Are genetic studies failing to deliver results ?

[Maciamo]

The Economist has a new article called The looming crisis in human genetics relating to the complexity of finding genetic variants linked to common diseases. They are basically saying that genetic studies have so far failed to determine the causes of most diseases.

Certainly, GWAS papers have reported a couple of hundred genetic variants that show statistically significant associations with a few traits. But the genes typically do not replicate across studies. Even when they do replicate, they never explain more than a tiny fraction of any interesting trait. In fact, classical Mendelian genetics based on family studies has identified far more disease-risk genes with larger effects than GWAS research has so far.

It is obvious that Mendelian genetics based on family studies should work better to determine some health risk. Knowing what the parents have, it is easy to estimate the risk for the children, because they may have inherited exactly the same noxious mutations. But that's beside the point. DNA studies attempt to discover underlying genetic mechanism that cause diseases. You cannot create efficient drugs without knowing exactly what's wrong in the body.

It's obvious that if one's parents died of Cystic Fibrosis one's chances have having it too are 50%. If 3 of your grandparents had Alzheimer's, your chance of developing it are very high. That's Mendelian genetics.

If family studies are always more accurate than comparison between strangers or across ethnic groups, it is not in itself a reason to shun personal genomics. First of all, not everybody knows his or her family's medical history. I am not just talking about adopted people or children who do not know their real biological father. What if a parent or grand-parent died fairly young in an accident ? That erases the potential information about old-age diseases like cancer or cardiovascular diseases.

If you are young and your parents are middle-aged and healthy, you are not going to wait that they die before having clues about your future health risk and the life-style changes you should undergo to prevent developing the same diseases. Even when you know everything about your family, you could always have inherited a series of minor mutations that are completely benign in isolation but have devastating effects when all combined together. This is the kind of information that Mendelian genetics cannot tell.


Another purpose of understanding the genetics of a disease, besides developing efficient medicine) is to be able to screen for it so as to prevent/eliminate it in future generations. This has already proved a successful method among Jewish couples. Ashkenazi Jews in particular have more genetic diseases than average due to the limited gene pool from which they evolved (a few founders) and the constant intermarriages within the community. Genetic screening has permitted to a young couple dating to know if they both carried the mutation for a genetic disease (e.g. Tay-Sachs). If they both did, they were advised to seek another partner to marry and have children with, or to resort to in vitro fertilisation, then selecting an embryo that lacks the disease mutations before implanting it.

This method of genetic selection can work for every disease that has a strong genetic component and does not involved too many genes.

Why the failure? The missing heritability may reflect limitations of DNA-chip design: GWAS methods so far focus on relatively common genetic variants in regions of DNA that code for proteins. They under-sample rare variants and DNA regions translated into non-coding RNA, which seems to orchestrate most organic development in vertebrates. Or it may be that thousands of small mutations disrupt body and brain in different ways in different populations. At worst, each human trait may depend on hundreds of thousands of genetic variants that add up through gene-expression patterns of mind-numbing complexity.
...
Full sequencing means analysing all 3 billion base pairs of an individual’s DNA rather than just a sample of 1m genetic variants as the DNA chips do. When sequencing costs drop within a few years below $1,000 per genome, researchers in Europe, China and India will start huge projects with vast sample sizes, sophisticated bioinformatics, diverse trait measures and detailed family structures. (American bioscience will prove too politically squeamish to fund such studies.) The missing heritability problem will surely be solved sooner or later.

This is indeed the reason of the apparent failure to identify the heritability in genes. If they know the answer to the problem why the alarming title for the article ? Just a way of making people read ?

The graph on the number of scientific publications on genome-wide association studies is enlightening with regards to the boom in genetics technologies in the last few years. In 2003 there were only 50 such publications. There are now 750. The soar is even more impressive for other species.

The trouble is, the resequencing data will reveal much more about human evolutionary history and ethnic differences than they will about disease genes. Once enough DNA is analysed around the world, science will have a panoramic view of human genetic variation across races, ethnicities and regions. We will start reconstructing a detailed family tree that links all living humans, discovering many surprises about mis-attributed paternity and covert mating between classes, castes, regions and ethnicities.

