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Thread: The looming crisis in human genetics

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    The looming crisis in human genetics

    The looming crisis in human genetics

    Nov 13th 2009

    From The World in 2010 print edition
    By Geoffrey Miller

    Some awkward news ahead

    Human geneticists have reached a private crisis of conscience, and it will become public knowledge in 2010. The crisis has depressing health implications and alarming political ones. In a nutshell: the new genetics will reveal much less than hoped about how to cure disease, and much more than feared about human evolution and inequality, including genetic differences between classes, ethnicities and races.

    About five years ago, genetics researchers became excited about new methods for “genome-wide association studies” (GWAS). We already knew from twin, family and adoption studies that all human traits are heritable: genetic differences explain much of the variation between individuals. We knew the genes were there; we just had to find them. Companies such as Illumina and Affymetrix produced DNA chips that allowed researchers to test up to 1m genetic variants for their statistical association with specific traits. America’s National Institutes of Health and Britain’s Wellcome Trust gave huge research grants for gene-hunting. Thousands of researchers jumped on the GWAS bandwagon. Lab groups formed and international research consortia congealed. The quantity of published GWAS research has soared.

    In 2010, GWAS fever will reach its peak. Dozens of papers will report specific genes associated with almost every imaginable trait—intelligence, personality, religiosity, sexuality, longevity, economic risk-taking, consumer preferences, leisure interests and political attitudes. The data are already collected, with DNA samples from large populations already measured for these traits. It’s just a matter of doing the statistics and writing up the papers for Nature Genetics. The gold rush is on throughout the leading behaviour-genetics centres in London, Amsterdam, Boston, Boulder and Brisbane.

    GWAS researchers will, in public, continue trumpeting their successes to science journalists and Science magazine. They will reassure Big Pharma and the grant agencies that GWAS will identify the genes that explain most of the variation in heart disease, cancer, obesity, depression, schizophrenia, Alzheimer’s and ageing itself. Those genes will illuminate the biochemical pathways underlying disease, which will yield new genetic tests and blockbuster drugs. Keep holding your breath for a golden age of health, happiness and longevity.

    In private, though, the more thoughtful GWAS researchers are troubled. They hold small, discreet conferences on the “missing heritability” problem: if all these human traits are heritable, why are GWAS studies failing so often? The DNA chips should already have identified some important genes behind physical and mental health. They simply have not been delivering the goods.


    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.

    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.
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    http://www.economist.com/displaystor...ry_id=14742737

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    Great find!

    Ballet Mom
    Awesome find!

    if all these human traits are heritable, why are GWAS studies failing so often?
    I've got an idea why geneticists might be having so much trouble. Maybe.... JUST MAYBE natural selection keeps most, common genetic disorders rare.

    On a related note scientists looking for Schizophrenia genes have been spending countless millions and wiping out for years.

    Gene-Hunters Find Hope and Hurdles in Schizophrenia Studies

    The search for common variants in schizophrenia, however, has not been very successful so far, though not for want of trying. There have been more than a thousand studies, implicating 3,608 genetic variants.

    But when all the data are pooled, only 24 of those variants turn out to be statistically significant, according to an analysis in the current issue of Nature Genetics by a group led by Dr. Lars Bertram of Massachusetts General Hospital.

    Most of the early studies had too few patients and focused on mutations in what seemed to be plausible genes, an approach that is rarely successful. A new and more fruitful method is to survey the whole genome without any prior assumptions, a strategy made possible by new gene chips and a database of human genetic variation known as the hapmap.

    But even these genome-wide association studies have had little success in finding common variants. Five such studies of schizophrenia have now been completed, and one of the largest found no common variants, Dr. Bertram said.
    Last edited by Dingo; 12-02-2009 at 08:16 PM.

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    maybe it's not heredity?

    I love this paragraph.

    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.
    The possibility that these diseases are caused by environmental damage, not heredity never enters the picture.

    This reminds me of that SNL skit from the 1990s, "Trent Markham, Lung Doctor"!
    Everybody chain smokes including the doctors. People keep getting "lung fever" and they can't understand why. Nobody ever considers that cigarettes might be the problem.

    Dr. Trent Markham: Dick, there's no way around it. Somehow, you've contracted.. Lung Fever!

    Wife: Why? Why him?!

    Dr. Trent Markham: All we know is that, somehow, the Lung Fever germ got into your system. It could have been from something you ate, something you drank.. even from shaking the hand of a stranger with Lung Fever!

    Dr. Trent Markham: [ solemn ] I'm afraid I've done all I can. [ sighs ] God knows how many nights I've stayed up - drinking coffee, smoking cigarettes.. reading the medical journals, trying to find the answer to this Lung Fever riddle! [ a beat ] Now it's in the Lord's hands.
    Last edited by Dingo; 12-02-2009 at 08:54 PM.

