Thrifty gene hypothesis
Encyclopedia
The thrifty gene hypothesis was proposed by geneticist
James V. Neel
in 1962 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 disease with a likely genetic component and 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.
The hypothesis has received various criticisms and several modified or alternative hypotheses have been proposed.
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. This would have been advantageous then but not in the current environment.
The hypothesis was proposed before there was a clear distinction between the different types of diabetes. Neel later stated that the hypothesis applied to non-insulin-dependent diabetes mellitus. In its original form the theory more specifically stated that diabetes may be due to a rapid insulin response which would prevent loss of glucose from the urine. Furthermore, it made use of a then popular theory which was later disproven. This argued that specific insulin antagonists were released in response to insulin with this causing diabetes.
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 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, Neel argued that "...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.
Neel in a 1998 review described an expanded form of the original hypothesis, diabetes being caused by "thrifty genes" adapted specifically for intermittent starvation, to a more complex theory of several related diseases such as diabetes, obesity, and hypertension (see also metabolic syndrome
) being caused by physiological systems adapted for an older environment being pushed beyond their limits by environmental changes. Thus, one possible remedy for these diseases is changing diet and exercise activity to more closely reflect that of the ancestral environment.
and environments, from South Pacific Islander
s, to Sub Saharan Africans
, to Native Americans
in the Southwestern United States
, to Inuit
.
The original "thrifty gene" hypothesis argued that famine
s were common and severe enough to select for thrifty gene in the 2.5 million years of human paleolithic
history. This assumption is criticized by some anthropological
evidence. 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
As a response to such criticisms, a modified "thrifty" gene hypothesis is that the famines and seasonal shortages of food that occurred only during the agricultural period may have exerted enough pressure to select for "thrifty" genes.
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."
The "thrifty epigenomic hypothesis" is a combination of the thrifty phenotype and thrifty genotype hypotheses. While it argues that there is an ancient, genetically coded, physiological system for being "thrifty", the theory argues that an individual's disease risk is primarily determined by epigenetic events, and that there may be epigenetic inheritance of disease risk.
Milind G Watve and Chittaranjan S Yajnik suggested that changing insulin resistance
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) (see r/K selection theory
); 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.
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.
Another 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 does not suggest that obesity have been under strong positive selection for a protracted period of time. It is argued instead that the obesity comes about because of genetic drift
in the genes controlling the upper limit on our body fatness. Such drift may have started because around 2 million years ago ancestral humans effectively removed the risk from predators, which was probably a key factor selecting against fatness. 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 a pressure for "thrifty" genes. These alternative arguments were published in two back-to-back papers in the International Journal of Obesity in November 2008.
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
James V. Neel
James V. Neel
James Van Gundia Neel was an American geneticist who played a key role in the development of human genetics as a field of research in the United States. He made important contributions to the emergence of genetic epidemiology and pursued an understanding of the influence of environment on genes...
in 1962 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 disease with a likely genetic component and 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
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
. 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
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
would have been advantageous for hunter-gatherer
Hunter-gatherer
A hunter-gatherer or forage society is one in which most or all food is obtained from wild plants and animals, in contrast to agricultural societies which rely mainly on domesticated species. Hunting and gathering was the ancestral subsistence mode of Homo, and all modern humans were...
populations, especially child-bearing
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
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.
The hypothesis has received various criticisms and several modified or alternative hypotheses have been proposed.
Hypothesis and research by Neel
James Neel, a professor of Human GeneticsHuman genetics
Human genetics describes the study of inheritance as it occurs in human beings. Human genetics encompasses a variety of overlapping fields including: classical genetics, cytogenetics, molecular genetics, biochemical genetics, genomics, population genetics, developmental genetics, clinical genetics,...
at the University of Michigan Medical School
University of Michigan Health System
The University of Michigan Health System is the wholly owned academic medical center of the University of Michigan in Ann Arbor. UMHS includes the U-M Medical School, with its Faculty Group Practice and many research laboratories; the U-M Hospitals and Health Centers, which includes University...
, 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
Western world
The Western world, also known as the West and the Occident , is a term referring to the countries of Western Europe , the countries of the Americas, as well all countries of Northern and Central Europe, Australia and New Zealand...
.
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
Genetic predisposition
A genetic predisposition is a genetic affectation which influences the phenotype of an individual organism within a species or population but by definition that phenotype can also be modified by the environmental conditions. In the rest of the population, conditions cannot have that effect...
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
Gene pool
In population genetics, a gene pool is the complete set of unique alleles in a species or population.- Description :A large gene pool indicates extensive genetic diversity, which is associated with robust populations that can survive bouts of intense selection...
.
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. This would have been advantageous then but not in the current environment.
The hypothesis was proposed before there was a clear distinction between the different types of diabetes. Neel later stated that the hypothesis applied to non-insulin-dependent diabetes mellitus. In its original form the theory more specifically stated that diabetes may be due to a rapid insulin response which would prevent loss of glucose from the urine. Furthermore, it made use of a then popular theory which was later disproven. This argued that specific insulin antagonists were released in response to insulin with this causing diabetes.
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 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
Impaired glucose tolerance
Impaired glucose tolerance is a pre-diabetic state of dysglycemia that is associated with insulin resistance and increased risk of cardiovascular pathology. IGT may precede type 2 diabetes mellitus by many years...
- 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, Neel argued that "...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.
Neel in a 1998 review described an expanded form of the original hypothesis, diabetes being caused by "thrifty genes" adapted specifically for intermittent starvation, to a more complex theory of several related diseases such as diabetes, obesity, and hypertension (see also metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...
