Right Answer, Wrong Question

Author’s Note: Post was written without access only to the abstract, not the full text, of the journal article in question. Note that the argument is not with the methods or results of the research, but with how the research question has been presented.

University of Chicago Medicine & Biological Sciences tweeted the following tweet on Twitter today highlighting the work of post-doc Laure Ségurel on genetic risks for Type 2 Diabetes:
Screen Shot 2013-03-08 at 8.33.27 AM
The work itself is interesting in its own right. Investigating the population genetic history of genetic markers associated with Type 2 Diabetes risk could have multiple applications, beyond the high level of intellectual interest.

The question used to frame the research, however, troubles me, because it plays to general misconceptions about the evolutionary dominance and efficiency of natural selection in humans:

Why is this deleterious disease so common, while the associated genetic variants should be removed by natural selection? –Ségurel et al (Eur J Hum Genet. 2013 Jan 23. doi: 10.1038/ejhg.2012.295)

Selection is not the only force that can drive evolution. Other options include drift, mutation, and migration. These forces are distinguished from selection by their blindness to their effects on the fitness of organisms. I use “the adaptionist paradigm” to refer to the assumption held by many, including scientists, that selection is almost always the primary driving force of evolution and that it is efficient.

Human population structure is not well suited for efficient selection due to a variety of features like not having a large effective population size (a genetics concept that can differ greatly from actual population size) and relatively long generation times. Under these conditions, it is hardly surprising that natural selection has failed to scrub all manner of deleterious genetic differences from humans, without having to postulate that what are now deleterious genetic differences were at one point “good for us”.

At the same time, I hardly blame the authors for taking this approach to present their work [UPDATE 9 Mar 2013: Underlined text added to clarify that “approach” does not refer to how the research was conducted-see comment thread]. Their research directly addresses the “thrifty” genotype hypothesis (insulin resistance was beneficial for hunter-gatherers) for Type 2 Diabetes genetic risk factors, which still has a lot of traction. It is an adaptionist hypothesis addressing a problem emerging from the adaptionist paradigm. That this problem is not well supported by evolutionary theory does not change the fact that it is relevant to the field of research.

There is also an issue of the genetic differences and this one requires paying close attention to the jargon. In particular, we need to distinguish between the words associated and causal:

The ‘thrifty genotype’ hypothesis proposed that the causal genetic variants were advantageous and selected for during the majority of human evolution. It remains, however, unclear whether genetic data support this scenario. In this study, we characterized patterns of selection at 10 variants associated with type 2 diabetes… –Ségurel et al (Eur J Hum Genet. 2013 Jan 23. doi: 10.1038/ejhg.2012.295) [Emphasis mine]

Causal genetic differences are the ones that actually cause the increased risk. These are the locations where having one base pair instead of another means you have a different likelihood to get the disease. Associated genetic differences are relatively common genetic variations in the human population that can be linked statistically to risk. Associated differences are markers for causal differences, because they are usually, but not always inherited together. It’s like the golden arches sign for McDonald’s. The sign is not the McDonald’s, but it is almost always right next to the McDonald’s; and it strongly suggests the nearby building will not be a Burger King.

We tend to use associated differences (thus, genome-wide association studies) because the large populations necessary for these studies need common variants and working with a known set of differences is much easier technologically (ie, much easier to genotype people).

This means that the researchers are, at some level, using a proxy for the evolutionary history of the causal differences. This can introduce multiple confounding issues, for example the causal mutation entering the population after the associated difference making it a poorer quality marker.  In such a case, natural selection could act to remove the causal difference, but leave the associated marker – though, in that case, the marker would no longer be associated with risk [UPDATE 19:53 – a version issue caused this sentence to be truncated when posted].

Most genetic markers only contribute marginally, but statistically significantly to a person’s individual risk. Their individual effect on individual fitness may not particularly large. In addition, Type 2 Diabetes frequently manifests at an age when people have already reproduced. Pile on top of that the fact that the human population structure (this pretty much goes for all large animals) does not have the characteristics necessary for the efficient operation of natural selection.

For my money, the better motivating question and the question the research really asks is:

Is selection acting on genetic differences associated with Type 2 Diabetes & is it favoring the risky or protective differences?

What they found was that selection is acting on genetic differences associated with Type 2 Diabetes risk and is favoring the protective variants. They also found that these results did not appear to depend on the lifestyle of the populations studied, refuting the “thrifty” genotype hypothesis. Selection seems to be favoring the genetic differences that protect against Type 2 Diabetes and it does not appear to be related to the lifestyle of the populations being studied. In doing so, it answers my questions, which I happen to believe are the “right” questions, but also perpetuates misconceptions about evolution.

I do understand why the researchers took this approach to present their work [UPDATE 9 Mar 2013: Underlined text added to clarify that “approach” does not refer to how the research was conducted-see comment thread]. The study is framed in a way that is relevant to the field, if not necessarily the science, which is kind of a shame, when you think about it.