I don't see how this is a problem. Understanding evolution and human history are always good things. Understanding more deeply the racial, ethnic and individual differences is not likely lead to racial problems because interpersonal differences within a same ethnicity can be bigger than across ethnicities. If anything genetics will prove the best argument against racism. Just Y-DNA studies, which have no (known) connection to health, character, intelligence or any other trait, have already shattered a lot of racist arguments and misconceptions. For example, Europeans have a considerable amount of fairly recent Middle Eastern and African ancestors. Germanic people aren't a "pure" race, but recent admixture of many different ethnic groups (which also includes Mongoloid and Near Eastern genes).

As for the mis-attributed paternity, scientific studies won't tell us that. People will only know if they and their father take a DNA test and compare their genes. Paternity tests have existed for decades, in fact at least since the 1930's (through serological testing), and with a good level of accuracy since the 1970's (with HLA tests). Some people want to know, others don't. That's a personal choice. It has nothing to do with scientific research.

If the shift from GWAS to sequencing studies finds evidence of such politically awkward and morally perplexing facts, we can expect the usual range of ideological reactions, including nationalistic retro-racism from conservatives and outraged denial from blank-slate liberals. The few who really understand the genetics will gain a more enlightened, live-and-let-live recognition of the biodiversity within our extraordinary species—including a clearer view of likely comparative advantages between the world’s different economies.

These ideological reactions will have no ground. Only people who do not understand anything about genetics (and therefore about themselves, about life, about the world) could be outraged by or deny the facts.

[Sprinkles]

You're confusing diseases of which there is a known cause to diseased where the cause is most likely environmental or, otherwise, within the domain of conscious action. You cannot compare a genetic disease with one of a psychiatric. The psyche is not contingent on genetic structure, in as much it is contingent on the environment(which included the being itself) expressing certain gene's more or less. In true case, cancer and other diseases, while have underlying genetic mutations does not confer to us that the cause is genetic although the effect is.

Certain diseases exist without genetic correlation since they are the product of irregular and dysfunctional genetic expression, not a genetic predisposition in and of itself.

[Maciamo]

You're confusing diseases of which there is a known cause to diseased where the cause is most likely environmental or, otherwise, within the domain of conscious action. You cannot compare a genetic disease with one of a psychiatric. The psyche is not contingent on genetic structure, in as much it is contingent on the environment(which included the being itself) expressing certain gene's more or less. In true case, cancer and other diseases, while have underlying genetic mutations does not confer to us that the cause is genetic although the effect is.
Certain diseases exist without genetic correlation since they are the product of irregular and dysfunctional genetic expression, not a genetic predisposition in and of itself.

There are many neuro-psychological diseases that have a proven heredity. Heredity can easily be established by comparing the family history of thousands of patients and see if the disease runs in families. Schizophrenia and MS, for instance, have been established to be (partially) hereditary, but the genetics behind it remain elusive. The same is true for some obvious hereditary traits, like body height.

[Sprinkles]

There are many neuro-psychological diseases that have a proven heredity. Heredity can easily be established by comparing the family history of thousands of patients and see if the disease runs in families. Schizophrenia and MS, for instance, have been established to be (partially) hereditary, but the genetics behind it remain elusive. The same is true for some obvious hereditary traits, like body height.

The problem with reductionist genetics is that even if there is a correlation found between a gene and a disease, it does not mean that is the cause of the disease. The gene might have action in other environments that is beneficial, while, at the same time, also act in a hostile environment in discontinuity with the organism. The structure or the being and his environment is determining the expression of the gene, genes that are associated with it and how those genes are interacting and creating a phenotype. The thought that gene x therefore disease y is pretty absurd, especially for health. Since we have no way to define any disease of the psyche, and even identification of them can become difficult (since there is no objective measure). I find it amusing that people jump to conclusions when their understanding of disease and existence is so limited that the disease they perpetuate is actually a spectrum of symptoms en mass, which when looked at opposites sides of this spectrum, have nothing to do with one and other - but create a mean, and with that mean produce understanding - when in reality, it is lack of understanding.

[LeBrok]

It is a complexity of the system that gives us hard time to understand causes and effects. Hundreds of thousands of genes and millions of environmental factors entangled in molecular dance. It’s a miracle it works pretty well considering the chaos.
Keep in mind that genetics is a very young discipline and knowledge of environment influence is still quite basic.
There is no doubt in my mind that with time we’ll have all the data and immense computing power of future supercomputers to make sense of it. It’s not a voodoo stuff not to understand, the system is complicated but fortunately not infinitely complicated.
I’m also sure that we rarely find a simple correlation of gene x giving us sickness y, as current data points to. Most of the cases will find spectrums, probabilities, statistical genetic-environmental correlations. But it should be enough to develop pills or gene therapies to cure or prevent.