) being caused by physiological systems adapted for an older environment being pushed beyond their limits by environmental changes. Thus, one possible remedy for these diseases is changing diet and exercise activity to more closely reflect that of the ancestral environment.
Other research
The thrifty genotype hypothesis has been used to explain high, and rapidly escalating, levels of obesity and diabetes among groups newly introduced to western dietsWestern pattern diet
The Western pattern diet, also called Western dietary pattern or the meat-sweet diet, is a dietary habit chosen by many people in developed countries, and increasingly in developing countries. It is characterized by high intakes of red meat, sugary desserts, high-fat foods, and refined grains...
and environments, from South Pacific Islander
Pacific Islander
Pacific Islander , is a geographic term to describe the indigenous inhabitants of any of the three major sub-regions of Oceania: Polynesia, Melanesia and Micronesia.According to the Encyclopædia Britannica, these three regions, together with their islands consist of:Polynesia:...
s, to Sub Saharan Africans
Sub-Saharan Africa
Sub-Saharan Africa as a geographical term refers to the area of the African continent which lies south of the Sahara. A political definition of Sub-Saharan Africa, instead, covers all African countries which are fully or partially located south of the Sahara...
, to Native Americans
Native Americans in the United States
Native Americans in the United States are the indigenous peoples in North America within the boundaries of the present-day continental United States, parts of Alaska, and the island state of Hawaii. They are composed of numerous, distinct tribes, states, and ethnic groups, many of which survive as...
in the Southwestern United States
Southwestern United States
The Southwestern United States is a region defined in different ways by different sources. Broad definitions include nearly a quarter of the United States, including Arizona, California, Colorado, Nevada, New Mexico, Oklahoma, Texas and Utah...
, to Inuit
Inuit
The Inuit are a group of culturally similar indigenous peoples inhabiting the Arctic regions of Canada , Denmark , Russia and the United States . Inuit means “the people” in the Inuktitut language...
.
The original "thrifty gene" hypothesis argued that famine
Famine
A famine is a widespread scarcity of food, caused by several factors including crop failure, overpopulation, or government policies. This phenomenon is usually accompanied or followed by regional malnutrition, starvation, epidemic, and increased mortality. Every continent in the world has...
s were common and severe enough to select for thrifty gene in the 2.5 million years of human paleolithic
Paleolithic
The Paleolithic Age, Era or Period, is a prehistoric period of human history distinguished by the development of the most primitive stone tools discovered , and covers roughly 99% of human technological prehistory...
history. This assumption is criticized by some anthropological
Anthropology
Anthropology is the study of humanity. It has origins in the humanities, the natural sciences, and the social sciences. The term "anthropology" is from the Greek anthrōpos , "man", understood to mean mankind or humanity, and -logia , "discourse" or "study", and was first used in 1501 by German...
evidence. 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
Body mass index
The body mass index , or Quetelet index, is a heuristic proxy for human body fat based on an individual's weight and height. BMI does not actually measure the percentage of body fat. It was invented between 1830 and 1850 by the Belgian polymath Adolphe Quetelet during the course of developing...
of hunter-gatherer and subsistence agriculturalists clearly show that between famines they do not deposit large fat stores
As a response to such criticisms, a modified "thrifty" gene hypothesis is that the famines and seasonal shortages of food that occurred only during the agricultural period may have exerted enough pressure to select for "thrifty" genes.
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
Lipid metabolism
Lipid metabolism refers to the processes that involve the intercourse and degradation of lipids.The types of lipids involved include:* Bile salts* Cholesterols* Eicosanoids* Glycolipids* Ketone bodies* Fatty acids - see also fatty acid 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."
Other alternative hypotheses
In response to the criticisms of the original thrifty genotype theory, several new ideas have been proposed for explaining the evolutionary bases of obesity and related diseases.The "thrifty epigenomic hypothesis" is a combination of the thrifty phenotype and thrifty genotype hypotheses. While it argues that there is an ancient, genetically coded, physiological system for being "thrifty", the theory argues that an individual's disease risk is primarily determined by epigenetic events, and that there may be epigenetic inheritance of disease risk.
Milind G Watve and Chittaranjan S Yajnik suggested that changing insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
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) (see r/K selection theory
R/K selection theory
In ecology, r/K selection theory relates to the selection of combinations of traits in an organism that trade off between quantity or quality of 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.
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.
Another alternative to the thrifty gene hypothesis is the drifty gene hypothesis
Drifty gene hypothesis
The “”Drifty gene hypothesis”” was proposed by the British biologist John Speakman as an alternative to the thrifty gene hypothesis originally proposed by James V Neel in 1962...
proposed by the British biologist John Speakman
John Speakman
Professor John Speakman is a British biologist working at the University of Aberdeen, Institute of Biological and Environmental Sciences. He directs the University's Energetics Research Group, which is one of the world's leading groups using doubly labeled water to investigate energy expenditure...
. The main feature of this idea is that the current pattern of obesity does not suggest that obesity have been under strong positive selection for a protracted period of time. It is argued instead that the obesity comes about because of genetic drift
Genetic drift
Genetic drift or allelic drift is the change in the frequency of a gene variant in a population due to random sampling.The alleles in the offspring are a sample of those in the parents, and chance has a role in determining whether a given individual survives and reproduces...
in the genes controlling the upper limit on our body fatness. Such drift may have started because around 2 million years ago ancestral humans effectively removed the risk from predators, which was probably a key factor selecting against fatness. 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 a pressure for "thrifty" genes. These alternative arguments were published in two back-to-back papers in the International Journal of Obesity in November 2008.