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    Maybe we should call it the blooming crisis in human genetics :-)

    There is a missing variable in all this. Do you think it may have to do with environment? I do. Why: Well things are known to alter DNA - for example, things like smoking. Bet a Google search would return a lot of things that effect DNA. Even prayer! So - how can one get a handle on something that is constantly evolving? Good question :-)

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    Gene expression influenced by environment

    Mamamax

    You are exactly right. Gene expression is heavily impacted by environment. Some genes turn on, others turn off depending on what trait is needed in a particular environment.

    Environmental factors weigh heavily in modulating gene expression in humans

    By studying gene expression of white blood cells in 46 Moroccan Amazighs, or Berbers – including desert nomads, mountain agrarians and coastal urban dwellers – the NC State researchers and collaborators in Morocco and the United States showed that up to one-third of genes are differentially expressed due to where and how the Moroccan Amazighs live.
    Obviously environmental damage can damage the way genes express. There is no reason that this couldn't lead to illness.

    On a related note this story suggests that child abuse alters the way genes express.
    Child Abuse May 'Mark' Genes In Brains Of Suicide Victims
    Last edited by Dingo; 12-02-2009 at 09:16 PM.

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    Quote Originally Posted by Dingo View Post
    Mamamax

    You are exactly right. Gene expression is heavily impacted by environment. Some genes turn on, others turn off depending on what trait is needed in a particular environment.

    Environmental factors weigh heavily in modulating gene expression in humans



    Obviously environmental damage can damage the way genes express. There is no reason that this couldn't lead to illness.

    On a related note this story suggests that child abuse alters the way genes express.
    Child Abuse May 'Mark' Genes In Brains Of Suicide Victims
    Interesting studies, Dingo. Thanks for posting.

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    positive traits

    BalletMom

    My favorite part of your link is that the body of scientific evidence shows that natural selection works exactly as predicted.

    The trouble is, the resequencing data will reveal much more about human evolutionary history and ethnic differences than they will about disease genes.
    Positive traits are easily mapped to genes, negative traits like diseases are not. It's sad that it took billions of dollars in research before the scientific community would come to this conclusion. Anyone with a simple understanding of natural selection could have predicted this outcome before a single gene was sequenced.

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    Quote Originally Posted by Dingo View Post
    BalletMom

    It's sad that it took billions of dollars in research before the scientific community would come to this conclusion. Anyone with a simple understanding of natural selection could have predicted this outcome before a single gene was sequenced.

    Oh, I doubt the research will go to waste....how could they not try to study this? I suspect good things will come out of it somehow. Now climate science on the other hand....

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    the focus

    BalletMom

    It's not that genes shouldn't be studied, they should. It's that every disease of unknown origin shouldn't be treated as a genetic disease. Until recently 90% of all Autism research dollars have gone towards genetics. That focus is all out of whack. Autism is an increasingly common disease that impacts children. If researchers had considered natural selection they would have known from the beginning that Autism wasn't typically caused by heredity. Most of the money slated for this and other common childhood disorders should go towards environment.

    Here is an article on the changing focus of Autism researchers.

    Boston Globe: Under suspicion
    Researchers now believe that autism can be caused by genes in combination with environmental triggers. The question is, what are those triggers?
    It's not that researchers aren't starting to look in the right direction. It's that simple logic should have pointed them in this direction 20 years ago. That's a whole generation of children, needlessly sick.
    Last edited by Dingo; 12-04-2009 at 09:17 PM.

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    Quote Originally Posted by Dingo View Post
    BalletMom

    It's not that genes shouldn't be studied, they should. It's that every disease of unknown origin shouldn't be treated as a genetic disease. Until recently 90% of all Autism research dollars have gone towards genetics. That focus is all out of whack. Autism is an increasingly common disease that impacts children. If researchers had considered natural selection they would have known from the beginning that Autism wasn't typically caused by heredity. Most of the money slated for this and other common childhood disorders should go towards environment.

    Here is an article on the changing focus of Autism researchers.

    Boston Globe: Under suspicion


    It's not that researchers aren't starting to look in the right direction. It's that simple logic should have pointed them in this direction 20 years ago. That's a whole generation of children, needlessly sick.
    Ah, I see what you're saying. It will be interesting to see what environmental discoveries will be made!

    I still think that as the technology developed to be able to study genetics, the interest would have been too intense not to have studied it heavily. I don't think you can really fault the researchers and funders too much on that.

    And now if they start studying the environment more, they will certainly understand with much greater insight how the genetics ties in with the environment to cause disease. Perhaps the genetics research had to come first to make greatest use of the environmental factors that may be discovered.

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    in a sense yes

    BalletMom

    In that sense you are correct. Scientists are developing increasingly sophisticated ways to detect microbes by looking for their DNA. So in that and other ways breakthroughs in genetics have helped researchers who are focused on the environment.

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