Thrifty gene hypothesis

The thrifty gene hypothesis was proposed by geneticist James V. Neel to resolve a fundamental problem. Diabetes is clearly a very harmful medical condition. Yet it is quite common, and it was already evident to Neel that it likely had a strong genetic basis. The problem is to understand how a phenotype with such negative effects may have been favoured by the process of natural selection. Neel suggested the resolution to this problem is that genes which predispose to diabetes (called 'thrifty genes') were historically advantageous, but they became detrimental in the modern world. In his words they were "rendered detrimental by 'progress'". Neel's primary interest was in diabetes, but the idea was soon expanded to also encompass obesity. Thrifty genes are genes which enable individuals to efficiently collect and process food to deposit fat during periods of food abundance.

According to the hypothesis, the 'thrifty' genotype would have been advantageous for hunter-gatherer populations, especially child-bearing women, because it would allow them to fatten more quickly during times of abundance. Fatter individuals carrying the thrifty genes would thus better survive times of food scarcity. However, in modern societies with a constant abundance of food, this genotype efficiently prepares individuals for a famine that never comes. The result is widespread chronic obesity and related health problems like diabetes.

Current popularity
While James Neel was engaged in the research that would lead him to reject the "thrifty genotype" hypothesis (see below), the notion of "thrifty genes" was catching on with other researchers and public health authorities.

Generally, "thrifty gene" proponents accepted the central assumption that famines were common and severe in the 2.5 million years of human paleolithic history. This assumption was contradicted by anthropological evidence, but the shaky foundation of this central assumption appeared to do little to dampen proponents' enthusiasm for the notion of "thrifty genes".

The thrifty genotype hypothesis has been used to explain high, and rapidly escalating, levels of obesity and diabetes among groups newly introduced to western diets and environments, from South Pacific Islanders, to Sub Saharan Africans, to Native Americans in the Southwestern United States, to Inuit. Conversely Europeans, according to the hypothesis, evolved in environments where famines were less common, and thus did not develop thrifty genes and consequently now suffer from lower overall rates of obesity and (Type II) diabetes than these non-western populations.

Refinement by Neel
James Neel, a professor of Human Genetics at the University of Michigan Medical School, proposed the "thrifty genotype" hypothesis in 1962 in his paper "Diabetes Mellitus: A 'Thrifty' Genotype Rendered Detrimental by 'Progress'?" Neel intended the paper to provoke further contemplation and research on the possible evolutionary and genetic causes of diabetes among populations that had only recently come into regular contact with Westerners.

The genetic paradox Neel sought to address was this: diabetes conferred a significant reproductive (and thus evolutionary) disadvantage to anyone who had it; yet the populations Neel studied had diabetes in such high frequencies that a genetic predisposition to develop diabetes seemed plausible. Neel sought to unravel the mystery of why genes that promote diabetes had not been naturally-selected out of the population's gene pool.

Neel proposed that a genetic predisposition to develop diabetes was adaptive to the feast and famine cycles of paleolithic human existence, allowing humans to fatten rapidly and profoundly during times of feast in order that they might better survive during times of famine.

While Neel considered the "thrifty genotype" notion worth further investigation, he also proposed in 1962 (yet did not develop until years later) a counter-hypothesis namely that "this frequency [of obesity and diabetes] is a relatively recent phenomenon" in which case the question would become "what changes in the environment are responsible for the increase?"

In the decades following the publications of his first paper on the "thrifty genotype" hypothesis, Neel researched the frequency of diabetes and (increasingly) obesity in a number of other populations and, as a proper scientist, sought out observations that might disprove or discount his "thrifty gene" hypothesis.

Neel's further investigations cast doubt on the "thrifty genotype" hypothesis. If a propensity to develop diabetes were an evolutionary adaptation, then diabetes would have been a disease of long standing in those populations currently experiencing a high frequency of diabetes. However, Neel found no evidence of diabetes among these populations earlier in the century. And when he tested younger members of these populations for glucose intolerance - which might have indicated a predisposition for diabetes - he found none.

In 1989, Neel published a review of his further research based on the "thrifty genotype" hypothesis and in the Introduction noted the following: "The data on which that (rather soft) hypothesis was based has now largely collapsed." However, this sentence clearly could only be applied to his original hypothesis, because later in the same paper where he continued to refine his concepts, Neel noted "...the concept of a "thrifty genotype" remains as viable as when first advanced...". He went on to advance that the thrifty genotype concept be thought of in the context of a "compromised" genotype that effects several other metabolically-related diseases.

This refinement is actually just a return by Neel to the alternative hypothesis to which he had alluded twenty years earlier - that modern, very-high levels of obesity and diabetes among formerly native populations were a relatively recent phenomenon most likely caused by changes in diet. Given that some "thrifty gene" populations (like the Inuit) experienced a rise in obesity and diabetes in conjunction with a reduction of the proportion of fat and protein in their diets, Neel surmised that the dietary causes of obesity and diabetes lay in carbohydrate consumption, "specifically the use of highly refined carbohydrate."

