Wednesday, January 31, 2007

Thrifty genotype hypothesis   posted by amnestic @ 1/31/2007 07:46:00 PM

For the population geneticist, diabetes mellitus has long presented an enigma. Here is a relatively frequent disease, often interfering with reproduction by virtue of an onset during the reproductive or even pre-reproductive years, with a well-defined genetic basis, perhaps as simple in many families as a single recessive or incompletely recessive gene. If the considerable frequency of the disease is of relatively long duration in the history of our species, how can this be accounted for in the face of obvious and strong genetic selection against the condition? If, on the other hand, this frequency is a relatively recent pheonomenon, what changes in the environment are responsible for the increase?

-James V. Neel, "Diabetes Mellitus: A 'Thrify' Genotype Rendered Detrimental by 'Progress'?" (1962) [pdf]
The above quote is from the abstract of the highly influential paper by James Neel outlining the so-called "thrifty genotype hypothesis" for the prevalence of diabetes in modern populations. As this hypothesis is still widely cited (on this website, it has both praised and criticized), I present here my interpretation of the original paper, with comments as to how the hypothesis could be falsified or bosltered by the generation of unprecedented levels of population genetic data that we see today. I must note that this paper was written in 1962, and knowledge has certainly progressed since then. Some of the literature discussed by Neel or the paradigms he takes for granted are rather puzzling to me, and I may have missed some of the sublety of his arguments; readers are invited to peruse the .pdf linked above at their convenience and call me out on any mistakes.

I. The understanding of diabetes circa 1962

In 1962, "diabetes" was still considered more or less a single disease-- it wasn't until later that the current split between type I and type II diabetes was formalized. The adult-onset diabetes relevant to Neel is type II, so from now on, when I say "diabetes", I will be referring to type II. Further, the notion of a "complex" disease was also absent-- as is apparent from the quote above, Neel considered diabetes to be possibly caused by a single recessive allele, a situation subsequent research essentially ruled out.

In terms of the disease phenotype itself, Neel puts together a number of observations that suggest a certain advantage to the diabetic genotype. First, the children of diabetic mothers have increased birthwights as compared to the children of non-diabetic mothers. The children of non-diabetic mothers with diabetic fathers have higher than average birthweights, as well. Further, children who later develop diabtes tend to reach puberty slightly earlier, and thus could perhaps bear more children, than children who do not eventually develop diabetes. These observations, Neel suggests, indicate that the early diabetic phenotype is "thrifty", in the sense that the children are particularly efficient in their use of the resources available to them.

Of course, the eventual diabetic phenotype consists of insensitivity to insulin and the inablility to properly process carbohydrates. Neel reconciles the apparent early "thriftiness" with this eventual insensitivity with a discussion of the physiology of diabetes. In this discussion, there are two major hormonal players who, while normally in equilibrium, are thrown out of balance in diabetes. The first hormone is insulin, which moves glucose from the blood to storage, and the second Neel refers to as "anti-insulins", a class I can only assume refers to hormones like glucagon which release glucose into the blookstream.

In diabetics, then, Neel argues, there is an initial over-production of insulin, which accounts for the "thrifty" aspects of the genotype early on (the increased body weight and early menarche), which is then compensated by the stimulation of the "anti-insulins". An inbalance results, and in adulthood this is manifested by insulin insensitivity[1]. The major question becomes, why has diabetes become so prevalent now?

II. The "thrifty genotype hypothesis"

Neel's major insight in forming an answer to the above question is to note that "during the first 99 per cent or more of man's life on earth, while he has existed as a hunter and gatherer, it was often feast or famine". That is, there has been a marked change in environment in "modern" societies. He mentions three possible changes relevant to the control of the insulin/anti-insulin balance:

1. "Primitive" groups have less opportunities to overeat, have lower caloric intake, and greater physical activity than "modern" groups. This results in less stimulation of insulin, which in turn results in no over-stimulation of the anti-insulins.

2. The stress response in modern societies is less often followed by physical exertion than in primitive societies, which may disturb a "physiologic balance" established during human evolution.

3. The release of adrenaline in modern societies is also less often followed by physical exertion than in primitive societies. As adrenaline results in increased insulin production, this is an opportunity for the over-compensation of anti-insulins.

These last two are both similar in that they are involved with the stress response; indeed, Neel tentatively calls diabetes a "stress disease" along with peptic ulcers and hypertension!

In sum, the thrifty genotype hypothesis poses 1. that diabates results from a relative over-production of insulin, but more importantly 2. that "what we must now regard as an 'over-production' with unfortunate consequences was, at an earlier stage in man's evolution, an asset in that is was an important energy conserving mechanism when food intake was irregular and obesity rare."

III. The value of this hypothesis today

Now, I've noted the myriad assumptions made by Neel which are simply wrong-- the assumption of a single gene being one of them[2]. I imagine the modern view on the physiology of diabetes is quite different than his as well. So what remains of this hypothesis?

I would argue that his key insight still remains valid-- that, in population genetics, environment matters. Selection coefficients are not constant, and the way we alter our environment plays a large role in the selective forces exerted on us. More concretely, though, in terms of the genetic basis for diabetes, I can think of a couple predictions. First, any risk allele found for the disease will be ancestral-- that is, a protective allele will have arisen recently. Second, the derived protective allele will have been under recent positive selection.

The prevalence of diabetes in different populations, assuming all have more or less the same diet, should also be negatively correlated with the time since switching from a hunter-gatherer lifestyle. This is the statement that is perhaps the most contentious-- newcomers to the "modern", high-carb diet certainly have high incidences of diabetes, but it's impossible to tell whether this is due to the new availability of food or rather due to the content of the food itself. This may end up being a prediction that's impossible to test, so my instinct is to stick with the genetic evidence. Of course, I'm a geneticist, so I would say that.

[1] I am not at all familiar with modern reseatch into diabetes, and Neel's views on all of this are likely a vast simplification or even entirely wrong. I don't think, however, that this takes away from his later insights.

[2] An aside on Neel's discussion of the genetics of diabetes. I found the following passage, under the heading "Some Eugenic Considerations", to be interesing:
If the dietary and cultural conditions which elicit the relatively high frequency of diabetes in the Western World are destined to spread and persist over the entire globe, then, to the extent that modern medicine makes it possible for diabetics to propogate, it interferes with genetic evolution. But if, on the other hand, the mounting pressure of population numbers means an eventual decline in the standard of living with, in many parts of the world, a persistence or return to seasonal fluctuations in the availability of food, then efforts to preserve the diabetic genotype through this transient period of plenty are in the interest of mankind. Here is a striking illustration of the need for caution in approaching what at first glance seem to be "obvious" eugenic considerations!