Thrifty gene hypothesis

The "thrifty gene" hypothesis was proposed in 1962 by geneticist James V. Neel to explain the tendency of certain ethnic groups, such as Native Americans, towards diabetes. [cite journal |author=Neel JV |title=Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"? |journal=Am. J. Hum. Genet. |volume=14 |issue= |pages=353–62 |year=1962 |pmid=13937884 |doi=] The argument has been extended by subsequent researchers to also explain relatively higher frequencies of obesity among some non-Western populations. In a general sense, this still popular hypothesis suggests the possibility that certain genes in humans have evolved to maximize metabolic efficiency and fat storage, and that in times of sustained abundance these genes predispose their carriers to obesity and diabetes.

According to the hypothesis, this diabetes-friendly genotype would have been advantageous for (formerly) hunter-gatherer populations, especially child-bearing women, because it would allow them to fatten (build-up energy reserves) more quickly during times of abundance, and thus better survive times of food-scarcity. However, with the modern constant abundance of food, perhaps coupled with sedentary behavior, this genotype becomes perversely disadvantageous because it leads to chronic obesity and related health problems.

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, [Cohen, M.N. 1989. "Health and the Rise of Civilization." New Haven, Conn.: Yale University Press.] [cite journal |author=Baschetti R |title=Diabetes epidemic in newly westernized populations: is it due to thrifty genes or to genetically unknown foods? |journal=J R Soc Med. |volume=91 |issue=12 |pages=622–625 |year=1998 |PMCID: PMC1296979] [Lee, R.B. 1968. "What Hunters Do for a Living, or, Hot to Make Out on Scarce Resources." in Lee and Devores, eds. 1968.] 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, [cite news | first=David Ewing | last=Duncan | coauthors= | title=Hunt for the 'thrifty gene' leads to South Seas island | date=2005-02-20 | publisher= | url =http://www.sfgate.com/cgi-bin/article.cgi?file=/chronicle/archive/2005/02/20/ING31BD37J1.DTL | work =San Francisco Chronicle | pages = | accessdate = 2008-03-22 | language = ] to Sub Saharan Africans, [cite news | first=Steve | last=Connor | coauthors= | title=Scientists link obesity to `thrifty gene' of our ancestors | date=2003-02-07 | publisher= | url =http://findarticles.com/p/articles/mi_qn4158/is_20030207/ai_n12677815 | work =The (London) Independent | pages = | accessdate = 2008-03-22 | language = ] to Native Americans in the Southwestern United States, [ cite journal|title= The thrifty genotype in type 2 diabetes|journal=Endocrine|date=1998-08-17 |first=Barry|last=Joffe|coauthors=Paul Zimmet|volume=9|issue=2|pages=139–141|doi= 10.1385/ENDO:9:2:139|url=|format=|accessdate=2008-03-22 ] to Inuit. [ cite web|url=http://www.hc-sc.gc.ca/fnih-spni/pubs/diabete/2001_evidence_faits/intro_e.html#ExecutiveSummary |title=Diabetes Among Aboriginal (First Nations, Inuit and Métis) People in Canada: The Evidence |accessdate=2008-03-22 |date=2005-07-20 |publisher=Health Canada ] 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.

Rejection 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. [Neel 1962, p.360]

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 1962, p.359]

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. [Neel 1962, p.355]

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?" [Neel 1962, p.353]

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 with a high frequency of diabetes. However, Neel found no evidence of diabetes among these populations earlier in the century. [Neel, J.V. 1982. "The Thrifty Genotype Revisited." In "The Genetics of Diabetes Mellitus", ed. J. Kobberling and R. Tattersall. New York: Academic Press, 293-93.] And when he tested younger members of these populations for glucose intolerance - which might have indicated a predisposition for diabetes - he found none. [Speilman, R.S., S.S. Fajans, J.V. Neel, S. Pek, J.C. Floyd, and W.J. Oliver. 1982. "Glucose Tolerance in Two Unacculturated Indian Tribes of Brazil." "Diabetologia". Aug.;23(2):90-93]

In 1989, Neel published a review of his further research based on the "thrifty genotype" hypothesis and wrote the following eulogy: "The data on which that (rather soft) hypothesis was based has now largely collapsed." [Neel, J.V. 1989. "Update to 'The Study of Natural Selection in Primitive and Civilized Human Populations.'" "Human Biology." Oct.-Dec.;61(5-6):811-23.]

Considering the "thrifty genotype" hypothesis defunct, Neel then returned to the 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." [Neel, J.V. 1999. "The 'Thrifty Genotype' in 1998." "Nutrition Reviews" May; 57(5, pt.2):S2-9]

Other challenges

Multiple sources have challenged a central premise of the thrifty gene hypothesis - namely that famines were common and severe enough (among the groups said to have thrifty genes) to strongly select for thrifty genes. [cite journal |author=Speakman JR |title=A nonadaptive scenario explaining the genetic predisposition to obesity: the "predation release" hypothesis |journal=Cell Metab. |volume=6 |issue=1 |pages=5–12 |year=2007 |pmid=17618852 |doi=10.1016/j.cmet.2007.06.004] 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."). [cite journal |author=Baschetti R |title=Diabetes epidemic in newly westernized populations: is it due to thrifty genes or to genetically unknown foods? |journal=J R Soc Med. |volume=91 |issue=12 |pages=622–625 |year=1998 |PMCID: PMC1296979] [Lee, R.B. 1968. "What Hunters Do for a Living, or, Hot to Make Out on Scarce Resources." in Lee and Devores, eds. 1968.]

Other relevant observations arose from metabolism researchers who note that for practically every other species on earth, fat metabolism is well regulated [Mrosovsky N. Cyclical obesity in hibernators: the search for the adjustable regulator. In: Hirsch J, Van Itallie TB (eds). Recent Advances in Obesity Research: IV. John Libbey & Co Ltd: London, 1983, pp. 45–56.] and that "most wild animals are in fact very lean" and that they remain lean "even when adequate food is supplied." For these reasons, two prominent researchers described the thrifty gene hypothesis as "facile and unlikely." [Rothwell, N.J. and M.J. Stock. 1981. "Thermogenesis: Comparative and Evolutionary Considerations." In Cioffi, James and Van Itallie, eds., 1981, 225-44.]

References