Other challenges
The central premise of the thrifty gene hypothesis - that famines were common and severe enough to select for thrifty genes has been recently challenged. Many of the populations that later developed high rates of obesity and diabetes appeared to have no discernible history of famine or starvation (for example, Pacific Islanders whose "tropical-equatorial islands had luxuriant vegetation all year round and were surrounded by lukewarm waters full of fish."). Moreover, one of the most significant problems for the 'thrifty gene' idea is that it predicts that modern hunter gatherers should get fat in the periods between famines. Yet data on the body mass index of hunter-gatherer and subsistence agriculturalists clearly show that between famines they do not deposit large fat stores.

Thrifty phenotype hypothesis
The thrifty phenotype hypothesis arose from challenges posed to the thrifty gene hypothesis. The thrifty phenotype hypothesis theorizes that instead of the "thrifty factors" arising from genetic factors, that instead it is a direct result of the environment within the womb during development. The development of insulin resistance is theorized to be directly related to the body "predicting" a life of starvation for the developing fetus.

Hence, one of the main causes of type 2 diabetes has been attributed to poor fetal and infant growth and the subsequent development of and the metabolic syndrome. Since the hypothesis was proposed, many studies world-wide have confirmed the initial epidemiological evidence. Although the relationship with insulin resistance is clear at all ages studied, but the relation of insulin secretion is less clear. The relative contribution of genes and environment to these relationships remains a matter of debate.

Other relevant observations arose from metabolism researchers who note that for practically every other species on earth, fat metabolism is well regulated and that "most wild animals are in fact very lean" and that they remain lean "even when adequate food is supplied."

Alternative hypotheses
In response to the increasingly apparent inadequacy of the thrifty genotype theory, several new ideas have been proposed.

A suggested different approach to the problem is the suggestion that rather than selection favouring a few genes that are "thrifty", we possess a genome that is by default "thrifty" selected primarily due to epigenetic events. This is a combination of the thrifty phenotype and thrifty genotype hypotheses called the "thrifty epigenomic hypothesis". The basic idea is that there has never been an opportunity in history to develop "unthrifty" genes because of the extreme pressure to select for those genes that promote fitness and survival through energy budgets. This idea therefore suffers from essentially the same problems as the original thrifty gene hypothesis because the evidence that such extreme pressure exists is very weak.

Milind G Watve and Chittaranjan S Yajnik suggested that insulin resistance is a socioecological adaptation that mediates two phenotypic transitions: a transition in reproductive strategy from "r" (large number of ill-nurtured offspring) to "K" (smaller number of carefully nurtured offspring); and a switch from a lifestyle dependent upon muscular strength to one dependent on brain power. Because the environmental conditions that would facilitate each transition are heavily overlapping, the scientists surmise, a common switch could have evolved for the two transitions. This idea has several major problems. First, there are many other K-selected species that do not have enhanced brain power or an increased risk of diabetes. Second, there is no evidence that our early ancestors were r-selected. Most apes are K-selected and it seems likley that Australopithecines were also.

An alternative idea to explain the greater prevalence of diabetes in more northerly populations was suggested by Moalem et al. who noted that recent animal research has uncovered the importance of the generation of elevated levels of glucose, glycerol and other sugar derivatives as a physiological means for cold adaptation. High concentrations of these substances depress the freezing point of body fluids and prevent the formation of ice crystals in cells through supercooling, thus acting as a cryoprotectant or antifreeze for vital organs as well as in their muscle tissue. They consequently suggested that factors predisposing to elevated levels of glucose, glycerol and other sugar derivatives may have been selected for, in part, as adaptive measures in exceedingly cold climates.

The authors suggest that this cryoprotective adaptation would have protected ancestral northern Europeans from the effects of suddenly increasingly colder climates, such as those believed to have arisen around 14,000 years ago and culminating in the Younger Dryas. While this appears to be an interesting idea the studies showing cryoprotective benefits of high levels of sugars are all animals that hibernate - including animals such as frogs that allow their tissues to freeze when they are hibernating. Humans in contrast are unable to allow their body temperatures to cool much below around 30 oC before they experience heart failure and death. Hence the importance of elevated blood glucose levels for cryoprotection as the climate cools seems at best marginal.

The most recent alternative to the thrifty gene hypothesis is the Drifty gene hypothesis proposed by the British biologist John Speakman. The main feature of this idea is that the current pattern of obesity and diabetes phenotypes does not suggest that they have been under strong positive selection for a protracted period of time. If we had been under such intense selection for the past 6 million years as argued by some proponents of the thrifty gene hypothesis then simple calculations of the spread of favourable alelles known since the 1920s indicate that we should all be obese and diabetic, which we clearly are not. It is argued instead that the obese phenotype comes about because of genetic drift in the genes encoding the regulation system controlling an upper limit on our body fatness. Such drift may have started because around 2 million years ago ancestral humans effectively removed the risk of predation, which was probably a key factor maintaining the upper boundary of the regulation system. The drifty gene hypothesis was presented as part of a presidential debate at the 2007 Obesity Society meeting in New Orleans, with the counter-arguments favouring the thrifty gene presented by British nutritionist Andrew Prentice. The main thrust of Prentice's argument against the drifty gene idea is that Speakman's critique of the thrifty gene hypothesis ignores the huge impact that famines have on fertility. It is argued by Prentice that famine may actually have only been a force driving evolution of thrifty genes for the past 15,000 years or so (since the invention of agriculture), but because famines exert effects on both survival and fertility the selection pressure may have been sufficient even over such a short timescale to generate the current phenotype distribution. These alternative arguments were published in two back to back papers in the International Journal of Obesity in November 2008