Personally I’m leaning towards bigger importance of genes over environment. Off course considering that the basic human needs are fulfilled, like: air, food, water, living in group for mental health and development.
The biggest example of importance of good genes over environment (considering that the basic is fulfilled to live) are studies of centenarians. They show how environmental factors are less important than good genes that protect body and regenerate it. 80 years of smoking, drinking, poverty, hunger or overeating, dirt, hard work, not taking care of once body, etc, can’t kill them the way most of us could.
They all conclude that centenarians can survive everything but the atom bomb, lol. I’m not excluding environmental factors completely, but man, I wish I had these centenarians genes running in my family.

[Maciamo]

I many cases, having a genetic predisposition toward a disease only means that the body is weaker at defending itself against the potentially harmful elements from the environment. It can mean that the immune system is too weak, or on the contrary too strong in the case of autoimmune diseases. Most autoimmune disease appear because our modern, sterilised environment does not provide enough microbes for our immune system to combat, and in consequence our own body ends up attacking itself with the surplus of anti-bodies.

Except from a few purely genetic diseases like Huntington's, genetics are indissociable from the environment. There is constant interaction between our body and its environment. It's the combination of the two that keeps us healthy or causes diseases.

[LeBrok]

Sickle cell disease comes to mind to as on gene mutation.
For overwhelming number of other diseases we need more genetic and environmental factors to succumb to death. Big part is due to hundreds of millions years of evolution, which equipped us in many back up systems and redundancies. I know it seams inefficient to use limited recourses and energy to double or triple of what just one system can do. It turned though, to be a very useful and critical thing in fight against single gene mutations. Otherwise one stupid mutation could get us sick and kill. But it made a job of tracing sickness to specific gene more difficult.

And, of course it gets worse, on top of it many proteins don't have one but multiple functions, number of receptors on cells, vitamins, minerals, environmental stressors (not too much, just right) or lack of them, new environmental polluters like plastics mimicking hormones, overdose of hormones from food production.

Robust and well functioning rebuilding, repairing or cell rejuvenation (whatever it's called) system is of great importance too. If our cells didn't had mechanism to fix everyday wear and tear we would be dead within a month or so. We would be falling apart like salmon after spawning. Centenarians must have this system functioning in high gear. This function definitely will come to many genes expression, otherwise it would be deciphered already.
One of the important genes in cell repair is Sir2/SIRT1 it can be activated with low calorie diet, or by resveratrol (found in red wine/grapes). When activated it can extend life by 30%.

[Haganus]

I cannot imagine myself how Germanic tribes mixed them with Mongoloid
people. Only very recently. I never heart about mixture of Germanic
tribes with other people.

I believe that by interbreeding the Germanic tribes, especially the
Frisian are very neurotic and autistic (Asperger). It is said that
autism is a deviation which had an origin from the Neanderthalers.

Erik

[Sprinkles]

The prevailing notion here is that a dysfunction is root caused by a certain reductionist sequence of genes. I have disagreed with that, and claimed that it was not genetic, yet, that it was a dysfunctional environment. And by dysfunctional environment I define it as such: the host and his interaction with the outside. I stand by the assertion that it is a dysfunctional environment facilitating the expression of unwanted genes that may or may not be beneficial in a functional environment. And if we further deconstruct this, we find that the highest level of functionality will be when the entire necessity of the genome is met to a degree of highest functionality within it's capacities to the environment.

What you are discussing is not dysfunction, it's an example of a functional organism (ie. aging). And when we have a functional organism, what we can do with this organism, with respect to our ability to facilitate function, is much better than what we can do with a dysfunctional organism. So, if we believe that with a functional organism (with respect to environment) and we alter a the expressions of genes to make it more function, then we arrive at a more functional state. With a dysfunctional organism, when we alleviate the dysfunction through genetic means without addressing the cause of the dysfunction we will not further in our ability to alleviate the dysfunction of the organism, yet, just provide a level of functionality. The organism will never be functioning to the most proper form if we do not address the cause of the dysfunction regardless of whether or not we address the expression of genes that are the effect of that dysfunction.