*This post is also a reminder to me to make sure you check what the researchers said about the topic, instead of jumping to the conclusion that the University press officer got carried away trying to explain why a study is “interesting”. In this case, the public article reflects what the researchers wrote in their peer-reviewed, subscription access journal article.

Author: Josh Witten


10 thoughts on “Right Answer, Wrong Question”

  1. It is a shame that the thrifty genotype hypothesis is such a commonly accepted default hypothesis – primarily because so many biomedical scientists are abysmally ignorant about evolutionary biology.

  2. I find the article to be reasonably well argued from an evolutionary biology standpoint. You’ll note that the introduction of the article does discuss drift etc as a possible explanation.

    There is reasonable support for a number of variants associated with type 2 diabetes risk/protection having unusual allele frequency patterns, or haplotype patterns, consistent with them [or something linked to them] having recently experienced some form of adaptation. These previous results take as their null a model of drift, based on genome-wide patterns of relatedness, and so have often already excluded the hypotheses put forward here. That said the authors do return to assess these null hypotheses. As such neither the article, or the press release [which can often oversell things], seems particularly out of line.

    1. You have excellent points throughout and I hope that my post did not come across as particularly negative about the actual results. As I tried to note at the beginning, I, like the rest of the public, only had access to the press release and the article abstract. The problematic bit was the question that was presented as the fundamental problem, “Why have deleterious alleles not been eliminated by selection?” This is a commonly held concept and reinforces an incomplete understanding of evolutionary theory.

      While it is reasonable to argue that the abstract is intended for a professional audience, the press release is intended for public consumption.

      The remaining commentary was intended to provide context to this type of research for those who do not have access to the actual article. It was not intended to imply that the researchers did not address these issues

      I greatly appreciate you taking the time to bring added depth and detail to the conversation with your comment.

    2. I should clarify my comment – I didn’t mean to imply that the authors had a poor understanding of evolution. However, the very second sentence of the abstract presents a common but wrong default assumption – deleterious alleles should have already been removed by natural selection. While the article itself is more sophisticated than this, the initial framing smacks to me of the same kind of nonsense we here in discussions of genome dark matter:

      “The vast majority of the human genome does not code for proteins and, until now, did not seem to contain defined gene-regulatory elements. Why evolution would maintain large amounts of ‘useless’ DNA had remained a mystery, and seemed wasteful. It turns out, however, that there are good reasons to keep this DNA.”

  3. Thanks for the response.

    The evolutionary question with common disease causing variants should often be why are these deleterious variants at high frequency when selection is expected to eliminate such alleles. The answer to this question may often be that they are only weakly deleterious [especially in non-modern environments] and so they may have drifted up in frequency. However, that shouldn’t stop us asking the question, as changing environments and pleiotropic effects are also potential explanations of the presence of these variants.

    I agreed that the press release could have been improved by a sentence or two about drift as a possible explanation. However, while that might be reasonable for a number of diseases, that is not really consistent with our current understanding of a number of variants involved in type 2. Although this is obviously always open for further debate, and folks are constantly retesting this.

    1. I think there is a big difference in the way professional researchers approach this and much of the public. Researchers look at a common allele associated with disease risk and ask about its evolutionary history. Often there are clues to suggest what the most relevant, detailed questions are. Phrasing as in the question in question implies potential problems with evolutionary theory.

      Without substantial background, it suggests thinking along the lines of, “That’s weird. Selection shouldn’t let that happen. How can we make this fit?” While it may not happen in academia, I regularly field questions from folks in my town who honestly think the publicizing of results of GWAS, particularly together with the CDCV model, are real problems for evolutionary theory.

      There was never any intent to imply that the work of the researchers needed improvement, but the presentation. In particular, researchers need to be aware that their abstract is going to be primary source material for press releases. This article release are, to me, an apt example precisely because the work appears to be of good quality. It is not only bad research that can contribute to misunderstandings.

  4. I did feel that your post, and the followup comment, did strongly imply that the authors hadn’t understood the issue of a null of genetic drift. And I appreciate you both clarifying this.

    Drift is one answer to this question, that had been addressed [and reasonably rejected] by many previous articles on some of the the variants involved in type 2. So that is not the question that the authors set out to address, a point that could have been much clearer in this post.

    I agree that people often have a very incomplete understanding of evolution, I teach this stuff on a daily basis this quarter and so know this first hand. But not every abstract has to go back to square one on these issues. On the other hand, I’m sure in hindsight every abstract I have written could have been better framed, so I do see your point.

    1. I cannot speak to Michael’s comment, which he has since clarified, but I took another look over the post in light of your impression. In my eyes, it is unclear when I refer to the “approach” of the researchers that I am referencing their approach to presenting the research, not their approach to conducting the research. Obviously, I knew what I meant. So, it was perfectly clear to me (the irony is also not lost on me). I am amending the text with notes to make this clear. Thanks for your feedback.

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