Crisis in human genetics?

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It is a bit over a year since Geoffrey Miller wrote this piece foreshadowing a crisis in conscience by human geneticists that would become public knowledge in 2010. The crisis had two parts: that new findings in genetics would reveal less than hoped about disease and that they would reveal more than feared about genetic differences between classes, ethnicities and race.

Now that we are through 2010 with no crisis (that I was aware of – is this crisis still happening in private?), I thought I’d revisit Miller’s suggestion that geneticists would show more than feared about class, ethnic and race differences.

At the time I first read the article, I found it hard to characterise this information as something to fear. As Miller identifies, it would be a consequence of some interesting progress:

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.

This sounds good to me. To understand the way genes spread as people migrated and mixed across the world will be to gain an important insight into human history.

Miller then points out that some people may be troubled when researchers start to identify genes that create physical and mental differences between populations and identify when those genes arose. Millers states:

If the shift from GWAS [genome wide association studies] 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.

But it is not all bad. He closes with:

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.

Reading that last sentence, the title to the article and the first paragraph appear over inflated. People will always misuse information and there will be another body of people who will make great use of it.

Looking back at Miller’s article from the vantage point of 2011, I am not sure much has changed. If anything, there has been a slow trickling of some of these ideas into spaces where they are starting to add value. GWAS studies are filling the journals and the store of population genetic data is increasing quickly. While most blank slaters continue to ignore it and the retro-racists use bits as they see fit, some of us are ploughing through it to learn something new.

Although Miller barely touches on it, the economic idea in that last sentence is interesting. If GWAS and sequencing studies result in different skills and comparative advantages being identified across the world’s populations and economies, research into economic development could be vastly changed. However, I am not convinced that we are particularly close to obtaining that sort of information. As I noted in my last post, it seems that we are some distance from taking the load of genetic information and the associated picture of human evolutionary history and being able to link it to characteristics that matter economically.

**This is a cross-post from my blog Evolving Economics.

4 Comments

  1. There hasn’t been enough time for the shift from GWAS to direct sequencing to occur. Direct sequencing is still expensive. Give it a few more years and we will be there. I would revisit around ’13 or ’14.

    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.

    Epicycles and more epicycles.

  2. “If the shift from GWAS [genome wide association studies] 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.”

    This quote assumes much more than is warranted. Even if we do get large numbers of fully sequenced DNA samples, what would it mean? We know just about nothing about how DNA affects the behavior. In fact, we know very little about how DNA affects disease.

  3. I was unhappily surprised at the lack of nuance in Miller’s article. I hadn’t read it before, and it read like is a devotee of David Goldstein and hasn’t interacted professionally with researchers with a more thorough grounding in quantitative genetics and population genetics (Eric Lander, Leonid Kruglyak, James Cheverud, Jason Wolf, etc.). GWAS has not failed, it has had remarkable success in the short period of time (or, short at least compared to the period of time where classic Mendelian diseases have been studied) that it has been used in human genetics…and it has also revealed that heritable traits exhibit more complexity than has previously been appreciated. It seems to me that many of the people who search frantically for the “missing heritability” are unfamiliar with most of the literature regarding epistasis in model organisms (since it has hardly been studied at all in humans). For at least some traits (morphological traits and obesity, in particular) there is evidence for a very substantial contribution to heritability from epistatic interactions. In others words, there is a very complex genetic architecture underlying many such traits. We aren’t talking about 10 or even 20 genes. We’re talking possibly 100s…and just examining the direct additive effects (as is primarily done in human GWAS studies) will not address the proportion of heritability that can be at least partially explained by additive-by-additive, additive-by-dominance and dominance-by-additive types of epistasis. This was a major topic of discussion at the 2010 Biology of Genomes conference at Cold Spring Harbor.

    The problems that are often touted about GWAS (lack of replication, lack of results) can be at least partially attributable to the following: (1) poor choice of cases (ie: for diseases with too loose a definition/characterization), (2) much too low a sample size (really, for low effect sizes, the power to detect effects is quite low at the typical 2000-5000 sample size level…the real sample sizes for direct effects should be a MINIMUM of ~10,000, and for epistasis, you need at least double that if not 5X that number of samples), (3) population effects. I’m not saying that you cannot detect anything from GWAS with low sample sizes…just look at the cannonical GWAS on AMD by Klein et al. But the cases must be very carefully chosen and the contribution from any single gene detected must be at least moderate for such a study design to work.

    It’s a shame to see articles written and theories espoused as though there can only really be one approach to understanding genetic variation and architecture. I propose that we’re likely to find that many Mendelian diseases have some lower level of contribution from other genes (“modifier genes” or small epistatic interaction effects that contribute to severity and penetrance, or age of onset, that kind of thing); complex diseases have some combination of effects from relatively common polymorphisms of small effect, rare mutations, epistasis, epigenetics and gene-by-environment interactions. In short, there is a continuum of genetic architecture and few diseases will fit entirely within the paradigm of “common disease common variant” or “classic Mendelian trait”.

    To get more to the point of this particular post, I also find that the economic implications of the work into different populations will be intriguing. However, trying to tie everything to genetic causes without considering environment would be a very large mistake, particularly when it comes to economic behavior (call it “development” or whatever…it comes down to behavior). At the point where such studies could actually be useful, I think we’ll see a confluence of collaborative studies between geneticists, economists, and either cultural anthropologists or sociologists. Let’s just hope that people keep their conclusions on the conservative side of data interpretation.

  4. “While most blank slaters continue to ignore it and the retro-racists use bits as they see fit, some of us are ploughing through it to learn something new. … However, I am not convinced that we are particularly close to obtaining that sort of information.”

    On these genetics blogs I am constantly hearing this mealy-mouthed blather about how complex human genetics is and that no individual genes are important. You sound like agnostics lecturing atheists. I can just imagine you lecturing doctors for prescribing drugs that target neurotransmitters. If a gene cannot have an important effect on a behavior, then why should a single type of molecule have an important effect on a behavior? You are all pointing to these pointless GWAS that focus entirely on SNPs, neglecting gene expression despite the ironic title of the blog. When a study attacked the depression gene, your blog attacked candidate gene research. When that study was disproved, your blog was silent. Candidate gene research gives us a small amount of immediately useful information. GWAS research gives us hope that someday, hopefully, we shall know a lot more about a more significant genetic contribution to behavior. Great, but that is not low-hanging fruit. This wouldn’t bother me if there was some attention being paid in the serious genetics blogosphere to candidate gene research. Blogs like Gene Expression used to do that. Now you have become Apostles for Ignorance.

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