In any regard, SIRT1/SIRT2 is proving useless in our understanding of the wine and or caloric restriction hypothesis of aging. Wine and caloric restriction, while both functionally are extending life, do not do so by simply altering SIRT1/SIRT2 expression. You can view this by Sinclair failure to extend life with their pursuit of drugs that alter their expression, as well as resveratrol's inability to do anything (partially, perhaps, due to liver processing). Red wine and caloric restriction affect the expression of a lot more than SIRT1 and SIRT2, genetically, through even psychology.

The question that still plagues me is that without a functional environment will genetics be of any use in solving disorder, as apposed to promoting order in a functional environment?

[LeBrok]

Had to read twice to develop a hang for your dysfunction and function way of explaining. J

Let’s make sure I completely understood.

The prevailing notion here is that a dysfunction is root caused by a certain reductionist sequence of genes. I have disagreed with that, and claimed that it was not genetic, yet, that it was a dysfunctional environment. And by dysfunctional environment I define it as such: the host and his interaction with the outside. I stand by the assertion that it is a dysfunctional environment facilitating the expression of unwanted genes that may or may not be beneficial in a functional environment. And if we further deconstruct this, we find that the highest level of functionality will be when the entire necessity of the genome is met to a degree of highest functionality within it's capacities to the environment.

Basically, is functional genome every genome that keeps host alive? From genome that makes a child die in age of 2, to centenarians; as long as they were alive?
From what I understood it is, because it’s not a fault of the genome but always the environment. Spontaneous mutations can be attributed to environment, granted, but if the mutations come form simple interaction inside the cell during genome building, then can we blame the environment for it? Surely, the environment of cell interior is its natural functional environment.
Can functional environment create dysfunctional genome?
Bad genes can also come from two same copies of parents DNA, under express or over express gene and lead to sickness. Sickle Cell anemia is proving that. It has nothing to do with dysfunctional environment.

What you are discussing is not dysfunction, it's an example of a functional organism (ie. aging). And when we have a functional organism, what we can do with this organism, with respect to our ability to facilitate function, is much better than what we can do with a dysfunctional organism. So, if we believe that with a functional organism (with respect to environment) and we alter a the expressions of genes to make it more function, then we arrive at a more functional state. With a dysfunctional organism, when we alleviate the dysfunction through genetic means without addressing the cause of the dysfunction we will not further in our ability to alleviate the dysfunction of the organism, yet, just provide a level of functionality. The organism will never be functioning to the most proper form if we do not address the cause of the dysfunction regardless of whether or not we address the expression of genes that are the effect of that dysfunction.

You got me at the end, lol, had to read last sentence 5 times.
It seams that in your mind the only thing causing illnesses is bad environment, or maybe more importantly fixing environment can fix all human ailments. Is this correct?

The reason I brought aging and centenarians into equation is to show how “highly” functioning genome can do well even in dysfunctional environments. It brings a thought, the dysfunctional environment for most of us, is quite functional for highly functional genome centenarians. Unless I still don’t dig the definitions. J
On top of it we can’t just slam functional organism to mean something. Every living human can be dysfunctional in many regards, some can’t even procreate (many reasons) failing most important reason for life, failing the prime purpose the DNA exist. How functional organism is this?

In any regard, SIRT1/SIRT2 is proving useless in our understanding of the wine and or caloric restriction hypothesis of aging. Wine and caloric restriction, while both functionally are extending life, do not do so by simply altering SIRT1/SIRT2 expression. You can view this by Sinclair failure to extend life with their pursuit of drugs that alter their expression, as well as resveratrol's inability to do anything (partially, perhaps, due to liver processing). Red wine and caloric restriction affect the expression of a lot more than SIRT1 and SIRT2, genetically, through even psychology.

Can you link me with “Sinclair failure”. So far I haven’t been able to find a shred of evidence that resveratrol doesn’t extend life. And it works from yeasts to rats, doesn’t make any sense to conclude that it won’t work on people.

The question that still plagues me is that without a functional environment will genetics be of any use in solving disorder, as apposed to promoting order in a functional environment?

Can you also explain or link us with functional environment definition or what characterizes dysfunctional one?

You remind me of my friend, he is an orthopedic surgeon and head of hospital, but he doesn’t believe in power of science, hehe.

Regards