH has a page called the Genetics Home Reference (http://ghr.nlm.nih.gov/), which can help with some basics, and also has a glossary page. If all you need are the vocabulary, the University of Kansas Medical Center has the terms and definitions in a single-page format (http://www.kumc.edu/gec/glossnew.html) (not all relevant to this particular discussion, but good for background information.) The Human Genome Project site map (http://www.ornl.gov/sci/techresources/Human_Genome/home.shtml#index) can also link you to information about the project, genetics, and educational sites for various levels of understanding.

Kevin Mitchell, the author of Wiring the Brain, also has an essay on PLoS called The Genetics of Brain Wiring: From Molecule to Mind (http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0050113) in which he explains a few aspects of the first article in the OP in a shorter format.

Enjoy.

immabum
04-23-13, 12:02 AM
Maybe not as comprehensive as the genome project link, but this looks like a nice quick snapshot website for ADHD reacted genes:
http://adhd.psych.ac.cn/topSNP.do

I had DNA testing done earlier this year, and its interesting to see some of my snp results such as Val158Met (I have Val/Val) and some of the different research correlates. Some specific to ADHD and some other interesting studies such as schizophrenia, sleep, placebo effects, depression, anxiety eg http://onlinelibrary.wiley.com/doi/10.1002/ajmg.b.32141/abstract

I still have so many other ones to read up on. Pretty cool stuff!

Amtram
04-23-13, 08:48 AM
I was searching quickly and came across a different link on that same site that didn't look as promising, results-wise. I'll take a bit longer look at that one.

I've been poking around this stuff for about 7 years now, and it's been interesting to see the development. The idea that gene clusters and loci are perhaps even more important that genes in pinpointing the origins of neurological differences has evolved a lot in just that time. Last year's Lancet paper showing the genes that showed up in five different conditions (including ADHD) shows the same kind of complexity that Dr. Mitchell's essays describe.

My feeling is that once these "clusters" show that a certain set of conditions have something in common, it'll become a jumping-off point to see if there are specific genes that make them different from one another, or whether they become different through some adaptive process that both authors mentioned.

Dr. Mitchell's examples are much more clearly processes that start with a genetic propensity and then develop into symptoms later in life. Schizophrenia and epilepsy may not show symptoms until after puberty. Autism has some signs in infancy that researchers are beginning to recognize, but most frequently there is a sudden regression at about 18-24 months.

With ADHD, we're also beginning to be able to see differences from the norm at earlier and earlier ages, and we already know that the symptoms and their severity change with age for many individuals. Your link on the other thread cited some studies that found genetic differences between children with ADHD and adults in whom ADHD had persisted. Figuring out how and why this difference exists and whether it's gene-based or epigenetic or an adaptive condition will go a long way towards a diagnosis that's appropriate and addresses the specific long-term needs of each kind of ADHD.

Amtram
04-23-13, 09:31 AM
OMG, I just found this absolutely adorable video on how the DNA fits into the nucleus of a cell from one of the article links. Watch it!

http://vimeo.com/user3414863/dna-is-long

Amtram
04-23-13, 09:37 AM
And though you can't get the whole article without subscribing, here's a brief summary of how transposons ("jumping genes") might have a role in conditions like ADHD:


Genes we inherit and environmental factors both influence human behaviors. Scientists have recently discovered other underlying processes at work.
So-called jumping genes, segments of DNA that can copy and paste them*selves into new places in the genome, can alter the activity of full-length genes. Occasionally they will turn on neighboring genes in these locations. That activity occurs more in the brain than other areas, resulting in different traits and behaviors, even in closely related individuals.
These mobile genetic elements may also turn out to play a role in people’s disposition to psychiatric disorders.
Researchers are now beginning to investigate whether jumping genes help us adapt to rapidly changing environmental conditions.

Amtram
04-23-13, 09:46 AM
Dr. Mitchell also expands on what we know about the potentials and limitations from twin studies in this essay (http://www.wiringthebrain.com/2009/06/nature-nurture-and-noise.html). An excerpt:

While neurology and neuroscience have offered direct evidence that differences in the brain affect behaviour, it is behavioural genetics that is typically seen as having contributed most directly to the nature-nurture debate. Twin and adoption studies, the mainstays of behavioural genetics, have demonstrated very conclusively that many aspects of personality, behaviour or other psychological traits are highly heritable – that is, a large proportion of the variance in the trait across the population is attributable to differences in genes.

The logic of the twin studies is usually the inverse of the statement above – to look at people who share various proportions of their genes and see how similar they are to each other. These generally show that monozygotic (“identical”) twins are far more similar to each other for most psychological traits than dizogytic (“fraternal”) twins. Also, adoptive children tend to resemble their biological relatives for psychological traits and are hardly more similar to their adoptive family members than they would be to any stranger in the street.

These data have demonstrated unequivocally that variation in genes can affect behaviour in humans. They have also, however, dramatically illustrated the limits of such genetic effects. Monozygotic twins, while much more similar to each other than would be expected for people who don’t share all their genes in common, are nonetheless clearly not identical for most psychological traits. In fact, on average, genetic variance only explains about 50% of the phenotypic variance. What is causing the rest of the variance?

Amtram
04-23-13, 09:52 AM
And in another, Probabilistic inheritance and neurodevelopmental phenotypes: location, location, location (http://www.wiringthebrain.com/2012/06/probabilistic-inheritance-and.html), he explains several examples, including ADHD, in which the very same mutation can cause different results depending on which cells it affects - hence a genetic marker that is common among diverse neurological conditions. From the article:

The interpretation is that this variability is intrinsic to the system – not due to anything external to the developing organism. It presumably originates from thermal noise – random fluctuations in molecular shape and movement that affect fundamental cellular processes like gene expression (http://wiringthebrain.blogspot.ie/2010/02/noisy-genes-and-limits-of-genetic.html)or cellular signaling. Normally, these fluctuations are buffered by intact molecular systems, which are adapted to deal with them and still produce the same outcome. But when some components are disrupted, this buffering can break down, making the outcome much more susceptible to noise.

At a higher level, such defects can sometimes lead to a discrete anatomical anomaly – a build-up of cells in the wrong place, for example (called "neuronal heterotopia (http://en.wikipedia.org/wiki/Gray_matter_heterotopia)”), or a change in connectivity between two brain regions. It is at this level that the variable expression of cellular phenotypes can be related to the variable expression or incomplete penetrance of clinical phenotypes.

Why should such discrete and gross defects arise from randomness that is independently affecting molecular processes across a population of cells? That is not really understood, but could reflect interactions between cells, such as differential adhesion – these could cause a small number of mis-migrated cells that happen to arise next to each other to nucleate additional cells, for example. What starts as a statistical blip in the distribution of a defect may thus be amplified by dynamic cellular interactions, resulting in a more discrete and significant anomaly.

Depending on where such anomalies arise, different brain systems may be impacted, resulting in a variable spectrum of phenotypes or clinical symptoms across people carrying a particular mutation (even identical twins). This fits with observations of variable phenotype in families where conditions like dyslexia, epilepsy or synaesthesia are segregating. In many cases, the tendency to develop the condition generally is quite strongly inherited, but the precise type that emerges is far less heritable.

ginniebean
04-23-13, 10:12 AM
http://i519.photobucket.com/albums/u356/tikarri/cute%20funny/brainbroke.jpg

And I'm not even close to half way thru!

It figures I'd have jumping genes!

Amtram
04-23-13, 10:22 AM
Do you even realize how hard it is right now not to make some terrible puns?